Impact of the ovarian microenvironment on serous cancer
2017-10-01
AWARD NUMBER: W81XWH-14-1-0182 TITLE: Impact of the ovarian microenvironment on serous cancer PRINCIPAL INVESTIGATOR: Joanna E. Burdette...Impact of the ovarian microenvironment on serous cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0182 5c. PROGRAM ELEMENT NUMBER 6...for intervention that would block serous cancer while still confined to the fallopian tubes. Using a series of normal, modified, and tumorigenic tubal
Serous ovarian, fallopian tube and primary peritoneal cancers
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Sørensen, Rie D; Schnack, Tine H; Karlsen, Mona A
2015-01-01
OBJECTIVE: The aim of this systematic review is to analyze data on risk factors, epidemiology, clinicopathology and molecular biology from studies comparing primary peritoneal cancer, fallopian tube cancer and ovarian cancer of serous histology, in order to achieve a greater understanding...... of whether or not these disorders should be considered as separate entities. METHODS: A systematic literature search was conducted in PubMed and MEDLINE. Case-control studies comparing primary serous peritoneal or fallopian tube carcinomas with primary serous ovarian carcinomas or a control group were...... included. RESULTS: Twenty-eight studies were found eligible. Primary peritoneal cancer patients were older, had higher parity, were more often obese and had poorer survival compared to ovarian cancer patients. Differences in protein expression patterns of Her2/neu, estrogen and progestin receptors...
Pathways to Genome-targeted Therapies in Serous Ovarian Cancer.
Axelrod, Joshua; Delaney, Joe
2017-07-01
Genome sequencing technologies and corresponding oncology publications have generated enormous publicly available datasets for many cancer types. While this has enabled new treatments, and in some limited cases lifetime management of the disease, the treatment options for serous ovarian cancer remain dismal. This review summarizes recent advances in our understanding of ovarian cancer, with a focus on heterogeneity, functional genomics, and actionable data.
Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.
Moran-Jones, Kim; Gloss, Brian S; Murali, Rajmohan; Chang, David K; Colvin, Emily K; Jones, Marc D; Yuen, Samuel; Howell, Viive M; Brown, Laura M; Wong, Carol W; Spong, Suzanne M; Scarlett, Christopher J; Hacker, Neville F; Ghosh, Sue; Mok, Samuel C; Birrer, Michael J; Samimi, Goli
2015-12-29
Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.
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Jönsson, Jenny-Maria; Johansson, Ida; Dominguez-Valentin, Mev
2014-01-01
expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal...
Expression profiling identifies genes involved in neoplastic transformation of serous ovarian cancer
International Nuclear Information System (INIS)
Merritt, Melissa A; Parsons, Peter G; Newton, Tanya R; Martyn, Adam C; Webb, Penelope M; Green, Adèle C; Papadimos, David J; Boyle, Glen M
2009-01-01
The malignant potential of serous ovarian tumors, the most common ovarian tumor subtype, varies from benign to low malignant potential (LMP) tumors to frankly invasive cancers. Given the uncertainty about the relationship between these different forms, we compared their patterns of gene expression. Expression profiling was carried out on samples of 7 benign, 7 LMP and 28 invasive (moderate and poorly differentiated) serous tumors and four whole normal ovaries using oligonucleotide microarrays representing over 21,000 genes. We identified 311 transcripts that distinguished invasive from benign tumors, and 20 transcripts that were significantly differentially expressed between invasive and LMP tumors at p < 0.01 (with multiple testing correction). Five genes that were differentially expressed between invasive and either benign or normal tissues were validated by real time PCR in an independent panel of 46 serous tumors (4 benign, 7 LMP, 35 invasive). Overexpression of SLPI and WNT7A and down-regulation of C6orf31, PDGFRA and GLTSCR2 were measured in invasive and LMP compared with benign and normal tissues. Over-expression of WNT7A in an ovarian cancer cell line led to increased migration and invasive capacity. These results highlight several genes that may play an important role across the spectrum of serous ovarian tumorigenesis
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Christopher K McCann
Full Text Available Recent evidence links aberrant activation of Hedgehog (Hh signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth.We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926.Both compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C, no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival.IPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting.
Rate of Appendiceal Metastasis with Non-Serous Epithelial Ovarian Cancer in Manitoba.
Altman, Alon D; Lefas, Georgia; Power, Laura; Lambert, Pascal; Lotocki, Robert; Dean, Erin; Nachtigal, Mark W
2018-02-01
This study sought to evaluate the rate of appendiceal involvement in non-serous mucinous and endometrioid-associated epithelial ovarian cancers. The Manitoba Cancer Registry and CancerCare database were used to find all women with non-serous epithelial ovarian, fallopian tube, or primary peritoneal cancer between 1995 and 2011. All patients with an appendectomy were then identified, and their final pathology findings were reviewed. Women who did not receive treatment or lacked follow-up were excluded. We identified 338 patients from 1995-2011 with no prior appendectomy. Of these, 16.6% received an appendectomy, and 22.8% were clinically evaluated. Most cases within this cohort were mucinous (62%) and stage 1 (63%). Four appendiceal metastases were identified (7.2%), and one half appeared clinically normal at the time of surgery (3.6%). Within the mucinous histologic type, 32.7% of patients received an appendectomy, with a metastatic rate of 5.7%. Of the 127 endometrioid cases, only 10 patients received an appendectomy, and 2 were found to have metastases. No metastases were found in the 85 patients in the clear cell cohort, only 5 of whom received an appendectomy. Routine appendectomy or clinical assessment of the appendix is valuable for all non-serous ovarian cancers. The rate of involvement for endometriosis-associated ovarian cancers may be significantly higher than expected, and further studies need to be conducted. Copyright © 2018 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.
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Yusuf Gunay
2012-01-01
Full Text Available Introduction. Reports of epithelial ovarian carcinomas metastatic to the pancreas are very rare. We herein present a metastasis of high grade papillary serous ovarian cancer to mid portion of pancreas. Case. A 42-year-old patient was admitted with a non-specified malignant cystic lesion in midportion of pancreas. She had a history of surgical treatment for papillary serous ovarian adenocarcinoma. A cystic lesion was revealed by an abdominal computerized tomography (CT performed in her follow up . It was considered as primary mid portion of pancreatic cancer and a distal pancreatectomy was performed. The final pathology showed high-grade papillary serous adenocarcinoma morphologically similar to the previously diagnosed ovarian cancer. Discussion. Metastatic pancreatic cancers should be considered in patients who present with a solitary pancreatic mass and had a previous non-pancreatic malignancy. Differential diagnosis of primary pancreatic neoplasm from metastatic malignancy may be very difficult. A biopsy for tissue confirmation is required to differentiate primary and secondary pancreatic tumors. Although, the value of surgical resection is poorly documented, resection may be considered in selected patients. Conclusion. Pancreatic metastasis of ovarian papillary serous adenocarcinoma has to be kept in mind when a patient with pancreatic mass has a history of ovarian malignancy.
Prevention of Ovarian High-Grade Serous Carcinoma by Elucidating Its Early Changes
2014-10-01
serous ovarian cancer carcinogenesis. Sophia HL George, Ramlogan Sowamber, Anca Milea, Noor Salman and Patricia Shaw. September 2014. Masha Rivkin Ovarian...in mesenchymal-to-epithelial transition during high-grade serous carcinogenesis. Masha Rivkin Ovarian Cancer Symposium September 2014, Seattle WA
Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome.
Tothill, Richard W; Tinker, Anna V; George, Joshy; Brown, Robert; Fox, Stephen B; Lade, Stephen; Johnson, Daryl S; Trivett, Melanie K; Etemadmoghadam, Dariush; Locandro, Bianca; Traficante, Nadia; Fereday, Sian; Hung, Jillian A; Chiew, Yoke-Eng; Haviv, Izhak; Gertig, Dorota; DeFazio, Anna; Bowtell, David D L
2008-08-15
The study aim to identify novel molecular subtypes of ovarian cancer by gene expression profiling with linkage to clinical and pathologic features. Microarray gene expression profiling was done on 285 serous and endometrioid tumors of the ovary, peritoneum, and fallopian tube. K-means clustering was applied to identify robust molecular subtypes. Statistical analysis identified differentially expressed genes, pathways, and gene ontologies. Laser capture microdissection, pathology review, and immunohistochemistry validated the array-based findings. Patient survival within k-means groups was evaluated using Cox proportional hazards models. Class prediction validated k-means groups in an independent dataset. A semisupervised survival analysis of the array data was used to compare against unsupervised clustering results. Optimal clustering of array data identified six molecular subtypes. Two subtypes represented predominantly serous low malignant potential and low-grade endometrioid subtypes, respectively. The remaining four subtypes represented higher grade and advanced stage cancers of serous and endometrioid morphology. A novel subtype of high-grade serous cancers reflected a mesenchymal cell type, characterized by overexpression of N-cadherin and P-cadherin and low expression of differentiation markers, including CA125 and MUC1. A poor prognosis subtype was defined by a reactive stroma gene expression signature, correlating with extensive desmoplasia in such samples. A similar poor prognosis signature could be found using a semisupervised analysis. Each subtype displayed distinct levels and patterns of immune cell infiltration. Class prediction identified similar subtypes in an independent ovarian dataset with similar prognostic trends. Gene expression profiling identified molecular subtypes of ovarian cancer of biological and clinical importance.
High grade serous ovarian carcinomas originate in the fallopian tube.
Labidi-Galy, S Intidhar; Papp, Eniko; Hallberg, Dorothy; Niknafs, Noushin; Adleff, Vilmos; Noe, Michael; Bhattacharya, Rohit; Novak, Marian; Jones, Siân; Phallen, Jillian; Hruban, Carolyn A; Hirsch, Michelle S; Lin, Douglas I; Schwartz, Lauren; Maire, Cecile L; Tille, Jean-Christophe; Bowden, Michaela; Ayhan, Ayse; Wood, Laura D; Scharpf, Robert B; Kurman, Robert; Wang, Tian-Li; Shih, Ie-Ming; Karchin, Rachel; Drapkin, Ronny; Velculescu, Victor E
2017-10-23
High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian cancer and has a poor outcome. It has been proposed that fallopian tube cancers may be precursors of HGSOC but evolutionary evidence for this hypothesis has been limited. Here, we perform whole-exome sequence and copy number analyses of laser capture microdissected fallopian tube lesions (p53 signatures, serous tubal intraepithelial carcinomas (STICs), and fallopian tube carcinomas), ovarian cancers, and metastases from nine patients. The majority of tumor-specific alterations in ovarian cancers were present in STICs, including those affecting TP53, BRCA1, BRCA2 or PTEN. Evolutionary analyses reveal that p53 signatures and STICs are precursors of ovarian carcinoma and identify a window of 7 years between development of a STIC and initiation of ovarian carcinoma, with metastases following rapidly thereafter. Our results provide insights into the etiology of ovarian cancer and have implications for prevention, early detection and therapeutic intervention of this disease.
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Skirnisdottir Ingiridur
2012-09-01
Full Text Available Abstract Background Ovarian cancer is a heterogeneous disease and prognosis for apparently similar cases of ovarian cancer varies. Recurrence of the disease in early stage (FIGO-stages I-II serous ovarian cancer results in survival that is comparable to those with recurrent advanced-stage disease. The aim of this study was to investigate if there are specific genomic aberrations that may explain recurrence and clinical outcome. Methods Fifty-one women with early stage serous ovarian cancer were included in the study. DNA was extracted from formalin fixed samples containing tumor cells from ovarian tumors. Tumor samples from thirty-seven patients were analysed for allele-specific copy numbers using OncoScan single nucleotide polymorphism arrays from Affymetrix and the bioinformatic tool Tumor Aberration Prediction Suite. Genomic gains, losses, and loss-of-heterozygosity that associated with recurrent disease were identified. Results The most significant differences (p Conclusions The results of our study indicate that presence of two aberrations in TP53 on 17p and LOH on 19q in early stage serous ovarian cancer is associated with recurrent disease. Further studies related to the findings of chromosomes 17 and 19 are needed to elucidate the molecular mechanism behind the recurring genomic aberrations and the poor clinical outcome.
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Amankwah, Ernest K; Wang, Qinggang; Schildkraut, Joellen M
2011-01-01
Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among...
The ovary is an alternative site of origin for high-grade serous ovarian cancer in mice.
Kim, Jaeyeon; Coffey, Donna M; Ma, Lang; Matzuk, Martin M
2015-06-01
Although named "ovarian cancer," it has been unclear whether the cancer actually arises from the ovary, especially for high-grade serous carcinoma (HGSC), also known as high-grade serous ovarian cancer, the most common and deadliest ovarian cancer. In addition, the tumor suppressor p53 is the most frequently mutated gene in HGSC. However, whether mutated p53 can cause HGSC remains unknown. In this study, we bred a p53 mutation, p53(R172H), into conditional Dicer-Pten double-knockout (DKO) mice, a mouse model duplicating human HGSC, to generate triple-mutant (TKO) mice. Like DKO mice, these TKO mice develop metastatic HGSCs originating from the fallopian tube. Unlike DKO mice, however, even after fallopian tubes are removed in TKO mice, ovaries alone can develop metastatic HGSCs, indicating that a p53 mutation can drive HGSC arising from the ovary. To confirm this, we generated p53(R172H)-Pten double-mutant mice, one of the genetic control lines for TKO mice. As anticipated, these double-mutant mice also develop metastatic HGSCs from the ovary, verifying the HGSC-forming ability of ovaries with a p53 mutation. Our study therefore shows that ovaries harboring a p53 mutation, as well as fallopian tubes, can be a distinct tissue source of high-grade serous ovarian cancer in mice.
International Nuclear Information System (INIS)
Chung, Hyun Hoon; Lee, Maria; Kim, Hee-Seung; Kim, Jae-Weon; Park, Noh-Hyun; Song, Yong Sang; Cheon, Gi Jeong
2017-01-01
To evaluate the prognostic value of metabolic activity of metastatic lesions measured by 18 F-flurodeoxyglucose ( 18 F-FDG) uptake on preoperative positron emission tomography/computed tomography (PET/CT) in patients with advanced serous epithelial ovarian cancer (EOC). Clinico-pathological variables and PET/CT parameters such as the maximum standardised uptake value of the ovarian cancer (SUV ovary ), metastatic lesions (SUV meta ), and the metastatic lesion-to-ovarian cancer standardised uptake value ratio (SUV meta /SUV ovary ) were assessed in International Federation of Gynaecology and Obstetrics (FIGO) stage III, IV patients. Clinico-pathological data were retrospectively reviewed for 94 eligible patients. The median progression-free survival (PFS) was 18.5 months (range, 6-90 months), and 57 (60.6%) patients experienced recurrence. Older age [P = 0.017, hazard ratio (HR) 1.036, 95% CI 1.006-1.066], residual disease after surgery (P = 0.024, HR 1.907, 95% CI 1.087-3.346), and high SUV meta /SUV ovary (P = 0.019, HR 2.321, 95% CI 1.148-4.692) were independent risk factors of recurrence. Patients with high SUV meta /SUV ovary showed a significantly worse PFS than those with low SUV meta /SUV ovary (P = 0.007, log-rank test). Preoperative SUV meta /SUV ovary was significantly associated with recurrence and has an incremental prognostic value for PFS in patients with advanced serous EOC. (orig.)
MUS81 is associated with cell proliferation and cisplatin sensitivity in serous ovarian cancer
Energy Technology Data Exchange (ETDEWEB)
Xie, Suhong; Zheng, Hui [Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai (China); Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Wen, Xuemei [Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Sun, Jiajun; Wang, Yanchun; Gao, Xiang; Guo, Lin [Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai (China); Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Lu, Renquan, E-mail: lurenquan@126.com [Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai (China); Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China)
2016-08-05
The dysfunction of DNA damage repair (DDR) pathway contributes to tumorigenesis and drug-resistance in cancer. MUS81 is a member of the conserved xeroderma pigmentosum group F (XPF) family protein of endonucleases, which is important to the DDR pathway. However, the role of MUS81 in the development of ovarian cancer remains uncertain. To explore the expression of MUS81 and its association to serous ovarian cancer (SOC), 43 biopsies of SOC patients were detected by qRT-PCR, and 29 specimens were further performed by immunohistochemistry analysis. Here, we observed that MUS81 was over-expressed in SOC tissues at both transcript and protein levels, and the expression level of MUS81 protein in ovarian cancer cell lines was also higher than that in human normal ovarian surface epithelial cell line (HOSEpiC). We also found that down-regulation of MUS81 expression in ovarian cancer cells inhibited cell proliferation and colony formation ability, and influenced cell cycle progression. Moreover, inhibition of MUS81 expression induced cellular senescence and enhanced the antitumor effect of cisplatin. Down-regulation of MUS81 expression could suppress the growth and development of SOC. These results indicate that MUS81 might play important roles in the progression of SOC and influence the antitumor effect of cisplatin. - Highlights: • MUS81 was overexpression in serous ovarian cancer (SOC). • Meanwhile down-regulation of inhibited cell proliferation and influenced cell cycle progression. • Inhibition of MUS81 induced cell cellular senescence and enhanced the antitumor effect of cisplatin. • Down-regulation of MUS81 expression could suppress the growth and development of SOC.
MUS81 is associated with cell proliferation and cisplatin sensitivity in serous ovarian cancer
International Nuclear Information System (INIS)
Xie, Suhong; Zheng, Hui; Wen, Xuemei; Sun, Jiajun; Wang, Yanchun; Gao, Xiang; Guo, Lin; Lu, Renquan
2016-01-01
The dysfunction of DNA damage repair (DDR) pathway contributes to tumorigenesis and drug-resistance in cancer. MUS81 is a member of the conserved xeroderma pigmentosum group F (XPF) family protein of endonucleases, which is important to the DDR pathway. However, the role of MUS81 in the development of ovarian cancer remains uncertain. To explore the expression of MUS81 and its association to serous ovarian cancer (SOC), 43 biopsies of SOC patients were detected by qRT-PCR, and 29 specimens were further performed by immunohistochemistry analysis. Here, we observed that MUS81 was over-expressed in SOC tissues at both transcript and protein levels, and the expression level of MUS81 protein in ovarian cancer cell lines was also higher than that in human normal ovarian surface epithelial cell line (HOSEpiC). We also found that down-regulation of MUS81 expression in ovarian cancer cells inhibited cell proliferation and colony formation ability, and influenced cell cycle progression. Moreover, inhibition of MUS81 expression induced cellular senescence and enhanced the antitumor effect of cisplatin. Down-regulation of MUS81 expression could suppress the growth and development of SOC. These results indicate that MUS81 might play important roles in the progression of SOC and influence the antitumor effect of cisplatin. - Highlights: • MUS81 was overexpression in serous ovarian cancer (SOC). • Meanwhile down-regulation of inhibited cell proliferation and influenced cell cycle progression. • Inhibition of MUS81 induced cell cellular senescence and enhanced the antitumor effect of cisplatin. • Down-regulation of MUS81 expression could suppress the growth and development of SOC.
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Chung, Hyun Hoon; Lee, Maria; Kim, Hee-Seung; Kim, Jae-Weon; Park, Noh-Hyun; Song, Yong Sang [Seoul National University College of Medicine, Department of Obstetrics and Gynaecology, Cancer Research Institute, Seoul (Korea, Republic of); Cheon, Gi Jeong [Seoul National University College of Medicine, Department of Nuclear Medicine, Cancer Research Institute, Seoul (Korea, Republic of)
2017-11-15
To evaluate the prognostic value of metabolic activity of metastatic lesions measured by {sup 18}F-flurodeoxyglucose ({sup 18}F-FDG) uptake on preoperative positron emission tomography/computed tomography (PET/CT) in patients with advanced serous epithelial ovarian cancer (EOC). Clinico-pathological variables and PET/CT parameters such as the maximum standardised uptake value of the ovarian cancer (SUV{sub ovary}), metastatic lesions (SUV{sub meta}), and the metastatic lesion-to-ovarian cancer standardised uptake value ratio (SUV{sub meta}/SUV{sub ovary}) were assessed in International Federation of Gynaecology and Obstetrics (FIGO) stage III, IV patients. Clinico-pathological data were retrospectively reviewed for 94 eligible patients. The median progression-free survival (PFS) was 18.5 months (range, 6-90 months), and 57 (60.6%) patients experienced recurrence. Older age [P = 0.017, hazard ratio (HR) 1.036, 95% CI 1.006-1.066], residual disease after surgery (P = 0.024, HR 1.907, 95% CI 1.087-3.346), and high SUV{sub meta}/SUV{sub ovary} (P = 0.019, HR 2.321, 95% CI 1.148-4.692) were independent risk factors of recurrence. Patients with high SUV{sub meta}/SUV{sub ovary} showed a significantly worse PFS than those with low SUV{sub meta}/SUV{sub ovary} (P = 0.007, log-rank test). Preoperative SUV{sub meta}/SUV{sub ovary} was significantly associated with recurrence and has an incremental prognostic value for PFS in patients with advanced serous EOC. (orig.)
Bilateral ovarian serous cystadenocarcinoma in a teenager: a case ...
African Journals Online (AJOL)
Epithelial ovarian cancers are uncommon among young girls and teenagers compared to germ cell tumors. We report a case of bilateral ovarian serous cystadenocarcinoma in a teenage girl with the attendant challenges of diagnosis, management and follow up. HT, 19 year old had presented at a secondary care level with ...
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Lanfang Li
Full Text Available Ovarian cancer is the most lethal type of malignant tumor in gynecological cancers and is associated with a high percentage of late diagnosis and chemotherapy resistance. Thus, it is urgent to identify a tumor marker or a molecular target that allows early detection and effective treatment. RNA-binding proteins (RBPs are crucial in various cellular processes at the post-transcriptional level. The eukaryotic translation initiation factor 4 gamma, 1(eIF4G1, an RNA-binding protein, facilitates the recruitment of mRNA to the ribosome, which is a rate-limiting step during the initiation phase of protein synthesis. However, little is known regarding the characteristics of eIF4G1 expression and its clinical significance in ovarian cancer. Therefore, we propose to investigate the expression and clinicopathological significance of eIF4G1 in ovarian cancer patients.We performed Real-time PCR in 40 fresh serous ovarian cancer tissues and 27 normal ovarian surface epithelial cell specimens to assess eIF4G1mRNA expression. Immunohistochemistry (IHC was used to examine the expression of eIF4G1 at the protein level in 134 patients with serous ovarian cancer and 18 normal ovarian tissues. Statistical analysis was conducted to determine the correlation of the eIF4G1 protein levels with the clinicopathological characteristics and prognosis in ovarian cancer.The expression of eIF4G1 was upregulated in serous ovarian cancer tissues at both the mRNA (P = 0.0375 and the protein (P = 0.0007 levels. The eIF4G1 expression was significantly correlated with the clinical tumor stage (P = 0.0004 and omentum metastasis (P = 0.024. Moreover, patients with low eIF4G1 protein expression had a longer overall survival time (P = 0.026.These data revealed that eIF4G1 is markedly expressed in serous ovarian cancer and that upregulation of the eIF4G1 protein expression is significantly associated with an advanced tumor stage. Besides, the patients with lower expression of eIF4G1 tend
International Nuclear Information System (INIS)
Skirnisdottir, Ingiridur; Mayrhofer, Markus; Rydåker, Maria; Åkerud, Helena; Isaksson, Anders
2012-01-01
Ovarian cancer is a heterogeneous disease and prognosis for apparently similar cases of ovarian cancer varies. Recurrence of the disease in early stage (FIGO-stages I-II) serous ovarian cancer results in survival that is comparable to those with recurrent advanced-stage disease. The aim of this study was to investigate if there are specific genomic aberrations that may explain recurrence and clinical outcome. Fifty-one women with early stage serous ovarian cancer were included in the study. DNA was extracted from formalin fixed samples containing tumor cells from ovarian tumors. Tumor samples from thirty-seven patients were analysed for allele-specific copy numbers using OncoScan single nucleotide polymorphism arrays from Affymetrix and the bioinformatic tool Tumor Aberration Prediction Suite. Genomic gains, losses, and loss-of-heterozygosity that associated with recurrent disease were identified. The most significant differences (p < 0.01) in Loss-of-heterozygosity (LOH) were identified in two relatively small regions of chromosome 19; 8.0-8,8 Mbp (19 genes) and 51.5-53.0 Mbp (37 genes). Thus, 56 genes on chromosome 19 were potential candidate genes associated with clinical outcome. LOH at 19q (51-56 Mbp) was associated with shorter disease-free survival and was an independent prognostic factor for survival in a multivariate Cox regression analysis. In particular LOH on chromosome 19q (51-56 Mbp) was significantly (p < 0.01) associated with loss of TP53 function. The results of our study indicate that presence of two aberrations in TP53 on 17p and LOH on 19q in early stage serous ovarian cancer is associated with recurrent disease. Further studies related to the findings of chromosomes 17 and 19 are needed to elucidate the molecular mechanism behind the recurring genomic aberrations and the poor clinical outcome
Chao, Kuan-Chong; Chen, Yi-Jen; Juang, Chi-Mou; Lau, Hei-Yu; Wen, Kuo-Chang; Sung, Pi-Lin; Fang, Feng-Ying; Twu, Nae-Fang; Yen, Ming-Shyen
2013-03-01
To compare the prognosis of patients with advanced-stage primary peritoneal serous papillary carcinoma (PSPC) or papillary serous ovarian cancer (PSOC). This was a retrospective case-control study and included two study groups: one with stage III/IV PSPC (n = 38) patients and the other with PSOC (n = 53) patients. Patients were matched for histologic subtype (serous tumor), tumor stage, tumor grade, residual disease at the end of debulking surgery (primary or interval), and age (±5 years). Mean age was significantly greater for patients with PSPC (63.03 ± 11.88 years) than for patients with PSOC (55.92 ± 12.56 years, p = 0.008). Optimal debulking surgery was performed initially in 71.9% of PSPC patients and 66.0% of PSOC patients. In addition, 93.9% of PSPC patients and 92.3% of PSOC patients were treated with platinum-paclitaxel chemotherapy. The frequency of high-grade tumors was significantly higher in the PSPC (100%) than in the PSOC group (68.3%; p statistic). PFS was similar for advanced-stage PSPC and PSOC patients. Since the PSPC patients tended to be older and have more high-grade tumors, OS was shorter for PSPC than for POSC patients. Thus, management of the two types of cancer should not differ. Copyright © 2013. Published by Elsevier B.V.
Encinas, Giselly; Maistro, Simone; Pasini, Fatima Solange; Hirata Katayama, Maria Lucia; Brentani, Maria Mitzi; de Bock, Geertruida Hendrika; Azevedo Koike Folgueira, Maria Aparecida
2015-01-01
Objective: our aim was to evaluate whether somatic mutations in five genes were associated with an early age at presentation of breast cancer (BC) or serous ovarian cancer (SOC). Methods: COSMIC database was searched for the five most frequent somatic mutations in BC and SOC. A systematic review of
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Jinhua Wang
Full Text Available BACKGROUND: Biomarkers play critical roles in early detection, diagnosis and monitoring of therapeutic outcome and recurrence of cancer. Previous biomarker research on ovarian cancer (OC has mostly focused on the discovery and validation of diagnostic biomarkers. The primary purpose of this study is to identify serum biomarkers for prognosis and therapeutic outcomes of ovarian cancer. EXPERIMENTAL DESIGN: Forty serum proteins were analyzed in 70 serum samples from healthy controls (HC and 101 serum samples from serous OC patients at three different disease phases: post diagnosis (PD, remission (RM and recurrence (RC. The utility of serum proteins as OC biomarkers was evaluated using a variety of statistical methods including survival analysis. RESULTS: Ten serum proteins (PDGF-AB/BB, PDGF-AA, CRP, sFas, CA125, SAA, sTNFRII, sIL-6R, IGFBP6 and MDC have individually good area-under-the-curve (AUC values (AUC = 0.69-0.86 and more than 10 three-marker combinations have excellent AUC values (0.91-0.93 in distinguishing active cancer samples (PD & RC from HC. The mean serum protein levels for RM samples are usually intermediate between HC and OC patients with active cancer (PD & RC. Most importantly, five proteins (sICAM1, RANTES, sgp130, sTNFR-II and sVCAM1 measured at remission can classify, individually and in combination, serous OC patients into two subsets with significantly different overall survival (best HR = 17, p<10(-3. CONCLUSION: We identified five serum proteins which, when measured at remission, can accurately predict the overall survival of serous OC patients, suggesting that they may be useful for monitoring the therapeutic outcomes for ovarian cancer.
Prognostic significance of normal-sized ovary in advanced serous epithelial ovarian cancer.
Paik, E Sun; Kim, Ji Hye; Kim, Tae Joong; Lee, Jeong Won; Kim, Byoung Gie; Bae, Duk Soo; Choi, Chel Hun
2018-01-01
We compared survival outcomes of advanced serous type epithelial ovarian cancer (EOC) patients with normal-sized ovaries and enlarged-ovarian tumors by propensity score matching analysis. The medical records of EOC patients treated at Samsung Medical Center between 2002 and 2015 were reviewed retrospectively. We investigated EOC patients with high grade serous type histology and International Federation of Gynecology and Obstetrics (FIGO) stage IIIB, IIIC, or IV who underwent primary debulking surgery (PDS) and adjuvant chemotherapy to identify patients with normal-sized ovaries. Propensity score matching was performed to compare patients with normal-sized ovaries to patients with enlarged-ovarian tumors (ratio, 1:3) according to age, FIGO stage, initial cancer antigen (CA)-125 level, and residual disease status after PDS. Of the 419 EOC patients, 48 patients had normal-sized ovary. Patients with enlarged-ovarian tumor were younger (54.0±10.3 vs. 58.4±9.2 years, p=0.005) than those with normal-sized ovary, and there was a statistically significant difference in residual disease status between the 2 groups. In total cohort with a median follow-up period of 43 months (range, 3-164 months), inferior overall survival (OS) was shown in the normal-sized ovary group (median OS, 71.2 vs. 41.4 months; p=0.003). After propensity score matching, the group with normal-sized ovary showed inferior OS compared to the group with enlarged-ovarian tumor (median OS, 72.1 vs. 41.4 months; p=0.031). In multivariate analysis for OS, normal-sized ovary remained a significant factor. Normal-sized ovary was associated with poor OS compared with the common presentation of enlarged ovaries in EOC, independent of CA-125 level or residual disease. Copyright © 2018. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology
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Takafumi Kuroda
Full Text Available Cancer stem-like cells (CSCs/cancer-initiating cells (CICs are defined as a small population of cancer cells that have high tumorigenicity. Furthermore, CSCs/CICs are resistant to several cancer therapies, and CSCs/CICs are therefore thought to be responsible for cancer recurrence after treatment and distant metastasis. In epithelial ovarian cancer (EOC cases, disease recurrence after chemotherapy is frequently observed, suggesting ovarian CSCs/CICs are involved. There are four major histological subtypes in EOC, and serous adenocarcinoma and clear cell adenocarcinoma are high-grade malignancies. We therefore analyzed ovarian CSCs/CICs from ovarian carcinoma cell lines (serous adenocarcinoma and clear cell adenocarcinoma and primary ovarian cancer cells in this study. We isolated ovarian CSCs/CICs as an aldehyde dehydrogenase 1 high (ALDH1(high population from 6 EOC cell lines (3 serous adenocarcinomas and 3 clear cell adenocarcinomas by the ALDEFLUOR assay. ALDH1(high cells showed greater sphere-forming ability, higher tumorigenicity and greater invasive capability, indicating that ovarian CSCs/CICs are enriched in ALDH1(high cells. ALDH1(high cells could also be isolated from 8 of 11 primary ovarian carcinoma samples. Immunohistochemical staining revealed that higher ALDH1 expression levels in ovary cancer cases are related to poorer prognosis in both serous adenocarcinoma cases and clear cell adenocarcinoma cases. Taken together, the results indicate that ALDH1 is a marker for ovarian CSCs/CICs and that the expression level of ALDH1 might be a novel biomarker for prediction of poor prognosis.
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Sharon E Johnatty
2010-07-01
Full Text Available We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC. In the discovery stage, cases with epithelial ovarian cancer (n=675 and controls (n=1,162 were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-alleleor=0.5. However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03. Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24 p=0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.
DEFF Research Database (Denmark)
Kar, Siddhartha P; Tyrer, Jonathan P; Li, Qiyuan
2015-01-01
BACKGROUND: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified...... in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). RESULTS: Gene set enrichment analysis...
Oxidatively Modified Proteins in the Serous Subtype of Ovarian Carcinoma
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Sharifeh Mehrabi
2014-01-01
Full Text Available Serous subtype of ovarian cancer is considered to originate from fallopian epithelium mucosa that has been exposed to physiological changes resulting from ovulation. Ovulation influences an increased in inflammation of epithelial ovarian cells as results of constant exposure of cells to ROS. The imbalance between ROS and antioxidant capacities, as well as a disruption of redox signaling, causes a wide range of damage to DNA, proteins, and lipids. This study applied spectrophotometric, dinitrophenylhydrazone (DNPH assay, two-dimensional gel electrophoresis, and Western blot analyses to assess the levels of oxidatively modified proteins in 100 primary serous epithelial ovarian carcinoma and normal/surrounding tissues. These samples were obtained from 56 Caucasian and 44 African-American patients within the age range of 61±10 years. Analyses showed that the levels of reactive protein carbonyl groups increased as stages progressed to malignancy. Additionally, the levels of protein carbonyls in serous ovarian carcinoma among African Americans are 40% (P<0.05 higher relative to Caucasian at similar advanced stages. Results suggest that oxidative stress is involved in the modification of carbonyl protein groups, leading to increased aggressiveness of epithelial ovarian tumors and may contribute to the disease's invasiveness among African Americans.
Yang, Junzheng; Zhou, Yilan; Ng, Shu-Kay; Huang, Kuan-Chun; Ni, Xiaoyan; Choi, Pui-Wah; Hasselblatt, Kathleen; Muto, Michael G; Welch, William R; Berkowitz, Ross S; Ng, Shu-Wing
2017-06-17
Ovarian cancer is the leading cause of death among gynecologic diseases in Western countries. We have previously identified a miR-200-E-cadherin axis that plays an important role in ovarian inclusion cyst formation and tumor invasion. The purpose of this study was to determine if the miR-200 pathway is involved in the early stages of ovarian cancer pathogenesis by studying the expression levels of the pathway components in a panel of clinical ovarian tissues, and fallopian tube tissues harboring serous tubal intraepithelial carcinomas (STICs), a suggested precursor lesion for high-grade serous tumors. RNA prepared from ovarian and fallopian tube epithelial and stromal fibroblasts was subjected to quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) to determine the expression of miR-200 families, target and effector genes and analyzed for clinical association. The effects of exogenous miR-200 on marker expression in normal cells were determined by qRT-PCR and fluorescence imaging after transfection of miR-200 precursors. Ovarian epithelial tumor cells showed concurrent up-regulation of miR-200, down-regulation of the four target genes (ZEB1, ZEB2, TGFβ1 and TGFβ2), and up-regulation of effector genes that were negatively regulated by the target genes. STIC tumor cells showed a similar trend of expression patterns, although the effects did not reach significance because of small sample sizes. Transfection of synthetic miR-200 precursors into normal ovarian surface epithelial (OSE) and fallopian tube epithelial (FTE) cells confirmed reduced expression of the target genes and elevated levels of the effector genes CDH1, CRB3 and EpCAM in both normal OSE and FTE cells. However, only FTE cells had a specific induction of CA125 after miR-200 precursor transfection. The activation of the miR-200 pathway may be an early event that renders the OSE and FTE cells more susceptible to oncogenic mutations and histologic differentiation. As high
Paradigm Shift in the Management Strategy for Epithelial Ovarian Cancer.
Fujiwara, Keiichi; McAlpine, Jessica N; Lheureux, Stephanie; Matsumura, Noriomi; Oza, Amit M
2016-01-01
The hypothesis on the pathogenesis of epithelial ovarian cancer continues to evolve. Although epithelial ovarian cancer had been assumed to arise from the coelomic epithelium of the ovarian surface, it is now becoming clearer that the majority of serous carcinomas arise from epithelium of the distal fallopian tube, whereas clear cell and endometrioid cancers arise from endometriosis. Molecular and genomic characteristics of epithelial ovarian cancer have been extensively investigated. Our understanding of pathogenesis of the various histologic types of ovarian cancer have begun to inform changes to the strategies for management of epithelial ovarian cancer, which represent a paradigm shift not only for treatment but also for prevention, which previously had not been considered achievable. In this article, we will discuss novel attempts at the prevention of high-grade serous ovarian cancer and treatment strategies for two distinct entities in epithelial ovarian cancer: low-grade serous and clear cell ovarian carcinomas, which are relatively rare and resistant to conventional chemotherapy.
Normal-sized ovarian papillary serous carcinoma: a case report.
Wu, W C; Lai, C I; Huang, L C; Chiu, T H; Hung, Y C; Chang, W C
2010-01-01
A normal-sized ovarian papillary serous carcinoma is rare. We present the case of a 46-year-old woman with progressive abdominal fullness of one week's duration. The medical evaluation revealed abdominal carcinomatosis with normal-sized ovaries and an elevated serum CA-125 level of 147,365.8 U/ml. Cytoreductive surgery (hysterectomy, bilateral salpingo-oophorectomy, omentectomy, lymphadenectomy, infracolic omentectomy, peritoneal biopsy, washing cytology, and appendectomy) was performed. The histologic examination revealed an ovarian serous papillary carcinoma. Adjuvant chemotherapy was administered. The serum CA-125 level decreased after completion of treatment. Normal-sized ovarian serous surface papillary carcinomas should be kept in mind as an origin of disease in patients who have peritoneal carcinomatosis, which sometimes is a diagnostic dilemma of the disease source. We report this case to emphasize the clinical symptoms and importance of the early and accurate diagnosis of a normal-sized ovarian papillary serous carcinoma.
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Alessandra Ciucci
Full Text Available Recent evidence links aberrant activation of Hedgehog (Hh signaling with the pathogenesis of several cancers including medulloblastoma, glioblastoma, melanoma as well as pancreas, colorectal, and prostate carcinomas. Here we investigated the role of the transcription factor Gli1 in ovarian cancer. To this end, the expression profile of Gli1 was examined in normal ovaries, ovarian tumors, and ovarian cancer cell lines, and the in vitro effects of a specific Hh-pathway blocker, KAAD-cyclopamine, or a specific Gli1 inhibitor (GANT58 on cell proliferation and on Hh target gene expression were also assessed. Results obtained showed that epithelial cells in ovarian cancer tissue express significantly higher levels of nuclear Gli1 than in normal ovarian tissue, where the protein was almost undetectable. In addition, multivariate analysis showed that nuclear Gli1 was independently associated to poor survival in advanced serous ovarian cancer patients (HR = 2.2, 95%CI 1.0-5.1, p = 0.04. In vitro experiments demonstrated Gli1 expression in the three ovarian carcinoma cell lines tested, A2780, SKOV-3 and OVCAR-3. Remarkably, although KAAD-cyclopamine led to decreased cell proliferation, this treatment did not inhibit hedgehog target gene expression in any of the three ovarian cancer cell lines, suggesting that the inhibition of cell proliferation was a nonspecific or toxic effect. In line with these data, no differences on cell proliferation were observed when cell lines were treated with GANT58. Overall, our clinical data support the role of Gli1 as a prognostic marker in advanced serous ovarian cancer and as a possible therapeutic target in this disease. However, our in vitro findings draw attention to the need for selection of appropriate experimental models that accurately represent human tumor for testing future therapies involving Hh pathway inhibitors.
DEFF Research Database (Denmark)
Madsen, C; Baandrup, Louise; Dehlendorff, Christian
2015-01-01
OBJECTIVE: According to the recent theories on the ovarian cancer origin, any protective effect of tubal ligation may vary with histologic subtype of ovarian cancer. Furthermore, bilateral salpingectomy may represent an opportunity for surgical prevention of serous ovarian cancer. DESIGN: Nationw......OBJECTIVE: According to the recent theories on the ovarian cancer origin, any protective effect of tubal ligation may vary with histologic subtype of ovarian cancer. Furthermore, bilateral salpingectomy may represent an opportunity for surgical prevention of serous ovarian cancer. DESIGN...... sampling. We required that cases and controls have no previous cancer and that controls have no previous bilateral oophorectomy. METHODS: Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals, adjusting for potential confounders. MAIN OUTCOME MEASURES: Epithelial...
Chene, Gautier; Cayre, Anne; Raoelfils, Ines; Lagarde, Nicole; Dauplat, Jacques; Penault-Llorca, Frederique
2014-12-01
Histopathological examination of material from prophylactic salpingo-oophorectomies performed in patients at genetic risk of ovarian cancer can reveal abnormalities interpreted as possible pre-cancerous "ovarian dysplasia" and tubal precursors lesions. We sought to study the morphological features and immunohistochemical expression patterns of neoplasia-associated markers in prophylactically removed ovaries and fallopian tubes (pBSO) in comparison with a group of serous tubal intraepithelial carcinoma (STIC) and non-cancerous controls. Morphological features and immunohistochemical expression patterns of Ki-67 (for proliferation biomarker), p53 (key pathway of mullerian serous tumorogenesis), Bcl2 (anti-apoptotic), γH2AX (a double-strand breaks marker) and ALDH1 (a stem cell marker significantly associated with early-stage ovarian cancer) were blindly evaluated by two pathologists in 111 pBSO, 12 STICs and 116 non-cancerous salpingo-oophorectomies (control group) (nBSO). Morphological ovarian and tubal dysplasia scores were significantly higher in the pBSO than in controls (respectively, 8.8 vs 3.12, pSTICs compared with the controls whereas expression patterns of Ki67, p53 and bcl2 were low to moderate in the pBSO group. STICs overexpressed Ki67 and p53 while bcl2 expression was low; Interestingly, ALDH1 expression was low in non dysplastic epithelium, high in dysplasia and constantly low in STICs. The morphological and immunohistochemical profile of tubo-ovarian dysplasia and STICs might be consistent with progression toward neoplastic transformation in the Serous Carcinogenesis Sequence. These changes may be pre-malignant and could represent an important phase in early neoplasia. ALDH1 activation in pBSO samples and its extinction in STICs should be considered as a target for prevention. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Brouwer, Jan; Kluiver, Joost; de Almeida, Rodrigo C.; Modderman, Rutger; Terpstra, Martijn; Kok, Klaas; Withoff, Sebo; Hollema, Harry; Reitsma, Welmoed; de Bock, Geertruida H.; Mourits, Marian J. E.; van den Berg, Anke
2016-01-01
AimsBRCA1 mutation carriers are at increased risk of developing high-grade serous ovarian cancer (HGSOC), a malignancy that originates from fallopian tube epithelium. We aimed to identify differentially expressed known and novel miRNAs in BRCA1-associated HGSOC. Methods Small RNA sequencing was
Wentzensen, Nicolas; Poole, Elizabeth M; Trabert, Britton; White, Emily; Arslan, Alan A; Patel, Alpa V; Setiawan, V Wendy; Visvanathan, Kala; Weiderpass, Elisabete; Adami, Hans-Olov; Black, Amanda; Bernstein, Leslie; Brinton, Louise A; Buring, Julie; Butler, Lesley M; Chamosa, Saioa; Clendenen, Tess V; Dossus, Laure; Fortner, Renee; Gapstur, Susan M; Gaudet, Mia M; Gram, Inger T; Hartge, Patricia; Hoffman-Bolton, Judith; Idahl, Annika; Jones, Michael; Kaaks, Rudolf; Kirsh, Victoria; Koh, Woon-Puay; Lacey, James V; Lee, I-Min; Lundin, Eva; Merritt, Melissa A; Onland-Moret, N Charlotte; Peters, Ulrike; Poynter, Jenny N; Rinaldi, Sabina; Robien, Kim; Rohan, Thomas; Sandler, Dale P; Schairer, Catherine; Schouten, Leo J; Sjöholm, Louise K; Sieri, Sabina; Swerdlow, Anthony; Tjonneland, Anna; Travis, Ruth; Trichopoulou, Antonia; van den Brandt, Piet A; Wilkens, Lynne; Wolk, Alicja; Yang, Hannah P; Zeleniuch-Jacquotte, Anne; Tworoger, Shelley S
2016-08-20
An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3). Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het ≤ .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas. The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype. © 2016 by American Society of Clinical Oncology.
Vargas, Hebert Alberto; Huang, Erich P; Lakhman, Yulia; Ippolito, Joseph E; Bhosale, Priya; Mellnick, Vincent; Shinagare, Atul B; Anello, Maria; Kirby, Justin; Fevrier-Sullivan, Brenda; Freymann, John; Jaffe, C Carl; Sala, Evis
2017-11-01
Purpose To evaluate interradiologist agreement on assessments of computed tomography (CT) imaging features of high-grade serous ovarian cancer (HGSOC), to assess their associations with time-to-disease progression (TTP) and HGSOC transcriptomic profiles (Classification of Ovarian Cancer [CLOVAR]), and to develop an imaging-based risk score system to predict TTP and CLOVAR profiles. Materials and Methods This study was a multireader, multi-institutional, institutional review board-approved, HIPAA-compliant retrospective analysis of 92 patients with HGSOC (median age, 61 years) with abdominopelvic CT before primary cytoreductive surgery available through the Cancer Imaging Archive. Eight radiologists from the Cancer Genome Atlas Ovarian Cancer Imaging Research Group developed and independently recorded the following CT features: characteristics of primary ovarian mass(es), presence of definable mesenteric implants and infiltration, presence of other implants, presence and distribution of peritoneal spread, presence and size of pleural effusions and ascites, lymphadenopathy, and distant metastases. Interobserver agreement for CT features was assessed, as were univariate and multivariate associations with TTP and CLOVAR mesenchymal profile (worst prognosis). Results Interobserver agreement for some features was strong (eg, α = .78 for pleural effusion and ascites) but was lower for others (eg, α = .08 for intraparenchymal splenic metastases). Presence of peritoneal disease in the right upper quadrant (P = .0003), supradiaphragmatic lymphadenopathy (P = .0004), more peritoneal disease sites (P = .0006), and nonvisualization of a discrete ovarian mass (P = .0037) were associated with shorter TTP. More peritoneal disease sites (P = .0025) and presence of pouch of Douglas implants (P = .0045) were associated with CLOVAR mesenchymal profile. Combinations of imaging features contained predictive signal for TTP (concordance index = 0.658; P = .0006) and CLOVAR profile (mean
Sherman-Baust, Cheryl A; Kuhn, Elisabetta; Valle, Blanca L; Shih, Ie-Ming; Kurman, Robert J; Wang, Tian-Li; Amano, Tomokazu; Ko, Minoru S H; Miyoshi, Ichiro; Araki, Yoshihiko; Lehrmann, Elin; Zhang, Yongqing; Becker, Kevin G; Morin, Patrice J
2014-07-01
Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp-TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse müllerian-specific Ovgp-1 promoter. Histological analysis of the fallopian tubes of mogp-TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal-appearing p53-positive epithelium that are similar to 'p53 signatures' in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these non-invasive precursor lesions, we also identified invasive adenocarcinoma in the ovaries of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp-TAg and wild-type (WT) C57BL/6. One of these genes, Top2a, which encodes topoisomerase IIα, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and was specifically elevated in mouse STICs but not in the surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumourigenesis, as well as
The Potential of Targeting Ribosome Biogenesis in High-Grade Serous Ovarian Cancer
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Shunfei Yan
2017-01-01
Full Text Available Overall survival for patients with ovarian cancer (OC has shown little improvement for decades meaning new therapeutic options are critical. OC comprises multiple histological subtypes, of which the most common and aggressive subtype is high-grade serous ovarian cancer (HGSOC. HGSOC is characterized by genomic structural variations with relatively few recurrent somatic mutations or dominantly acting oncogenes that can be targeted for the development of novel therapies. However, deregulation of pathways controlling homologous recombination (HR and ribosome biogenesis has been observed in a high proportion of HGSOC, raising the possibility that targeting these basic cellular processes may provide improved patient outcomes. The poly (ADP-ribose polymerase (PARP inhibitor olaparib has been approved to treat women with defects in HR due to germline BRCA mutations. Recent evidence demonstrated the efficacy of targeting ribosome biogenesis with the specific inhibitor of ribosomal RNA synthesis, CX-5461 in v-myc avian myelocytomatosis viral oncogene homolog (MYC-driven haematological and prostate cancers. CX-5461 has now progressed to a phase I clinical trial in patients with haematological malignancies and phase I/II trial in breast cancer. Here we review the currently available targeted therapies for HGSOC and discuss the potential of targeting ribosome biogenesis as a novel therapeutic approach against HGSOC.
Simultaneous Serous Cyst Adenoma and Ovarian Pregnancy in An Infertile Woman
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Mahbod Ebrahimi
2014-03-01
Full Text Available Ovarian pregnancy is a rare form of extra uterine pregnancy. Serous cyst adenoma is a benign variant of epithelial cell tumors of ovary. The coexistence of a cyst adenoma with an ovarian pregnancy in the same ovary is extremely rare. Some studies suggested that infertility or ovulation-inducing drugs can be involved in increased risk of ovarian tumors and ovarian pregnancies. A 28-year-old infertile woman presented with a ruptured ovarian pregnancy following ovulation induction with metformin. She had a concurrent benign serous cyst adenoma in the same ovary. Resection of both ovarian pregnancy and tumoral mass were performed. The ovary was preserved. Removal of gestational tissue and preservation of the involved ovary are the best options for management of ovarian pregnancy in young patient. Although there is an association between infertility/ovulation inducting medications and ovarian gestation, their connections with serous cyst adenoma are undetermined.
Chay, Wen Yee; McCluggage, W Glenn; Lee, Cheng-Han; Köbel, Martin; Irving, Julie; Millar, Joanne; Gilks, C Blake; Tinker, Anna V
2016-03-01
The natural history and optimal management of serous tubal intraepithelial carcinoma (STIC), regardless of BRCA status, is unknown. We report the follow-up findings of a series of incidental fallopian tube high-grade serous carcinomas (HGSCs) and STICs identified in women at low risk for hereditary breast and ovarian cancer (HBOC), undergoing surgery for other indications. Cases of incidental STIC and HGSC were identified from 2008. Patients with known BRCA1 or BRCA2 mutations, or a family history of ovarian or breast cancer before the diagnosis of STIC or HGSC were excluded. A retrospective chart review was conducted to obtain clinical data. Eighteen cases were identified with a median follow-up of 25 months (range, 4-88 months). Twelve of 18 patients had a diagnosis of STIC with no associated invasive HGSC and 6 had STIC associated with other invasive malignancies. Completion staging surgery was performed on 7 of the 18 patients, including 5 of 12 in which there was STIC only identified on primary surgery; 3 cases were upstaged from STIC only to HGSC based on the staging surgery. Recurrence of HGSC occurred in 2 of the 18 patients. BRCA testing was performed on 3 patients, 1 of whom tested positive for a pathogenic BRCA1 mutation. Our study suggests that completion staging surgery for incidental STICs in non-BRCA patients may be considered. These patients should be offered hereditary testing. The Pelvic-Ovarian cancer INTerception (POINT) Project is an international registry set up to add to our understanding of STICs.
Zhang, Fan; Yang, Kai; Deng, Kui; Zhang, Yuanyuan; Zhao, Weiwei; Xu, Huan; Rong, Zhiwei; Li, Kang
2018-04-16
We sought to identify stable single-gene prognostic signatures based on a large collection of advanced stage serous ovarian cancer (AS-OvCa) gene expression data and explore their functions. The empirical Bayes (EB) method was used to remove the batch effect and integrate 8 ovarian cancer datasets. Univariate Cox regression was used to evaluate the association between gene and overall survival (OS). The Database for Annotation, Visualization and Integrated Discovery (DAVID) tool was used for the functional annotation of genes for Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The batch effect was removed by the EB method, and 1257 patient samples were used for further analysis. We selected 341 single-gene prognostic signatures with FDR matrix organization, focal adhesion and DNA replication which are closely associated with cancer. We used the EB method to remove the batch effect of 8 datasets, integrated these datasets and identified stable prognosis signatures for AS-OvCa.
Wouters, Maartje C. A.; Komdeur, Fenne L.; Workel, Hagma H.; Klip, Harry G.; Plat, Annechien; Kooi, Neeltje M.; Wisman, G. Bea A.; Mourits, Marian J. E.; Arts, Henriette J. G.; Oonk, Maaike H. M.; Yigit, Refika; de Jong, Steven; Melief, Cornelis J. M.; Hollema, Harry; Duiker, Evelien W.; Daemen, Toos; de Bruyn, Marco; Nijman, Hans W.
2016-01-01
Purpose: Tumor-infiltrating lymphocytes (TIL) are associated with a better prognosis in high-grade serous ovarian cancer (HGSC). However, it is largely unknown how this prognostic benefit of TIL relates to current standard treatment of surgical resection and (neo-)adjuvant chemotherapy. To address
Molecular targets in serous gynecologic cancers
Groeneweg, J.W.
2015-01-01
In this thesis we describe a series of studies assessing the effectiveness of targeted therapeutics that inhibit Notch signaling or the HER2 receptor in serous gynecologic cancers. In the first part of the thesis, we have confirmed previous data by showing expression of Notch1 and Notch3 in ovarian
Identification of novel therapeutic targets in microdissected clear cell ovarian cancers.
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Michael P Stany
Full Text Available Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients.
Kobayashi, Yusuke; Kashima, Hiroyasu; Wu, Ren-Chin; Jung, Jin-Gyoung; Kuan, Jen-Chun; Gu, Jinghua; Xuan, Jianhua; Sokoll, Lori; Visvanathan, Kala; Shih, Ie-Ming; Wang, Tian-Li
2015-10-15
Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Because TP53 mutations occur in almost all ovarian high-grade serous carcinoma (HGSC), we determined whether statins suppressed tumor growth in animal models of ovarian cancer. Two ovarian cancer mouse models were used. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously developed serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the antitumor effects of lovastatin were also investigated. Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced antiproliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease. ©2015 American Association for Cancer Research.
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Varvara Vitiazeva
Full Text Available Mucins are heavily O-glycosylated proteins where the glycosylation has been shown to play an important role in cancer. Normal epithelial ovarian cells do not express secreted mucins, but their abnormal expression has previously been described in epithelial ovarian cancer and may relate to tumor formation and progression. The cyst fluids were shown to be a rich source for acidic glycoproteins. The study of these proteins can potentially lead to the identification of more effective biomarkers for ovarian cancer.In this study, we analyzed the expression of the MUC5AC and the O-glycosylation of acidic glycoproteins secreted into ovarian cyst fluids. The samples were obtained from patients with serous and mucinous ovarian tumors of different stages (benign, borderline, malignant and grades. The O-linked oligosaccharides were released and analyzed by negative-ion graphitized carbon Liquid Chromatography (LC coupled to Electrospray Ionization tandem Mass Spectrometry (ESI-MSn. The LC-ESI-MSn of the oligosaccharides from ovarian cyst fluids displayed differences in expression of fucose containing structures such as blood group ABO antigens and Lewis-type epitopes.The obtained data showed that serous and mucinous benign adenomas, mucinous low malignant potential carcinomas (LMPs, borderline and mucinous low-grade carcinomas have a high level of blood groups and Lewis type epitopes. In contrast, this type of fucosylated structures were low abundant in the high-grade mucinous carcinomas or in serous carcinomas. In addition, the ovarian tumors that showed a high level of expression of blood group antigens also revealed a strong reactivity towards the MUC5AC antibody. To visualize the differences between serous and mucinous ovarian tumors based on the O-glycosylation, a hierarchical cluster analysis was performed using mass spectrometry average compositions (MSAC.Mucinous benign and LMPs along with mucinous low-grade carcinomas appear to be different from
High-grade ovarian cancer secreting effective exosomes in tumor angiogenesis.
Yi, Huan; Ye, Jun; Yang, Xiao-Mei; Zhang, Li-Wen; Zhang, Zhi-Gang; Chen, Ya-Ping
2015-01-01
Ovarian cancer, the most lethal gynecological cancer, related closely to tumor stage. High-grade ovarian cancer always results in a late diagnose and high recurrence, which reduce survival within five years. Until recently, curable therapy is still under research and anti-angiogenesis proves a promising way. Tumor-derived exosomes are essential in tumor migration and metastases such as angiogenesis is enhanced by exosomes. In our study, we have made comparison between high-grade and unlikely high-grade serous ovarian cancer cells on exosomal function of endothelial cells proliferation, migration and tube formation. Exosomes derived from high-grade ovarian cancer have a profound impact on angiogenesis with comparison to unlikely high-grade ovarian cancer. Proteomic profiles revealed some potential proteins involved in exosomal function of angiogenesis such as ATF2, MTA1, ROCK1/2 and so on. Therefore, exosomes plays an influential role in angiogenesis in ovarian serous cancer and also function more effectively in high-grade ovarian cancer cells.
The Molecular Fingerprint of High Grade Serous Ovarian Cancer Reflects Its Fallopian Tube Origin
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Thomas Meyer
2013-03-01
Full Text Available High grade serous ovarian cancer (HGSC, the most lethal and frequent type of epithelial ovarian cancer (EOC, has poor long term prognosis due to a combination of factors: late detection, great metastatic potential and the capacity to develop resistance to available therapeutic drugs. Furthermore, there has been considerable controversy concerning the etiology of this malignancy. New studies, both clinical and molecular, strongly suggest that HGSC originates not from the surface of the ovary, but from the epithelial layer of the neighboring fallopian tube fimbriae. In this paper we summarize data supporting the central role of fallopian tube epithelium in the development of HGSC. Specifically, we address cellular pathways and regulatory mechanisms which are modulated in the process of transformation, but also genetic changes which accumulate during disease progression. Similarities between fallopian tube mucosa and the malignant tissue of HGSC warrant a closer analysis of homeostatic mechanisms in healthy epithelium in order to elucidate key steps in disease development. Finally, we highlight the importance of the cancer stem cell (CSC identification and understanding of its niche regulation for improvement of therapeutic strategies.
Kobayashi, Yusuke; Kashima, Hiroyasu; Wu, Ren-Chin; Jung, Jin- Gyoung; Kuan, Jen-Chun; Gu, Jinghua; Xuan, Jianhua; Sokoll, Lori; Visvanathan, Kala; Shih, Ie-Ming; Wang, Tian-Li
2015-01-01
Purpose Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Since TP53 mutations occur in almost all of the ovarian high-grade serous carcinoma, we determined if statins suppressed tumor growth in animal models of ovarian cancer. Experimental Design Two ovarian cancer mouse models were employed. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously develop serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the anti-tumor effects of lovastatin were also investigated. Results Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced anti-proliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. Conclusion The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease. PMID:26109099
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Giselly Encinas
2015-10-01
Full Text Available Summary Objective: our aim was to evaluate whether somatic mutations in five genes were associated with an early age at presentation of breast cancer (BC or serous ovarian cancer (SOC. Methods: COSMIC database was searched for the five most frequent somatic mutations in BC and SOC. A systematic review of PubMed was performed. Young age for BC and SOC patients was set at ≤35 and ≤40 years, respectively. Age groups were also classified in <30years and every 10 years thereafter. Results: twenty six (1,980 patients, 111 younger and 16 studies (598, 41 younger, were analyzed for BC and SOC, respectively. In BC, PIK3CA wild type tumor was associated with early onset, not confirmed in binary regression with estrogen receptor (ER status. In HER2-negative tumors, there was increased frequency of PIK3CA somatic mutation in older age groups; in ER-positive tumors, there was a trend towards an increased frequency of PIK3CA somatic mutation in older age groups. TP53 somatic mutation was described in 20% of tumors from both younger and older patients; PTEN, CDH1 and GATA3 somatic mutation was investigated only in 16 patients and PTEN mutation was detected in one of them. In SOC, TP53 somatic mutation was rather common, detected in more than 50% of tumors, however, more frequently in older patients. Conclusion: frequency of somatic mutations in specific genes was not associated with early-onset breast cancer. Although very common in patients with serous ovarian cancer diagnosed at all ages, TP53 mutation was more frequently detected in older women.
Kar, Siddhartha P; Tyrer, Jonathan P; Li, Qiyuan; Lawrenson, Kate; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Chenevix-Trench, Georgia; Baker, Helen; Bandera, Elisa V; Bean, Yukie T; Beckmann, Matthias W; Berchuck, Andrew; Bisogna, Maria; Bjørge, Line; Bogdanova, Natalia; Brinton, Louise; Brooks-Wilson, Angela; Butzow, Ralf; Campbell, Ian; Carty, Karen; Chang-Claude, Jenny; Chen, Yian Ann; Chen, Zhihua; Cook, Linda S; Cramer, Daniel; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas F; Edwards, Robert P; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus K; Hosono, Satoyo; Iversen, Edwin S; Jakubowska, Anna; Paul, James; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kjaer, Susanne K; Kelemen, Linda E; Kellar, Melissa; Kelley, Joseph; Kiemeney, Lambertus A; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; McNeish, Iain A; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Narod, Steven A; Nedergaard, Lotte; Ness, Roberta B; Nevanlinna, Heli; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste Leigh; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jennifer; Phelan, Catherine M; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schildkraut, Joellen M; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Sucheston-Campbell, Lara E; Tangen, Ingvild L; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S; van Altena, Anne M; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Sellers, Thomas A; Monteiro, Alvaro N A; Freedman, Matthew L; Gayther, Simon A; Pharoah, Paul D P
2015-10-01
Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. ©2015 American Association for Cancer Research.
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Dong Tianfa; Wu Meixian; Zhang Jiayun; Song Ting
2009-01-01
Objective: To assess the diagnostic value of contrast-enhanced 64-row CT scanning in deciding benign or malignant serous ovarian tumors. Methods: Fifty-eight cases of serous ovarian tumors proved pathologically were reviewed, including 25 malignant tumors, 25 benign, 8 borderline tumors. All patients underwent 64-row CT scanning, including plain scanning and contrast-enhance scanning. The tumors' shape, density, blood supply and enhancement features were evaluated. Results: Twenty-five cases of benign serous cystic adenoma were mostly unicameral, and showed a moderate mural enhancement only in 4 cases (16%) due to chronic pelvic infection and the others (21/25, 84%) had no of slight enhancement. Malignant tumors were cystic-solid mass with unclear margin, irregular shape and septa. Twenty-two cases of serous cystadenocarcinoma out of 25 cases (88%) appeared obvious enhancement and other 3 cases no enhancement. And 7 cases out of 8 (87.5%) borderlined serous cystadenomas showed different enhancement patterns. Conclusion: Benign ovarian serous neoplasms were mostly unicameral and no strong mural enhancement, suggesting a lack of blood supply. While, there were obvious enhancement in the ovarian serous cystadenocarcinoma and borderline serous cystadenoma with malignant potential. The 64-row CT is helpful for differentiating the nature of the serous ovarian neoplasm. (authors)
Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci
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Kar, Siddhartha P; Adler, Emily; Tyrer, Jonathan
2017-01-01
BACKGROUND: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors...... (TFs) critical to somatic tumorigenesis. METHODS: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery...... to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P
Harris, Holly R; Babic, Ana; Webb, Penelope M; Nagle, Christina M; Jordan, Susan J; Risch, Harvey A; Rossing, Mary Anne; Doherty, Jennifer A; Goodman, Marc T; Modugno, Francesmary; Ness, Roberta B; Moysich, Kirsten B; Kjær, Susanne K; Høgdall, Estrid; Jensen, Allan; Schildkraut, Joellen M; Berchuck, Andrew; Cramer, Daniel W; Bandera, Elisa V; Wentzensen, Nicolas; Kotsopoulos, Joanne; Narod, Steven A; Phelan, Catherine M; McLaughlin, John R; Anton-Culver, Hoda; Ziogas, Argyrios; Pearce, Celeste L; Wu, Anna H; Terry, Kathryn L
2018-02-01
Background: Polycystic ovary syndrome (PCOS), and one of its distinguishing characteristics, oligomenorrhea, have both been associated with ovarian cancer risk in some but not all studies. However, these associations have been rarely examined by ovarian cancer histotypes, which may explain the lack of clear associations reported in previous studies. Methods: We analyzed data from 14 case-control studies including 16,594 women with invasive ovarian cancer ( n = 13,719) or borderline ovarian disease ( n = 2,875) and 17,718 controls. Adjusted study-specific ORs were calculated using logistic regression and combined using random-effects meta-analysis. Pooled histotype-specific ORs were calculated using polytomous logistic regression. Results: Women reporting menstrual cycle length >35 days had decreased risk of invasive ovarian cancer compared with women reporting cycle length ≤35 days [OR = 0.70; 95% confidence interval (CI) = 0.58-0.84]. Decreased risk of invasive ovarian cancer was also observed among women who reported irregular menstrual cycles compared with women with regular cycles (OR = 0.83; 95% CI = 0.76-0.89). No significant association was observed between self-reported PCOS and invasive ovarian cancer risk (OR = 0.87; 95% CI = 0.65-1.15). There was a decreased risk of all individual invasive histotypes for women with menstrual cycle length >35 days, but no association with serous borderline tumors ( P heterogeneity = 0.006). Similarly, we observed decreased risks of most invasive histotypes among women with irregular cycles, but an increased risk of borderline serous and mucinous tumors ( P heterogeneity ovarian cancer risk differentially based on histotype. Impact: These results highlight the importance of examining ovarian cancer risk factors associations by histologic subtype. Cancer Epidemiol Biomarkers Prev; 27(2); 174-82. ©2017 AACR . ©2017 American Association for Cancer Research.
Liu, Changmei; Yang, Fangmei
2015-09-01
Ovarian cancers present a mild clinical course when diagnosed early but an aggressive pathway when diagnosed in the peri- and postmenopausal periods. However, the predictability of tumor progression is stochastic and is difficult to predict. In the present study, we hypothesized to examine the key pathways that are dysregulated to promote epithelial-mesenchymal transition in serous ovarian carcinoma. Examination of these steps would help to identify ascitic fluid with cells poised for metastasis or otherwise. We focused on examining the Akt2 expression, mainly because of its report as being overamplified in the aggressive variants of ovarian cancer, as well as TGFbeta-sensitivity of Akt2 that forms the key basis for metastasis initiation of most kinds of carcinoma. We obtained primary ovarian carcinoma samples as well as ascitic fluid and distantly metastatic ovarian carcinoma to examine the expression of Akt2. The results of the study demonstrated that in malignant exfoliated ovarian cancer cells, Smad4 expression was tremendously increased in the nuclei, suggesting nuclear translocation of Smad, which thereafter may have activated ZEB2, and thereafter genomically affected the expression of E-cadherin, myosin II, and vimentin, key components for initiating and sustaining metastasis. All of these may have been stimulated by increased cellular expression of Akt2 in metastatic variants of the serous ovarian carcinoma. The reliance on Akt2 and TGF beta signaling may also potentiate the case for Akt inhibitors or small molecule inhibitors of TGFbeta signaling like doxycycline as adjunct chemotherapy in serous ovarian carcinoma, especially the metastatic variants.
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Matyunina Lilya V
2009-12-01
Full Text Available Abstract Background Accumulating evidence suggests that somatic stem cells undergo mutagenic transformation into cancer initiating cells. The serous subtype of ovarian adenocarcinoma in humans has been hypothesized to arise from at least two possible classes of progenitor cells: the ovarian surface epithelia (OSE and/or an as yet undefined class of progenitor cells residing in the distal end of the fallopian tube. Methods Comparative gene expression profiling analyses were carried out on OSE removed from the surface of normal human ovaries and ovarian cancer epithelial cells (CEPI isolated by laser capture micro-dissection (LCM from human serous papillary ovarian adenocarcinomas. The results of the gene expression analyses were randomly confirmed in paraffin embedded tissues from ovarian adenocarcinoma of serous subtype and non-neoplastic ovarian tissues using immunohistochemistry. Differentially expressed genes were analyzed using gene ontology, molecular pathway, and gene set enrichment analysis algorithms. Results Consistent with multipotent capacity, genes in pathways previously associated with adult stem cell maintenance are highly expressed in ovarian surface epithelia and are not expressed or expressed at very low levels in serous ovarian adenocarcinoma. Among the over 2000 genes that are significantly differentially expressed, a number of pathways and novel pathway interactions are identified that may contribute to ovarian adenocarcinoma development. Conclusions Our results are consistent with the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as the origin of ovarian adenocarcinoma. While our findings do not rule out the possibility that ovarian cancers may also arise from other sources, they are inconsistent with claims that ovarian surface epithelia cannot serve as the origin of ovarian cancer initiating cells.
Malmberg, Karin; Klynning, Charlotta; Flöter-Rådestad, Angelique; Carlson, Joseph W
2016-06-01
Ovarian carcinoma is the deadliest gynecological malignancy. Previous studies have suggested that the fallopian tube may be the primary site for high-grade serous carcinoma. In prophylactic salpingo-oophorectomies from women with hereditary high risk for ovarian cancer, precursors can be assessed prior to onset and studied as a model for serous cancer precursor lesions. Epidemiologic studies indicate that carcinogenesis may be a result of chronic fallopian tube injury. The aims of this study were to (1) to examine the incidence of serous tubal intraepithelial carcinoma (STIC) in relation to other clinical parameters and (2) to evaluate whether chronic fallopian tube injury was related to cancer development. This study enrolled 101 women, comprising the following three groups: hereditary (n = 60), sporadic serous cancer (n = 18; endometrial cancers were excluded), and control (n = 23). The cases were histologically examined and clinical risk factors were collected. The histological changes were compared between different patients and correlated to clinical risk factors. STICs were identified primarily on the fallopian tube fimbria. The incidence of STIC was 3 % in the hereditary patients. In sporadic serous cancer cases, 61 % were associated with STIC and tubal carcinoma (p STIC and invasive cancer were seen more often in the older patients than in the younger patients (p = 0.528). This small study, no correlation with chronic tubal injury or inflammation was identified.
Kuhn, Elisabetta; Meeker, Alan; Wang, Tian-Li; Sehdev, Ann Smith; Kurman, Robert J; Shih, Ie-Ming
2010-06-01
Short telomeres are one of the main genetic manifestations in human cancer, as they have been shown to play an important role in inducing chromosomal instability and in contributing to tumor progression. The purpose of this study was to determine if changes in telomere length occur in serous tubal intraepithelial carcinoma (STIC), the putative precursor of "ovarian" high-grade serous carcinoma (HGSC). Twenty-two STICs from 15 patients with concurrent but discrete HGSCs were analyzed for telomere length on formalin-fixed, paraffin-embedded sections by conducting p53 immunofluorescence to assist in identifying STICs and telomere-specific FISH. Telomere length (short, long, or no change) in STICs was compared with HGSCs using normal fallopian tube epithelium and stromal cells as controls. We found that STICs had the shortest telomeres, as 18 (82%) of 22 STICs had short telomeres, whereas only 2 (9%) showed no change and 2 (9%) had long telomeres compared with the normal-looking tubal epithelium. In contrast, among 12 paired HGSCs and STICs, 6 HGSCs showed an increase in telomere length, one showed a decrease in length and 5 did not show any change when compared with their matched STICs, although, such as STICs, the majority of HGSCs had shorter telomeres than the associated normal tubal epithelial cells. These differences in telomere length between normal tubal epithelial cells and STICs, and between STICs and HGSCs were statisticaly significant (PSTICs provides further support to the proposal that STICs are precursors of HGSC and opens new areas of research in elucidating the early events of ovarian high-grade serous carcinogenesis.
Systematic evaluation of candidate blood markers for detecting ovarian cancer.
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Chana Palmer
2008-07-01
Full Text Available Epithelial ovarian cancer is a significant cause of mortality both in the United States and worldwide, due largely to the high proportion of cases that present at a late stage, when survival is extremely poor. Early detection of epithelial ovarian cancer, and of the serous subtype in particular, is a promising strategy for saving lives. The low prevalence of ovarian cancer makes the development of an adequately sensitive and specific test based on blood markers very challenging. We evaluated the performance of a set of candidate blood markers and combinations of these markers in detecting serous ovarian cancer.We selected 14 candidate blood markers of serous ovarian cancer for which assays were available to measure their levels in serum or plasma, based on our analysis of global gene expression data and on literature searches. We evaluated the performance of these candidate markers individually and in combination by measuring them in overlapping sets of serum (or plasma samples from women with clinically detectable ovarian cancer and women without ovarian cancer. Based on sensitivity at high specificity, we determined that 4 of the 14 candidate markers--MUC16, WFDC2, MSLN and MMP7--warrant further evaluation in precious serum specimens collected months to years prior to clinical diagnosis to assess their utility in early detection. We also reported differences in the performance of these candidate blood markers across histological types of epithelial ovarian cancer.By systematically analyzing the performance of candidate blood markers of ovarian cancer in distinguishing women with clinically apparent ovarian cancer from women without ovarian cancer, we identified a set of serum markers with adequate performance to warrant testing for their ability to identify ovarian cancer months to years prior to clinical diagnosis. We argued for the importance of sensitivity at high specificity and of magnitude of difference in marker levels between cases and
Subtypes of Ovarian Cancer and Ovarian Cancer Screening
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Masafumi Koshiyama
2017-03-01
Full Text Available Ovarian cancer is the foremost cause of gynecological cancer death in the developed world, as it is usually diagnosed at an advanced stage. In this paper we discuss current issues, the efficacy and problems associated with ovarian cancer screening, and compare the characteristics of ovarian cancer subtypes. There are two types of ovarian cancer: Type I carcinomas, which are slow-growing, indolent neoplasms thought to arise from a precursor lesion, which are relatively common in Asia; and Type II carcinomas, which are clinically aggressive neoplasms that can develop de novo from serous tubal intraepithelial carcinomas (STIC and/or ovarian surface epithelium and are common in Europe and the USA. One of the most famous studies on the subject reported that annual screening using CA125/transvaginal sonography (TVS did not reduce the ovarian cancer mortality rate in the USA. In contrast, a recent study in the UK showed an overall average mortality reduction of 20% in the screening group. Another two studies further reported that the screening was associated with decreased stage at detection. Theoretically, annual screening using CA125/TVS could easily detect precursor lesions and could be more effective in Asia than in Europe and the USA. The detection of Type II ovarian carcinoma at an early stage remains an unresolved issue. The resolving power of CA125 or TVS screening alone is unlikely to be successful at resolving STICs. Biomarkers for the early detection of Type II carcinomas such as STICs need to be developed.
Subtypes of Ovarian Cancer and Ovarian Cancer Screening.
Koshiyama, Masafumi; Matsumura, Noriomi; Konishi, Ikuo
2017-03-02
Ovarian cancer is the foremost cause of gynecological cancer death in the developed world, as it is usually diagnosed at an advanced stage. In this paper we discuss current issues, the efficacy and problems associated with ovarian cancer screening, and compare the characteristics of ovarian cancer subtypes. There are two types of ovarian cancer: Type I carcinomas, which are slow-growing, indolent neoplasms thought to arise from a precursor lesion, which are relatively common in Asia; and Type II carcinomas, which are clinically aggressive neoplasms that can develop de novo from serous tubal intraepithelial carcinomas (STIC) and/or ovarian surface epithelium and are common in Europe and the USA. One of the most famous studies on the subject reported that annual screening using CA125/transvaginal sonography (TVS) did not reduce the ovarian cancer mortality rate in the USA. In contrast, a recent study in the UK showed an overall average mortality reduction of 20% in the screening group. Another two studies further reported that the screening was associated with decreased stage at detection. Theoretically, annual screening using CA125/TVS could easily detect precursor lesions and could be more effective in Asia than in Europe and the USA. The detection of Type II ovarian carcinoma at an early stage remains an unresolved issue. The resolving power of CA125 or TVS screening alone is unlikely to be successful at resolving STICs. Biomarkers for the early detection of Type II carcinomas such as STICs need to be developed.
Adult body mass index and risk of ovarian cancer by subtype
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Dixon, Suzanne C; Nagle, Christina M; Thrift, Aaron P
2016-01-01
BACKGROUND: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may......, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would...... be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC. METHODS: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles...
Differential hRad17 expression by histologic subtype of ovarian cancer
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Young Jennifer L
2011-03-01
Full Text Available Abstract Background In the search for unique ovarian cancer biomarkers, ovarian specific cDNA microarray analysis identified hRad17, a cell cycle checkpoint protein, as over-expressed in ovarian cancer. The aim of this study was to validate this expression. Methods Immunohistochemistry was performed on 72 serous, 19 endometrioid, 10 clear cell, and 6 mucinous ovarian cancers, 9 benign ovarian tumors, and 6 normal ovarian tissue sections using an anti-hRad17 antibody. Western blot analysis and quantitative PCR were performed using cell lysates and total RNA prepared from 17 ovarian cancer cell lines and 6 normal ovarian epithelial cell cultures (HOSE. Results Antibody staining confirmed upregulation of hRad17 in 49.5% of ovarian cancer cases. Immunohistochemistry demonstrated that only 42% of serous and 47% of endometrioid subtypes showed overexpression compared to 80% of clear cell and 100% of mucinous cancers. Western blot confirmed overexpression of hRad17 in cancer cell lines compared to HOSE. Quantitative PCR demonstrated an upregulation of hRad17 RNA by 1.5-7 fold. hRad17 RNA expression differed by subtype. Conclusions hRad17 is over-expressed in ovarian cancer. This over-expression varies by subtype suggesting a role in the pathogenesis of these types. Functional studies are needed to determine the potential role of this protein in ovarian cancer.
Vang, Russell; Levine, Douglas A; Soslow, Robert A; Zaloudek, Charles; Shih, Ie-Ming; Kurman, Robert J
2016-01-01
The Cancer Genome Atlas has reported that 96% of ovarian high-grade serous carcinomas (HGSCs) have TP53 somatic mutations suggesting that mutation of this gene is a defining feature of this neoplasm. In the current study, 5 gynecologic pathologists independently evaluated hematoxylin and eosin slides of 14 available cases from The Cancer Genome Atlas classified as HGSC that lacked a TP53 mutation. The histologic diagnoses rendered by these pathologists and the accompanying molecular genetic data are the subject of this report. Only 1 case (Case 5), which contained a homozygous deletion of TP53, had unanimous interobserver agreement for a diagnosis of pure HGSC. In 1 case (Case 3), all 5 observers (100%) rendered a diagnosis of HGSC; however, 3 observers (60%) noted that the histologic features were not classic for HGSC and suggested this case may have arisen from a low-grade serous carcinoma (arisen from an alternate pathway compared with the usual HGSC). In 2 cases (Cases 4 and 12), only 3 observers (60%) in each case, respectively, interpreted it as having a component of HGSC. In the remaining 10 (71%) of tumors (Cases 1, 2, 6-11, 13, and 14), the consensus diagnosis was not HGSC, with individual diagnoses including low-grade serous carcinoma, high-grade endometrioid carcinoma, HGSC, metastatic carcinoma, clear cell carcinoma, atypical proliferative (borderline) serous tumor, and adenocarcinoma, not otherwise specified. Therefore, 13 (93%) of the tumors (Cases 1-4 and 6-14) were either not a pure HGSC or represented a diagnosis other than HGSC, all with molecular results not characteristic of HGSC. Accordingly, our review of the TP53 wild-type HGSCs reported in The Cancer Genome Atlas suggests that 100% of de novo HGSCs contain TP53 somatic mutations or deletions, with the exception of the rare HGSCs that develop from a low-grade serous tumor precursor. We, therefore, propose that lack of molecular alterations of TP53 are essentially inconsistent with the
Sex Steroid Hormone Receptor Expression Affects Ovarian Cancer Survival
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Jönsson, Jenny-Maria; Skovbjerg Arildsen, Nicolai; Malander, Susanne
2015-01-01
BACKGROUND AND AIMS: Although most ovarian cancers express estrogen (ER), progesterone (PR), and androgen (AR) receptors, they are currently not applied in clinical decision making. We explored the prognostic impact of sex steroid hormone receptor protein and mRNA expression on survival...... in epithelial ovarian cancer. METHODS: Immunohistochemical stainings for ERα, ERβ, PR, and AR were assessed in relation to survival in 118 serous and endometrioid ovarian cancers. Expression of the genes encoding the four receptors was studied in relation to prognosis in the molecular subtypes of ovarian cancer...... in ovarian cancer and support that tumors should be stratified based on molecular as well as histological subtypes in future studies investigating the role of endocrine treatment in ovarian cancer....
Nishida, Naoyo; Murakami, Fumihiro; Higaki, Koichi
2016-06-01
The frequency of ovarian cancers in Japan has increased; however, doubts have been raised concerning the mechanism by which high-grade serous adenocarcinomas (HGSCs) arise. Conventionally, HGSC is thought to originate from the ovarian surface epithelium or epithelial inclusion cyst. However, recent data indicate that HGSCs may in fact develop from precursor lesions in the fallopian tube, including epithelia with a p53 signature, serous tubal intraepithelial carcinomas (STICs), secretory cell outgrowths (SCOUTs), and tubal intraepithelial lesions in transition (TILT). Here, we determined the frequency of these fallopian tube precursors in surgically excised samples from 123 patients with benign pelvic diseases. We identified 12 cases with a p53 signature (9.7%), 26 with observable SCOUTs (21.1%), and 4 with TILT (3.2%), but no STIC cases. Although the lifetime risk for developing ovarian cancer is only around 1.4% for women without germ-line mutations, it is important to evaluate the presence of precursor lesions to understand HGSC pathogenesis better. Taken together, salpingectomy appears to be an option for women who are past their childbearing age and plan to undergo elective pelvic surgery. To our knowledge, this is the first study to investigate the presence of these specific precursors post-salpingectomy in low-risk patients. © 2016 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.
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Amankwah, Ernest K; Wang, Qinggang; Schildkraut, Joellen M
2011-01-01
Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among...... and replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (P(heterogeneity)≥0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; P(trend) = 0.001 to 0.03). Results from replication set 2 were statistically...... homogeneous (P(heterogeneity)≥0.13) and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; P(trend)≤0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (P(heterogeneity)≤0.03), which precluded combining. In post...
Yang, Qiuyun; Zhao, Jinghe; Cui, Manhua; Gi, Shuting; Wang, Wei; Han, Xiaole
2015-12-01
Recent studies have demonstrated that the neural precursor cell expressed, developmentally downregulated 4-like (Nedd4L) gene plays a role in the progression of various cancers. However, reports describing Nedd4L expression in ovarian cancer tissues are limited. A cohort (n = 117) of archival formalin-fixed, paraffin embedded resected normal ovarian epithelial tissues (n = 10), benign ovarian epithelial tumor tissues (n = 10), serous borderline ovarian epithelial tumor tissues (n = 14), mucous borderline ovarian epithelial tumor tissues (n = 11), and invasive ovarian epithelial cancer tissues (n = 72) were assessed for Nedd4L protein expression using immunohistochemistry. Nedd4L protein expression was significantly decreased in invasive ovarian epithelial cancer tissues compared to non-cancer tissues (P < 0.05). Decreased Nedd4L protein expression correlated with clinical stage, pathological grade, lymph node metastasis and survival (P < 0.05). Nedd4L protein expression may be an independent prognostic marker of ovarian cancer development. © 2015 Japan Society of Obstetrics and Gynecology.
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Tess eSchenberg
2014-02-01
Full Text Available Risk-reducing bilateral salpingo-oophorectomy is a proven strategy to reduce the risk of serous ovarian cancer associated with germline BRCA mutations. It is most effective when performed before natural menopause but it will render a woman prematurely menopausal. The tubal hypothesis of serous ovarian cancer brings with it the possibility of the alternative surgical approach in younger women comprising of risk-reducing bilateral salpingectomy while conserving their ovaries until nearer the age of natural menopause when a delayed bilateral oophorectomy can be performed. This article will review the evidence behind the tubal hypothesis of serous ovarian cancer and explore the opportunities for translating this into clinical cancer prevention practice.
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Shen, Hui; Fridley, Brooke L; Song, Honglin
2013-01-01
HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we...... comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs......11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous...
International Nuclear Information System (INIS)
Koti, Madhuri; Evans, Kenneth; Feilotter, Harriet E; Park, Paul C; Squire, Jeremy A; Gooding, Robert J; Nuin, Paulo; Haslehurst, Alexandria; Crane, Colleen; Weberpals, Johanne; Childs, Timothy; Bryson, Peter; Dharsee, Moyez
2013-01-01
Resistance to platinum-based chemotherapy remains a major impediment in the treatment of serous epithelial ovarian cancer. The objective of this study was to use gene expression profiling to delineate major deregulated pathways and biomarkers associated with the development of intrinsic chemotherapy resistance upon exposure to standard first-line therapy for ovarian cancer. The study cohort comprised 28 patients divided into two groups based on their varying sensitivity to first-line chemotherapy using progression free survival (PFS) as a surrogate of response. All 28 patients had advanced stage, high-grade serous ovarian cancer, and were treated with standard platinum-based chemotherapy. Twelve patient tumours demonstrating relative resistance to platinum chemotherapy corresponding to shorter PFS (< eight months) were compared to sixteen tumours from platinum-sensitive patients (PFS > eighteen months). Whole transcriptome profiling was performed using an Affymetrix high-resolution microarray platform to permit global comparisons of gene expression profiles between tumours from the resistant group and the sensitive group. Microarray data analysis revealed a set of 204 discriminating genes possessing expression levels which could influence differential chemotherapy response between the two groups. Robust statistical testing was then performed which eliminated a dependence on the normalization algorithm employed, producing a restricted list of differentially regulated genes, and which found IGF1 to be the most strongly differentially expressed gene. Pathway analysis, based on the list of 204 genes, revealed enrichment in genes primarily involved in the IGF1/PI3K/NF κB/ERK gene signalling networks. This study has identified pathway specific prognostic biomarkers possibly underlying a differential chemotherapy response in patients undergoing standard platinum-based treatment of serous epithelial ovarian cancer. In addition, our results provide a pathway context for
Features of ovarian cancer in Lynch syndrome (Review).
Nakamura, Kanako; Banno, Kouji; Yanokura, Megumi; Iida, Miho; Adachi, Masataka; Masuda, Kenta; Ueki, Arisa; Kobayashi, Yusuke; Nomura, Hiroyuki; Hirasawa, Akira; Tominaga, Eiichiro; Aoki, Daisuke
2014-11-01
Lynch syndrome is a hereditary ovarian cancer with a prevalence of 0.9-2.7%. Lynch syndrome accounts for 10-15% of hereditary ovarian cancers, while hereditary breast and ovarian cancer syndrome accounts for 65-75% of these cancers. The lifetime risk for ovarian cancer in families with Lynch syndrome is ~8%, which is lower than colorectal and endometrial cancers, and ovarian cancer is not listed in the Amsterdam Criteria II. More than half of sporadic ovarian cancers are diagnosed in stage III or IV, but ≥80% of ovarian cancers in Lynch syndrome are diagnosed in stage I or II. Ovarian cancers in Lynch syndrome mostly have non-serous histology and different properties from those of sporadic ovarian cancers. A screening method for ovarian cancers in Lynch syndrome has yet to be established and clinical studies of prophylactic administration of oral contraceptives are not available. However, molecular profiles at the genetic level indicate that ovarian cancer in Lynch syndrome has a more favorable prognosis than sporadic ovarian cancer. Inhibitors of the phosphatidylinositol 3-kinase/mammalian target of the rapamycin pathway and anti-epidermal growth factor antibodies may have efficacy for the disease. To the best of our knowledge, this is the first review focusing on ovarian cancer in Lynch syndrome.
Characterization of aldehyde dehydrogenase isozymes in ovarian cancer tissues and sphere cultures
International Nuclear Information System (INIS)
Saw, Yu-Ting; Thompson, David; Vasiliou, Vasilis; Berkowitz, Ross S; Ng, Shu-Wing; Yang, Junzheng; Ng, Shu-Kay; Liu, Shubai; Singh, Surendra; Singh, Margit; Welch, William R; Tsuda, Hiroshi; Fong, Wing-Ping
2012-01-01
Aldehyde dehydrogenases belong to a superfamily of detoxifying enzymes that protect cells from carcinogenic aldehydes. Of the superfamily, ALDH1A1 has gained most attention because current studies have shown that its expression is associated with human cancer stem cells. However, ALDH1A1 is only one of the 19 human ALDH subfamilies currently known. The purpose of the present study was to determine if the expression and activities of other major ALDH isozymes are associated with human ovarian cancer and ovarian cancer sphere cultures. Immunohistochemistry was used to delineate ALDH isozyme localization in clinical ovarian tissues. Western Blot analyses were performed on lysates prepared from cancer cell lines and ovarian cancer spheres to confirm the immunohistochemistry findings. Quantitative reverse transcription-polymerase chain reactions were used to measure the mRNA expression levels. The Aldefluor® assay was used to measure ALDH activity in cancer cells from the four tumor subtypes. Immunohistochemical staining showed significant overexpression of ALDH1A3, ALDH3A2, and ALDH7A1 isozymes in ovarian tumors relative to normal ovarian tissues. The expression and activity of ALDH1A1 is tumor type-dependent, as seen from immunohistochemisty, Western blot analysis, and the Aldefluor® assay. The expression was elevated in the mucinous and endometrioid ovarian epithelial tumors than in serous and clear cell tumors. In some serous and most clear cell tumors, ALDH1A1 expression was found in the stromal fibroblasts. RNA expression of all studied ALDH isozymes also showed higher expression in endometrioid and mucinous tumors than in the serous and clear cell subtypes. The expression of ALDH enzymes showed tumor type-dependent induction in ovarian cancer cells growing as sphere suspensions in serum-free medium. The results of our study indicate that ALDH enzyme expression and activity may be associated with specific cell types in ovarian tumor tissues and vary according to
STICS, SCOUTs and p53 signatures; a new language for pelvic serous carcinogenesis.
Mehra, Karishma; Mehrad, Mitra; Ning, Geng; Drapkin, Ronny; McKeon, Frank D; Xian, Wa; Crum, Christopher P
2011-01-01
The events leading to the most common and most lethal ovarian carcinoma - high grade serous carcinoma - have been poorly understood. However, the detailed pathologic study of asymptomatic women with germ-line BRCA 1 or BRCA2 (BCRA+) mutations has unearthed an early malignancy, serous tubal intraepithelial carcinomas (STIC), which has linked many peritoneal and ovarian serous carcinomas to the fimbria. The distinction between high-grade serous and endometrioid carcinomas continues to narrow, with shared alterations in expression of pTEN, PAX2 and p53. Moreover, the discovery of clonal alterations in p53 in benign tubal epithelium, - p53 signatures - has established a foundation for a serous cancer precursor in the fimbria. We have expanded this concept to include a generic secretory cell outgrowth (SCOUT) in the fallopian tube that is associated with altered PAX2 expression. As the repertoire of gene alterations is expanded and its link to serous carcinogenesis clarified, a cogent pathway to high-grade Mullerian carcinomas will emerge. This will challenge conventional thinking about ovarian carcinogenesis but will provide a new template for studies of ovarian cancer prevention.
Epidemiology of ovarian cancers in Zaria, Northern Nigeria: a 10-year study
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Zayyan MS
2017-11-01
Full Text Available Marliyya Sanusi Zayyan,1 Saad Aliyu Ahmed,2 Adekunle O Oguntayo,1 Abimbola O Kolawole,1 Tajudeen Ayodeji Olasinde3 1Gynaecological Oncology Unit, 2Department of Histopathology, 3Department of Radiation Oncology, Ahmadu Bello University, Zaria, Nigeria Background: Globally, the absence of a premalignant stage of ovarian cancer and a reliable screening tool make early diagnosis difficult. Locally, poverty, ignorance, and lack of organized cancer services make prognosis poor. We describe the epidemiological features of ovarian cancer seen at Ahmadu Bello University Teaching Hospital Zaria, Northern Nigeria, a tertiary referral center, over a 10-year period in this challenging setting. Methods: All cases of histologically diagnosed ovarian cancer between January 1, 2004 and December 31, 2013 were included in the study. Case notes were retrieved to collect clinical data including age, parity, clinical stage of disease at presentation, and known associated factors. Results were analyzed using Epi info™. Results: A total of 78 patients were included in the study. About 4–13 cases were seen every year with a tendency to increasing incidence. The patients were aged 8–80 years with mean of 37 years. Sixty-two (79.5% patients were premenopausal while postmenopausal women accounted for only seven cases or 9.0%. There were 17 cases (22.3% of aggressive cancers in patients aged ≤20 years. A majority of the patients, 65 (83.3%, were parous with only nine (11.5% patients being nulliparous. Serous cyst adenocarcinoma accounted for 32 (41% cases. Granulosa cell tumor was the second commonest with 18 cases (23.1%. The mean age of occurrence of serous cyst adenocarcinoma was 31 years and for epithelial ovarian cancers in general it was 33.5 years. Endometrioid adenocarcinoma was rare with only one case in 10 years. Factors like age, parity, and premenopausal status did not appear to be protective to the occurrence of malignant ovarian tumor in this group
Avijeet; Naveen; Manohar; Gopal
2013-01-01
ABSTRACT: Ovarian cancer accounts for 5% of all cancers among women and causes more deaths than any other female genital tract cancer. The majority (85-90%) of ovarian cancers is epithelial in origin and arises typically in postmenopa usal patients. An ovarian serous cystadenocarcinoma forms the malignant end of ovari an serous tumours. It is the most common malignant ovarian tumor and is derived from glandul ar epithelium, in which cystic accumulations of ret...
Emmanuel, Catherine; Gava, Natalie; Kennedy, Catherine; Balleine, Rosemary L.; Sharma, Raghwa; Wain, Gerard; Brand, Alison; Hogg, Russell; Etemadmoghadam, Dariush; George, Joshy; Birrer, Michael J.; Clarke, Christine L.; Chenevix-Trench, Georgia; Bowtell, David D. L.; Harnett, Paul R.; deFazio, Anna
2011-01-01
Molecular events leading to epithelial ovarian cancer are poorly understood but ovulatory hormones and a high number of life-time ovulations with concomitant proliferation, apoptosis, and inflammation, increases risk. We identified genes that are regulated during the estrous cycle in murine ovarian surface epithelium and analysed these profiles to identify genes dysregulated in human ovarian cancer, using publically available datasets. We identified 338 genes that are regulated in murine ovarian surface epithelium during the estrous cycle and dysregulated in ovarian cancer. Six of seven candidates selected for immunohistochemical validation were expressed in serous ovarian cancer, inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium. Most were overexpressed in ovarian cancer compared with ovarian surface epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2 were expressed as highly in fallopian tube epithelium as in ovarian cancer. We prioritised the 338 genes for those likely to be important for ovarian cancer development by in silico analyses of copy number aberration and mutation using publically available datasets and identified genes with established roles in ovarian cancer as well as novel genes for which we have evidence for involvement in ovarian cancer. Chromosome segregation emerged as an important process in which genes from our list of 338 were over-represented including two (BUB1, NCAPD2) for which there is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface epithelium in proestrus and predicted to have a driver mutation in ovarian cancer, was examined in a larger cohort of serous ovarian cancer where patients with lower NUAK2 expression had shorter overall survival. In conclusion, defining genes that are activated in normal epithelium in the course of ovulation that are also dysregulated in cancer has identified a number of pathways and novel candidate genes that may contribute
Kurman, Robert J.; Vang, Russell; Junge, Jette; Hannibal, Charlotte Gerd; Kjaer, Susanne K.; Shih, Ie-Ming
2011-01-01
In contrast to the controversy regarding the terminology and behavior of ovarian noninvasive low-grade serous tumors (atypical proliferative serous tumor [APST] and serous borderline tumor [SBT]), little attention has been directed to their origin. Similarly, until recently, proliferative lesions in the fallopian tube have not been extensively studied. The recent proposal that ovarian high-grade serous carcinomas are derived from intraepithelial carcinoma in the fallopian tube prompted us to evaluate the possible role of the fallopian tube in the genesis of low-grade serous tumors. We have identified a lesion, designated “papillary tubal hyperplasia (PTH)”, characterized by small rounded clusters of tubal epithelial cells and small papillae, with or without associated psammoma bodies, that are present within the tubal lumen and which are frequently associated with APSTs. Twenty-two cases in this study were selected from a population-based study in Denmark of approximately 1000 patients with low-grade ovarian serous tumors in whom implants were identified on the fallopian tube. Seven additional cases were seen recently in consultation at The Johns Hopkins Hospital (JHH). These 7 cases were not associated with an ovarian tumor. Papillary tubal hyperplasia was found in 20 (91%) of the 22 cases in the Danish study. Based on this association of PTH with APSTs with implants and the close morphologic resemblance of PTH, not only to the primary ovarian APSTs but also to the noninvasive epithelial implants and endosalpingiosis, we speculate that the small papillae and clusters of cells from the fallopian tubes implant on ovarian and peritoneal surfaces to produce these lesions. The 7 JHH cases of PTH that were not associated with an ovarian tumor support the view that PTH is the likely precursor lesion. We propose a model for the development of ovarian and extraovarian low-grade serous proliferations (APST, noninvasive epithelial implants and endosalpingiosis) that
Aurora-A overexpression and aneuploidy predict poor outcome in serous ovarian carcinoma.
Lassus, Heini; Staff, Synnöve; Leminen, Arto; Isola, Jorma; Butzow, Ralf
2011-01-01
Aurora-A is a potential oncogene and therapeutic target in ovarian carcinoma. It is involved in mitotic events and overexpression leads to centrosome amplification and chromosomal instability. The objective of this study was to evaluate the clinical significance of Aurora-A and DNA ploidy in serous ovarian carcinoma. Serous ovarian carcinomas were analysed for Aurora-A protein by immunohistochemistry (n=592), Aurora-A copy number by CISH (n=169), Aurora-A mRNA by real-time PCR (n=158) and DNA ploidy by flowcytometry (n=440). Overexpression of Aurora-A was found in 27% of the tumors, cytoplasmic overexpression in 11% and nuclear in 17%. The cytoplasmic and nuclear overexpression were nearly mutually exclusive. Both cytoplasmic and nuclear overexpression were associated with shorter survival, high grade, high proliferation index and aberrant p53. Interestingly, only cytoplasmic expression was associated with aneuploidy and expression of phosphorylated Aurora-A. DNA ploidy was associated with poor patient outcome as well as aggressive clinicopathological parameters. In multivariate analysis, Aurora-A overexpression appeared as an independent prognostic factor for disease-free survival, together with grade, stage and ploidy. Aurora-A protein expression is strongly linked with poor patient outcome and aggressive disease characteristics, which makes Aurora-A a promising biomarker and a potential therapeutic target in ovarian carcinoma. Cytoplasmic and nuclear Aurora-A protein may have different functions. DNA aneuploidy is a strong predictor of poor prognosis in serous ovarian carcinoma. Copyright © 2010 Elsevier Inc. All rights reserved.
Survival-related profile, pathways, and transcription factors in ovarian cancer.
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Anne P G Crijns
2009-02-01
Full Text Available BACKGROUND: Ovarian cancer has a poor prognosis due to advanced stage at presentation and either intrinsic or acquired resistance to classic cytotoxic drugs such as platinum and taxoids. Recent large clinical trials with different combinations and sequences of classic cytotoxic drugs indicate that further significant improvement in prognosis by this type of drugs is not to be expected. Currently a large number of drugs, targeting dysregulated molecular pathways in cancer cells have been developed and are introduced in the clinic. A major challenge is to identify those patients who will benefit from drugs targeting these specific dysregulated pathways.The aims of our study were (1 to develop a gene expression profile associated with overall survival in advanced stage serous ovarian cancer, (2 to assess the association of pathways and transcription factors with overall survival, and (3 to validate our identified profile and pathways/transcription factors in an independent set of ovarian cancers. METHODS AND FINDINGS: According to a randomized design, profiling of 157 advanced stage serous ovarian cancers was performed in duplicate using approximately 35,000 70-mer oligonucleotide microarrays. A continuous predictor of overall survival was built taking into account well-known issues in microarray analysis, such as multiple testing and overfitting. A functional class scoring analysis was utilized to assess pathways/transcription factors for their association with overall survival. The prognostic value of genes that constitute our overall survival profile was validated on a fully independent, publicly available dataset of 118 well-defined primary serous ovarian cancers. Furthermore, functional class scoring analysis was also performed on this independent dataset to assess the similarities with results from our own dataset. An 86-gene overall survival profile discriminated between patients with unfavorable and favorable prognosis (median survival, 19
[Ovarian cancer. II. Procedures, histology, and complications].
Szpakowski, M; Nowak, M; Malinowski, A; Romanowicz, H; Wieczorek, A; Szpakowski, A; Raczkowska, Z; Władziński, J; Wilczyński, J R; Kamiński, T; Maciołek-Blewniewska, G
2000-09-01
The purpose of our study was to analyse the operative procedures and complications in patients operated for the first time for ovarian cancer. A retrospective review of patients' charts with ovarian cancer operated at the Department of Gynaecological Surgery of Polish Mother's Memorial Hospital-Research Institute in 1990-1999 was conducted. We analysed the data of women operated for the first time for this disease. In every case we tried to perform radical operation consisted of hysterectomy with bilateral adnexectomy, omentectomy, appendectomy (if needed), and additionally optimal debulking in advanced cancer. Between January 1990 and December 1999, 107 patients were operated for the first time for ovarian cancer. FIGO staging was as follows: I--13.1%, II--14.95%, III--59.8%, IV--12.15%. The most frequent findings on histology were serous (39.3%), endometrioid (26.2%), undifferentiated (11.2%) and clear cell cancers (10.7%). In 60.7% of cases we performed hysterectomy with bilateral adnexectomy, in 15.0% bilateral adnexectomy, in 4.7% of patients cytoreductive tumorectomy, and in 19.6% of cases only excisions for histology were taken. 69.0% of patients underwent also omentectomy and 42.6% appendectomy. In 58.9% of patients we performed radical operation; its incidence significantly decreased with the increase of FIGO staging: I--100%, II--87.5%, III--51.6%, IV--15.4% (p serous and endometrioid ovarian cancer. The great majority of patients was diagnosed to late and operated in III and IV stage of the disease, but in almost 60% of cases radical operation was performed.
Characterization of aldehyde dehydrogenase isozymes in ovarian cancer tissues and sphere cultures
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Saw Yu-Ting
2012-08-01
Full Text Available Abstract Background Aldehyde dehydrogenases belong to a superfamily of detoxifying enzymes that protect cells from carcinogenic aldehydes. Of the superfamily, ALDH1A1 has gained most attention because current studies have shown that its expression is associated with human cancer stem cells. However, ALDH1A1 is only one of the 19 human ALDH subfamilies currently known. The purpose of the present study was to determine if the expression and activities of other major ALDH isozymes are associated with human ovarian cancer and ovarian cancer sphere cultures. Methods Immunohistochemistry was used to delineate ALDH isozyme localization in clinical ovarian tissues. Western Blot analyses were performed on lysates prepared from cancer cell lines and ovarian cancer spheres to confirm the immunohistochemistry findings. Quantitative reverse transcription-polymerase chain reactions were used to measure the mRNA expression levels. The Aldefluor® assay was used to measure ALDH activity in cancer cells from the four tumor subtypes. Results Immunohistochemical staining showed significant overexpression of ALDH1A3, ALDH3A2, and ALDH7A1 isozymes in ovarian tumors relative to normal ovarian tissues. The expression and activity of ALDH1A1 is tumor type-dependent, as seen from immunohistochemisty, Western blot analysis, and the Aldefluor® assay. The expression was elevated in the mucinous and endometrioid ovarian epithelial tumors than in serous and clear cell tumors. In some serous and most clear cell tumors, ALDH1A1 expression was found in the stromal fibroblasts. RNA expression of all studied ALDH isozymes also showed higher expression in endometrioid and mucinous tumors than in the serous and clear cell subtypes. The expression of ALDH enzymes showed tumor type-dependent induction in ovarian cancer cells growing as sphere suspensions in serum-free medium. Conclusions The results of our study indicate that ALDH enzyme expression and activity may be associated
Auer, Katharina; Bachmayr-Heyda, Anna; Aust, Stefanie; Grunt, Thomas W; Pils, Dietmar
2017-03-01
High grade serous ovarian cancer (HGSOC) is characterized by extensive local, i.e. peritoneal, tumor spread, manifested in two different clinical presentations, miliary (many millet sized peritoneal implants) and non-miliary (few large exophytically growing peritoneal nodes), and an overall unfavorable outcome. HGSOC is thought to arise from fallopian tube secretory epithelial cells, via so called serous tubal intraepithelial carcinomas (STICs) but an ovarian origin was never ruled out for at least some cases. Comparative transcriptome analyses of isolated tumor cells from fresh HGSOC tissues and (immortalized) ovarian surface epithelial and fallopian tube secretory epithelial cell lines revealed a close relation between putative origin and tumor spread characteristic, i.e. miliary from tubes and non-miliary from ovaries. The latter were characterized by more mesenchymal cell characteristics, more adaptive tumor immune infiltration, and a favorable overall survival. Several molecular sub-classification systems (Crijns' overall survival signature, Yoshihara's subclasses, and a collagen-remodeling signature) seem to already indicate origin. Putative origin alone is a significant independent predictor for HGSOC outcome, validated in independent patient cohorts. Characteristics of both spread types could guide development of new targeted therapeutics, which are urgently needed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
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Lee, Alice W; Bomkamp, Ashley; Bandera, Elisa V
2016-01-01
Menopausal estrogen-alone therapy (ET) is a well-established risk factor for serous and endometrioid ovarian cancer. Genetics also plays a role in ovarian cancer, which is partly attributable to 18 confirmed ovarian cancer susceptibility loci identified by genome-wide association studies. The int...
The role of the fallopian tube in ovarian cancer.
Tone, Alicia A; Salvador, Shannon; Finlayson, Sarah J; Tinker, Anna V; Kwon, Janice S; Lee, Cheng-Han; Cohen, Trevor; Ehlen, Tom; Lee, Marette; Carey, Mark S; Heywood, Mark; Pike, Judith; Hoskins, Paul J; Stuart, Gavin C; Swenerton, Kenneth D; Huntsman, David G; Gilks, C Blake; Miller, Dianne M; McAlpine, Jessica N
2012-05-01
High-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer. Research over the past decade has strongly suggested that "ovarian" HGSC arises in the epithelium of the distal fallopian tube, with serous tubal intraepithelial carcinomas (STICs) being detected in 5-10% of BRCA1/2 mutation carriers undergoing risk-reducing surgery and up to 60% of unselected women with pelvic HGSC. The natural history, clinical significance, and prevalence of STICs in the general population (ie, women without cancer and not at an increased genetic risk) are incompletely understood, but anecdotal evidence suggests that these lesions have the ability to shed cells with metastatic potential into the peritoneal cavity very early on. Removal of the fallopian tube (salpingectomy) in both the average and high-risk populations could therefore prevent HGSC, by eliminating the site of initiation and interrupting spread of potentially cancerous cells to the ovarian/peritoneal surfaces. Salpingectomy may also reduce the incidence of the 2 next most common subtypes, endometrioid and clear cell carcinoma, by blocking the passageway linking the lower genital tract to the peritoneal cavity that enables ascension of endometrium and factors that induce local inflammation. The implementation of salpingectomy therefore promises to significantly impact ovarian cancer incidence and outcomes.
Canine ovarian serous papillary adenocarcinoma with neoplastic hypercalcemia.
Hori, Yasutomo; Uechi, Masami; Kanakubo, Kayo; Sano, Tadashi; Oyamada, Toshifumi
2006-09-01
A female golden retriever was referred to assess a history of a palpable abdominal mass. A serum chemistry analysis revealed elevated concentrations of blood urea nitrogen, creatinine, calcium, and parathyroid hormone-related protein (PTH-rP). Exploratory laparotomy revealed an ovoid mass within the right ovary. This mass was removed surgically by performing an ovariohysterectomy. The right ovarian mass was diagnosed as a serous papillary adenocarcinoma. Following surgery, the dog recovered, and the serum calcium and PTH-rP concentrations decreased. Therefore, concentrations of PTH-rP and calcium might be associated with serous papillary adenocarcinomas. Serial evaluation of the serum PTH-rP and calcium was useful for evaluating the prognosis.
Ivy, S Percy; Liu, Joyce F; Lee, Jung-Min; Matulonis, Ursula A; Kohn, Elise C
2016-01-01
An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC. Preclinical and clinical studies of single agent cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts. Advances in the treatment of HGSOC that improve progression-free and overall survival have proven elusive despite examination of molecularly targeted therapy. HGSOC patients with deleterious germline or somatic mutations in BRCA1 or BRCA2 (BRCAm) are most responsive to PARP inhibitors (PARPi). PARPi combined with angiogenesis inhibition improved anti-cancer response and duration in both BRCAm and BRCA wild type HGSOC patients, compared to olaparib single agent treatment, demonstrating therapeutic chemical and contextual synthetic lethality.
Plexin-B1 silencing inhibits ovarian cancer cell migration and invasion
International Nuclear Information System (INIS)
Ye, Shuangmei; Chen, Yin; You, Lanying; Zhang, Yiqun; Xu, Gang; Zhou, Jianfeng; Ma, Ding; Wang, Shixuan; Hao, Xing; Zhou, Ting; Wu, Mingfu; Wei, Juncheng; Wang, Yongjun; Zhou, Li; Jiang, Xuefeng; Ji, Li
2010-01-01
Elevated Plexin-B1 expression has been found in diverse human cancers and in non-neoplastic tissues, and it mediates diverse biological and pathological activities. However, whether or not Plexin-B1 expression is involved in human ovarian tumors remains unclear. In the present study, Plexin-B1 expression was explored in benign and malignant human ovarian tumor tissues. In addition, the impact of Plexin-B1 expression on ovarian cancer cell proliferation, migration and invasion were investigated in vitro. Plexin-B1 expression was analyzed in normal and benign ovarian tissues and serous ovarian tumors (both borderline and malignant) by immunohistochemical staining, as well as in four human ovarian cancer cell lines (A2780, C13*, SKOV3, and OV2008) by RT-PCR and western blot analyses. Furthermore, endogenous Plexin-B1 expression was suppressed by Plexin-B1 siRNA in SKOV3 cells, which overexpress Plexin-B1. Protein levels of Plexin-B1, AKT and AKT Ser473 were examined by western blot analysis. Cell proliferation, migration and invasion were measured with MTT, wound healing and boyden chamber assays, respectively, and the cytoskeleton was monitored via F-actin staining. Expression levels of Plexin-B1 protein were significantly higher in serous ovarian carcinomas than in normal ovaries or benign ovarian neoplasms, and in the former, Plexin-B1 expression was positively correlated with lymphatic metastasis, and the membrane and cytoplasm of cancer cells stained positively. SKOV3 cells displayed the highest Plexin-B1 expression at both the mRNA and protein levels among the four tested human ovarian cancer cell lines and was selected as a cell model for further in vitro experiments. Plexin-B1 siRNA significantly suppressed phosphorylation of AKT at Ser473 in SKOV3 cells, but it did not alter total AKT expression. In addition, silencing of Plexin-B1 in SKOV3 cells inhibited cell migration and invasion and reorganized the cytoskeleton, whereas cell proliferation was not
Prostate Cancer Susceptibility Polymorphism rs2660753 Is Not Associated with Invasive Ovarian Cancer
DEFF Research Database (Denmark)
Amankwah, Ernest K; Kelemen, Linda E; Wang, Qinggang
2011-01-01
BACKGROUND: We previously reported an association between rs2660753, a prostate cancer susceptibility polymorphism, and invasive epithelial ovarian cancer (EOC; OR = 1.2, 95% CI=1.0-1.4, P(trend) = 0.01) that showed a stronger association with the serous histological subtype (OR = 1.3, 95% CI = 1...
2018-02-14
Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Brenner Tumor; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Stage IIA Fallopian Tube Cancer AJCC v6 and v7; Stage IIA Ovarian Cancer AJCC V6 and v7; Stage IIB Fallopian Tube Cancer AJCC v6 and v7; Stage IIB Ovarian Cancer AJCC v6 and v7; Stage IIC Fallopian Tube Cancer AJCC v6 and v7; Stage IIC Ovarian Cancer AJCC v6 and v7; Stage IIIA Fallopian Tube Cancer AJCC v7; Stage IIIA Ovarian Cancer AJCC v6 and v7; Stage IIIA Primary Peritoneal Cancer AJCC v7; Stage IIIB Fallopian Tube Cancer AJCC v7; Stage IIIB Ovarian Cancer AJCC v6 and v7; Stage IIIB Primary Peritoneal Cancer AJCC v7; Stage IIIC Fallopian Tube Cancer AJCC v7; Stage IIIC Ovarian Cancer AJCC v6 and v7; Stage IIIC Primary Peritoneal Cancer AJCC v7; Stage IV Fallopian Tube Cancer AJCC v6 and v7; Stage IV Ovarian Cancer AJCC v6 and v7; Stage IV Primary Peritoneal Cancer AJCC v7; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma
[Microcytomorphometric video-image detection of nuclear chromatin in ovarian cancer].
Grzonka, Dariusz; Kamiński, Kazimierz; Kaźmierczak, Wojciech
2003-09-01
Technology of detection of tissue preparates precisious evaluates contents of nuclear chromatine, largeness and shape of cellular nucleus, indicators of mitosis, DNA index, ploidy, phase-S fraction and other parameters. Methods of detection of picture are: microcytomorphometry video-image (MCMM-VI), flow, double flow and activated by fluorescence. Diagnostic methods of malignant neoplasm of ovary are still nonspecific and not precise, that is a reason of unsatisfied results of treatment. Evaluation of microcytomorphometric measurements of nuclear chromatine histopathologic tissue preparates (HP) of ovarian cancer and comparison to normal ovarian tissue. Estimated 10 paraffin embedded tissue preparates of serous ovarian cancer, 4 preparates mucinous cancer and 2 cases of tumor Kruckenberg patients operated in Clinic of Perinatology and Gynaecology Silesian Medical Academy in Zabrze in period 2001-2002, MCMM-VI estimation based on computer aided analysis system: microscope Axioscop 20, camera tv JVCTK-C 1380, CarlZeiss KS Vision 400 rel.3.0 software. Following MCMM-VI parameters assessed: count of pathologic nucleus, diameter of nucleus, area, min/max diameter ratio, equivalent circle diameter (Dcircle), mean of brightness (mean D), integrated optical density (IOD = area x mean D), DNA index and 2.5 c exceeding rate percentage (2.5 c ER%). MCMM-VI performed on the 160 areas of 16 preparates of cancer and 100 areas of normal ovarian tissue. Statistical analysis was performed by used t-Student test. We obtained stastistically significant higher values parameters of nuclear chromatine, DI, 2.5 c ER of mucinous cancer and tumor Kruckenberg comparison to serous cancer. MCMM-VI parameters of chromatine malignant ovarian neoplasm were statistically significantly higher than normal ovarian tissue. Cytometric and karyometric parametres of nuclear chromatine estimated MCMM-VI are useful in the diagnostics and prognosis of ovarian cancer.
Directory of Open Access Journals (Sweden)
Jayaprakash Aravindakshan
2006-12-01
Full Text Available Ovarian cancer is a deadly disease with long latency. To understand the consequences of loss of folliclestimulating hormone receptor (FSH-R signaling and to explore why the atrophic and anovulatory ovaries of follitropin receptor knockout (FORKO mice develop different types of ovarian tumors, including serous papillary epithelial adenoma later in life, we used mRNA expression profiling to gain a comprehensive view of misregulated genes. Using real-time quantitative reverse transcription-polymerase chain reaction, protein analysis, and cellular localization, we show, for the first time, in vivo evidence that, in the absence of FSH-R signaling, claudin-3, claudin-4, and claudin-11 are selectively upregulated, whereas claudin-1 decreases in ovarian surface epithelium and tumors in comparison to wild type. In vitro experiments using a mouse ovarian surface epithelial cell line derived from wild-type females reveal direct hormonal influence on claudin proteins. Although recent studies suggest that cell junction proteins are differentially expressed in ovarian tumors in women, the etiology of such changes remains unclear. Our results suggest an altered hormonal environment resulting from FSH-R loss as a cause of early changes in tight junction proteins that predispose the ovary to late-onset tumors that occur with aging. More importantly, this study identifies claudin-11 overexpression in mouse ovarian serous cystadenoma.
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Kohei Nakamura
2016-04-01
Full Text Available Ovarian low-grade serous carcinoma is thought to begin as a serous cystadenoma or adenofibroma that progresses in a slow stepwise fashion. Among the low-grade serous carcinomas, there is a high frequency of activating mutations in the KRAS or BRAF genes; however, it remains unclear as to how these mutations contribute to tumor progression. This is the first report to track the histopathological progression of serous adenofibroma to low-grade serous carcinoma. Each stage was individually analyzed by pathological and molecular genetic methods to determine what differences occur between the distinct stages of progression.
DEFF Research Database (Denmark)
Gosvig, Camilla F; Kjaer, Susanne K; Blaakær, Jan
2015-01-01
BACKGROUND: Epidemiological studies that have investigated the association between coffee, tea and caffeine consumption and ovarian cancer risk have produced conflicting results. Furthermore, only few studies have examined the role of coffee and tea consumption separately for borderline ovarian...... tumors. By use of data from a large Danish population-based case-control study, we examined the risk of ovarian tumors associated with coffee, tea, and caffeine consumption with a particular focus on characterizing risks by tumor behavior and histology. MATERIAL AND METHODS: From 1995 through 1999, we....... RESULTS: Both coffee (OR = 0.90; 95% CI 0.84-0.97 per cup/day) and total caffeine consumption from coffee and tea combined (OR = 0.93; 95% CI 0.88-0.98 per 100 mg/day) decreased the risk of ovarian cancer. These associations were significant only for the serous and "other" subtypes of ovarian cancer...
Profiles of Genomic Instability in High-Grade Serous Ovarian Cancer Predict Treatment Outcome
DEFF Research Database (Denmark)
Wang, Zhigang C.; Birkbak, Nicolai Juul; Culhane, Aedín C.
2012-01-01
Purpose: High-grade serous cancer (HGSC) is the most common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR cause...
Shen, Hui; Fridley, Brooke L.; Song, Honglin; Lawrenson, Kate; Cunningham, Julie M.; Ramus, Susan J.; Cicek, Mine S.; Tyrer, Jonathan; Stram, Douglas; Larson, Melissa C.; Köbel, Martin; Ziogas, Argyrios; Zheng, Wei; Yang, Hannah P.; Wu, Anna H.
2013-01-01
HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide poly...
Termination of Pregnancy in a Patient with Advanced Ovarian Cancer
Suna Özdemir; Çetin Çelik; Kazım Gezginç; Hasan Esen
2010-01-01
Ovarian cancer during pregnancy is a rare entity and the management of the disease can be challenging for the patient and the clinician. In this case, we report a case of advanced ovarian carcinoma diagnosed during pregnancy, which was managed with termination of pregnancy and chemotheraphy. The patient was underwent exploratory laparatomy including the right ovarian cystectomy, omentectomy, appendectomy, pelvic and para-aortic lymphadenectomy after frozen section of borderline serous cystade...
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Na-Yiyuan Wu
2017-03-01
Full Text Available High-grade serous ovarian carcinoma (HGSOC originates mainly from the fallopian tube (FT epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs and hemoglobin-rich follicular fluid (FF after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4 could eliminate p53-defective FT cells. Here we show that P4, via P4 receptors (PRs, induces necroptosis in Trp53−/− mouse oviduct epithelium and in immortalized human p53-defective fimbrial epithelium through the TNF-α/RIPK1/RIPK3/MLKL pathway. Necroptosis occurs specifically at diestrus, recovers at the proestrus phase of the estrus cycle, and can be augmented with P4 supplementation. These results reveal the mechanism of the well-known ability of progesterone to prevent ovarian cancer.
2018-04-24
Nausea and Vomiting; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Cystadenocarcinoma; Stage II Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma
Directory of Open Access Journals (Sweden)
Kan Casina WS
2012-12-01
Full Text Available Abstract Background There is a critical need for improved diagnostic markers for high grade serous epithelial ovarian cancer (SEOC. MicroRNAs are stable in the circulation and may have utility as biomarkers of malignancy. We investigated whether levels of serum microRNA could discriminate women with high-grade SEOC from age matched healthy volunteers. Methods To identify microRNA of interest, microRNA expression profiling was performed on 4 SEOC cell lines and normal human ovarian surface epithelial cells. Total RNA was extracted from 500 μL aliquots of serum collected from patients with SEOC (n = 28 and age-matched healthy donors (n = 28. Serum microRNA levels were assessed by quantitative RT-PCR following preamplification. Results microRNA (miR-182, miR-200a, miR-200b and miR-200c were highly overexpressed in the SEOC cell lines relative to normal human ovarian surface epithelial cells and were assessed in RNA extracted from serum as candidate biomarkers. miR-103, miR-92a and miR -638 had relatively invariant expression across all ovarian cell lines, and with small-nucleolar C/D box 48 (RNU48 were assessed in RNA extracted from serum as candidate endogenous normalizers. No correlation between serum levels and age were observed (age range 30-79 years for any of these microRNA or RNU48. Individually, miR-200a, miR-200b and miR-200c normalized to serum volume and miR-103 were significantly higher in serum of the SEOC cohort (P Conclusions We identified serum microRNAs able to discriminate patients with high grade SEOC from age-matched healthy controls. The addition of these microRNAs to current testing regimes may improve diagnosis for women with SEOC.
DEFF Research Database (Denmark)
Hogdall, E.V.; Christensen, L.; Blaakaer, J.
2008-01-01
from 189 women diagnosed with low malignant potential ovarian tumours (LMP, borderline ovarian tumours) and 571 women diagnosed with ovarian cancer (OC). RESULTS: Using 30% as the cut-off level for CEA over-expression, 18% of LMPs and 4% of OCs were positive. A higher proportion of mucinous tumours...... (I to IV), the highest CEA expression compared with no expression was found to be a prognostic factor (level 3 versus negative: HR = 2.12, 95%CI 1.11-4.05). FIGO stage, residual tumour after primary surgery, age at diagnosis, other histological types versus serous adenocarcinoma and low versus high...
Shared genetics underlying epidemiological association between endometriosis and ovarian cancer
DEFF Research Database (Denmark)
Lu, Yi; Cuellar-Partida, Gabriel; Painter, Jodie N
2015-01-01
Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address...... this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested...... that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We...
Cheng, Jung-Chien; Chang, Hsun-Ming; Leung, Peter C K
2017-10-17
Ovarian low-grade serous carcinoma (LGSC) is a rare disease and is now considered to be a distinct entity from high-grade serous carcinoma (HGSC), which is the most common and malignant form of epithelial ovarian cancer. Connective tissue growth factor (CTGF) is a secreted matricellular protein that has been shown to modulate many biological functions by interacting with multiple molecules in the microenvironment. Increasing evidence indicates that aberrant expression of CTGF is associated with cancer development and progression. Transforming growth factor-β1 (TGF-β1) is a well-known molecule that can strongly up-regulate CTGF expression in different types of normal and cancer cells. Our previous study demonstrated that TGF-β1 induces apoptosis of LGSC cells. However, the effect of TGF-β1 on CTGF expression in LGSC needs to be defined. In addition, whether CTGF mediates TGF-β1-induced LGSC cell apoptosis remains unknown. In the present study, we show that TGF-β1 treatment up-regulates CTGF expression by activating SMAD3 signaling in two human LGSC cell lines. Additionally, siRNA-mediated CTGF knockdown attenuates TGF-β1-induced cell apoptosis. Moreover, our results show that the inhibitory effect of the CTGF knockdown on TGF-β1-induced cell apoptosis is mediated by down-regulating SMAD3 expression. This study demonstrates an important role for CTGF in mediating the pro-apoptotic effects of TGF-β1 on LGCS.
Lawrenson, Kate; Li, Qiyuan; Kar, Siddhartha; Seo, Ji-Heui; Tyrer, Jonathan; Spindler, Tassja J; Lee, Janet; Chen, Yibu; Karst, Alison; Drapkin, Ronny; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V; Bean, Yukie; Beckmann, Matthias W; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Anne; Chen, Zhihua; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T; Edwards, Robert P; Eilber, Ursula; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S; Jakubowska, Anna; James, Paul; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kruger Kjaer, Susanne; Kelemen, Linda E; Kellar, Melissa; Kelley, Joseph L; Kiemeney, Lambertus A; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; Nevanlinna, Heli; McNeish, Ian; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Narod, Steven A; Nedergaard, Lotte; Ness, Roberta B; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jennifer; Phelan, Catherine M; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schildkraut, Joellen M; Schwaab, Ira; Sellers, Thomas A; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Sucheston, Lara; Tangen, Ingvild L; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S; van Altena, Anne M; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Monteiro, Alvaro; Pharoah, Paul D; Gayther, Simon A; Freedman, Matthew L
2015-09-22
Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
Kelemen, Linda E; Abbott, Sarah; Qin, Bo; Peres, Lauren Cole; Moorman, Patricia G; Wallace, Kristin; Bandera, Elisa V; Barnholtz-Sloan, Jill S; Bondy, Melissa; Cartmell, Kathleen; Cote, Michele L; Funkhouser, Ellen; Paddock, Lisa E; Peters, Edward S; Schwartz, Ann G; Terry, Paul; Alberg, Anthony J; Schildkraut, Joellen M
2017-07-01
Smoking is a risk factor for mucinous ovarian cancer (OvCa) in Caucasians. Whether a similar association exists in African Americans (AA) is unknown. We conducted a population-based case-control study of incident OvCa in AA women across 11 geographic locations in the US. A structured telephone interview asked about smoking, demographic, health, and lifestyle factors. Odds ratios and 95% confidence intervals (OR, 95% CI) were estimated from 613 cases and 752 controls using unconditional logistic regression in multivariable adjusted models. Associations were greater in magnitude for serous OvCa than for all OvCa combined. Compared to never smokers, increased risk for serous OvCa was observed for lifetime ever smokers (1.46, 1.11-1.92), former smokers who quit within 0-2 years of diagnosis (5.48, 3.04-9.86), and for total pack-years smoked among lifetime ever smokers (0-5 pack-years: 1.79, 1.23-2.59; >5-20 pack-years: 1.52, 1.05-2.18; >20 pack-years: 0.98, 0.61-1.56); however, we observed no dose-response relationship with increasing duration or consumption and no significant associations among current smokers. Smoking was not significantly associated with mucinous OvCa. Associations for all OvCa combined were consistently elevated among former smokers. The proportion of ever smokers who quit within 0-2 years was greater among cases (23%) than controls (7%). Cigarette smoking may be associated with serous OvCa among AA, which differs from associations reported among Caucasians. Exposure misclassification or reverse causality may partially explain the absence of increased risk among current smokers and lack of dose-response associations. Better characterization of smoking patterns is needed in this understudied population.
Dahm-Kähler, Pernilla; Borgfeldt, Christer; Holmberg, Erik; Staf, Christian; Falconer, Henrik; Bjurberg, Maria; Kjölhede, Preben; Rosenberg, Per; Stålberg, Karin; Högberg, Thomas; Åvall-Lundqvist, Elisabeth
2017-01-01
The aim of the study was to determine survival outcome in patients with serous cancer in the ovary, fallopian tube, peritoneum and of undesignated origin. Nation-wide population-based study of women≥18years with histologically verified non-uterine serous cancer, included in the Swedish Quality Registry for primary cancer of the ovary, fallopian tube and peritoneum diagnosed 2009-2013. Relative survival (RS) was estimated using the Ederer II method. Simple and multivariable analyses were estimated by Poisson regression models. Of 5627 women identified, 1246 (22%) had borderline tumors and 4381 had malignant tumors. In total, 2359 women had serous cancer; 71% originated in the ovary (OC), 9% in the fallopian tube (FTC), 9% in the peritoneum (PPC) and 11% at an undesignated primary site (UPS). Estimated RS at 5-years was 37%; for FTC 54%, 40% for OC, 34% for PPC and 13% for UPS. In multivariable regression analyses restricted to women who had undergone primary or interval debulking surgery for OC, FTC and PPC, site of origin was not independently associated with survival. Significant associations with worse survival were found for advanced stages (RR 2.63, Pcancer at UPS than for ovarian, fallopian tube and peritoneal cancer. Serous cancer at UPS needs to be addressed when reporting and comparing survival rates of ovarian cancer. Copyright © 2016 Elsevier Inc. All rights reserved.
DEFF Research Database (Denmark)
Schnack, Tine H; Sørensen, Rie D; Nedergaard, Lotte
2014-01-01
OBJECTIVES: Invasive serous adenocarcinomas may present as primary ovarian (POC), primary fallopian tube (PFC) or primary peritoneal (PPC) carcinomas. Whether they are variants of the same malignancy or develop through different pathways is debated. METHODS: Population-based prospectively collected...... data on POC (n=1443), PPC (n=268) and PFC (n=171) cases was obtained from the Danish Gynecological Cancer Database (2005-2013). Chi-square, Fisher's or Wilcoxon-Mann-Whitney test, multivariate logistic regression, Kaplan-Meier and multivariate Cox-regression were used as appropriate. Statistical tests...
Gross, Amy L; Kurman, Robert J; Vang, Russell; Shih, Ie-Ming; Visvanathan, Kala
2010-01-01
The lack of proven screening tools for early detection and the high mortality of ovarian serous carcinoma (OSC), particularly high grade, have focused attention on identifying putative precursor lesions with distinct morphological and molecular characteristics. The finding of occult invasive and intraepithelial fallopian tube carcinomas in prophylactically removed specimens from asymptomatic high-risk BRCA 1/2-mutation carriers supports the notion of an origin for OSC in the fallopian tube. The intraepithelial carcinomas have been referred to as serous intraepithelial carcinomas (STICs) but our own findings (unpublished data) and recent reports have drawn attention to a spectrum of changes that fall short of STICs that we have designated serous tubal intraepithelial lesions (STILs).
Directory of Open Access Journals (Sweden)
Amy L. Gross
2010-01-01
Full Text Available The lack of proven screening tools for early detection and the high mortality of ovarian serous carcinoma (OSC, particularly high grade, have focused attention on identifying putative precursor lesions with distinct morphological and molecular characteristics. The finding of occult invasive and intraepithelial fallopian tube carcinomas in prophylactically removed specimens from asymptomatic high-risk BRCA 1/2-mutation carriers supports the notion of an origin for OSC in the fallopian tube. The intraepithelial carcinomas have been referred to as serous intraepithelial carcinomas (STICs but our own findings (unpublished data and recent reports have drawn attention to a spectrum of changes that fall short of STICs that we have designated serous tubal intraepithelial lesions (STILs.
Wolsky, Rebecca J; Price, Matt A; Zaloudek, Charles J; Rabban, Joseph T
2018-05-01
Malignant transformation of the fallopian tube mucosa, followed by exfoliation of malignant cells onto ovarian and/or peritoneal surfaces, has been implicated as the origin of most pelvic high-grade serous carcinoma. Whether a parallel pathway exists for pelvic low-grade serous tumors [ovarian serous borderline tumor (SBT) and low-grade serous carcinoma (LGSC)] remains to be fully elucidated. The literature is challenging to interpret due to variation in the diagnostic criteria and terminology for cytologically low-grade proliferations of the fallopian tube mucosa, as well as variation in fallopian tube specimen sampling. Recently, a candidate fallopian tube precursor to ovarian SBT, so-called papillary tubal hyperplasia, was described in advanced stage patients. The current study was designed to identify fallopian tube mucosal proliferations unique to patients with low-grade serous ovarian tumors (serous cystadenoma, SBT, LGSC) and to determine if they may represent precursors to the ovarian tumors. Fallopian tubes were thinly sliced and entirely examined microscopically, including all of the fimbriated and nonfimbriated portions of the tubes, from patients with ovarian serous cystadenoma (35), SBT (61), and LGSC (11) and from a control population of patients with ovarian mucinous cystadenoma (28), mature cystic teratoma (18) or uterine leiomyoma (14). The slides of the fallopian tubes were examined in randomized order, without knowledge of the clinical history or findings in the ovaries or other organs. Alterations of the mucosa of the fallopian tube were classified as type 1: nonpapillary proliferation of cytologically bland tubal epithelium exhibiting crowding, stratification, and/or tufting without papillary fibrovascular cores or as type 2: papillary alterations consisting of a fibrovascular core lined by a cytologically bland layer of tubal epithelium. A third abnormality, type 3, consisted of detached intraluminal papillae, buds, or nests of epithelium that
MRI appearances of pure epithelial papillary serous borderline ovarian tumours
International Nuclear Information System (INIS)
Naqvi, J.; Nagaraju, E.; Ahmad, S.
2015-01-01
Borderline epithelial ovarian tumours (BOT) represent 15–20% of all non-benign ovarian epithelial neoplasms. Compared to malignant ovarian tumours, they usually present at a younger age and carry a far superior prognosis. Fertility-conserving surgery is an important treatment option for patients with BOT. Ultrasound and CT are both widely available and play roles in the initial investigation and staging of BOT, respectively. However, lack of soft-tissue contrast limits their ability to characterize BOT. MRI can facilitate recognition of pure epithelial serous BOT (SBOT), including the cystic papillary and surface papillary subtypes. An abundance of hyperintense papillary projections with low signal internal branching and ovarian stroma preservation with a hypointense ovarian capsular margin on T2-weighted imaging are features strongly suggestive of SBOT. In this review we will discuss the general morphological features of SBOT, the benefits and drawbacks of ultrasound and CT in the initial work-up, and the principal MRI features enabling recognition of surface papillary and cystic papillary SBOT
Bradaric, Michael J; Penumatsa, Krishna; Barua, Animesh; Edassery, Seby L; Yu, Yi; Abramowicz, Jacques S; Bahr, Janice M; Luborsky, Judith L
2013-01-01
Spontaneous ovarian cancer in chickens resembles human tumors both histologically and biochemically. The goal was to determine if there are differences in lymphocyte content between normal ovaries and ovarian tumors in chickens as a basis for further studies to understand the role of immunity in human ovarian cancer progression. Hens were selected using grey scale and color Doppler ultrasound to determine if they had normal or tumor morphology. Cells were isolated from ovaries (n = 6 hens) and lymphocyte numbers were determined by flow cytometry using antibodies to avian CD4 and CD8 T and B (Bu1a) cells. Ovarian sections from another set of hens (n = 26) were assessed to verify tumor type and stage and to count CD4, CD8 and Bu1a immunostained cells by morphometric analysis. T and B cells were more numerous in ovarian tumors than in normal ovaries by flow cytometry and immunohistochemistry. There were less CD4+ cells than CD8+ and Bu1a+ cells in normal ovaries or ovarian tumors. CD8+ cells were the dominant T cell sub-type in both ovarian stroma and in ovarian follicles compared to CD4+ cells. Bu1a+ cells were consistently found in the stroma of normal ovaries and ovarian tumors but were not associated with follicles. The number of immune cells was highest in late stage serous tumors compared to endometrioid and mucinous tumors. The results suggest that similar to human ovarian cancer there are comparatively more immune cells in chicken ovarian tumors than in normal ovaries, and the highest immune cell content occurs in serous tumors. Thus, this study establishes a foundation for further study of tumor immune responses in a spontaneous model of ovarian cancer which will facilitate studies of the role of immunity in early ovarian cancer progression and use of the hen in pre-clinical vaccine trials.
Chen, F; Gaitskell, K; Garcia, M J; Albukhari, A; Tsaltas, J; Ahmed, A A
2017-05-01
Serous tubal intraepithelial carcinomas (STICs) have been documented in high-grade serous ovarian carcinomas (HGSOCs). However, the rate of association between STICs and HGSOCs and, therefore, the fraction of HGSOCs that are likely to have originated from the fallopian tube (FT), has remained unclear. To appraise the literature describing the association between STICs and established HGSOCs. Ovid MEDLINE and EMBASE were searched. Studies were included if they evaluated the frequency of STICs in HGSOCs, and were published in an English peer-reviewed journal. Appropriate studies were evaluated for their compliance with the 'Strengthening and Reporting of Observational Studies in Epidemiology (STROBE)' criteria. Ten articles met the study selection criteria. The reported coexistence between STICs and HGSOCs ranged from 11% to 61% (mean: 31%, 95% CI: 17-46%). STICs were rarely found in other gynaecological cancers. Small sample size, lack of objective criteria to identify STICs and the retrospective nature of the studies contributed to the variability in reporting the rate of the association. STICs were identified commonly in the FTs of women with HGSOC. Finding the true rate of association between STICs and HGSOCs will require further investigations. While there is evidence that a fraction of HGSOCs arise from the FTs, an accurate estimate of that fraction remains to be determined. The lack of an accurate estimate of the association makes it difficult to evaluate the potential magnitude of reduction of HGSOCs following prophylactic salpingectomy. A systematic review of the incidence of STICs in HGSOCs identifies significant methodological inconsistencies. © 2017 Royal College of Obstetricians and Gynaecologists.
Prevalence of BRCA1 mutations in familial and sporadic greek ovarian cancer cases.
Directory of Open Access Journals (Sweden)
Alexandra V Stavropoulou
Full Text Available Germline mutations in the BRCA1 and BRCA2 genes contribute to approximately 18% of hereditary ovarian cancers conferring an estimated lifetime risk from 15% to 50%. A variable incidence of mutations has been reported for these genes in ovarian cancer cases from different populations. In Greece, six mutations in BRCA1 account for 63% of all mutations detected in both BRCA1 and BRCA2 genes. This study aimed to determine the prevalence of BRCA1 mutations in a Greek cohort of 106 familial ovarian cancer patients that had strong family history or metachronous breast cancer and 592 sporadic ovarian cancer cases. All 698 patients were screened for the six recurrent Greek mutations (including founder mutations c.5266dupC, p.G1738R and the three large deletions of exon 20, exons 23-24 and exon 24. In familial cases, the BRCA1 gene was consequently screened for exons 5, 11, 12, 20, 21, 22, 23, 24. A deleterious BRCA1 mutation was found in 43/106 (40.6% of familial cancer cases and in 27/592 (4.6% of sporadic cases. The variant of unknown clinical significance p.V1833M was identified in 9/698 patients (1.3%. The majority of BRCA1 carriers (71.2% presented a high-grade serous phenotype. Identifying a mutation in the BRCA1 gene among breast and/or ovarian cancer families is important, as it enables carriers to take preventive measures. All ovarian cancer patients with a serous phenotype should be considered for genetic testing. Further studies are warranted to determine the prevalence of mutations in the rest of the BRCA1 gene, in the BRCA2 gene, and other novel predisposing genes for breast and ovarian cancer.
[The molecular biology of epithelial ovarian cancer].
Leary, Alexandra; Pautier, Patricia; Tazi, Youssef; Morice, Philippe; Duvillard, Pierre; Gouy, Sébastien; Uzan, Catherine; Gauthier, Hélène; Balleyguier, Corinne; Lhommé, Catherine
2012-12-01
Epithelial ovarian cancer frequently presents at an advanced stage where the cornerstone of management remains surgery and platinum-based chemotherapy. Unfortunately, despite sometimes dramatic initial responses, advanced ovarian cancer almost invariably relapses. Little progress has been made in the identification of effective targeted-therapies for ovarian cancer. The majority of clinical trials investigating novel agents have been negative and the only approved targeted-therapy is bevacizumab, for which reliable predictive biomarkers still elude us. Ovarian cancer is treated as a uniform disease. Yet, biological studies have highlighted the heterogeneity of this malignancy with marked differences in histology, oncogenesis, prognosis, chemo-responsiveness, and molecular profile. Recent high throughput molecular analyses have identified a huge number of genomic/phenotypic alterations. Broadly speaking, high grade serous carcinomas (type II) display significant genomic instability and numerous amplifications and losses; low grade (type I) tumors are genomically stable but display frequent mutations. Importantly, many of these genomic alterations relate to known oncogenes for which targeted-therapies are available or in development. There is today a real potential for personalized medicine in ovarian cancer. We will review the current literature regarding the molecular characterization of epithelial ovarian cancer and discuss the biological rationale for a number of targeted strategies. In order to translate these biological advances into meaningful clinical improvements for our patients, it is imperative to incorporate translational research in ovarian cancer trials, a number of strategies will be proposed such as the acquisition of quality tumor samples, including sequential pre- and post-treatment biopsies, the potential of liquid biopsies, and novel trial designs more adapted to the molecular era of ovarian cancer research.
Potential role of miR-9 and miR-223 in recurrent ovarian cancer
Directory of Open Access Journals (Sweden)
McGuinness Eamonn
2008-04-01
Full Text Available Abstract Background MicroRNAs (miRNAs are small, noncoding RNAs that negatively regulate gene expression by binding to target mRNAs. miRNAs have not been comprehensively studied in recurrent ovarian cancer, yet an incurable disease. Results Using real-time RT-PCR, we obtained distinct miRNA expression profiles between primary and recurrent serous papillary ovarian adenocarcinomas (n = 6 in a subset of samples previously used in a transcriptome approach. Expression levels of top dysregulated miRNA genes, miR-223 and miR-9, were examined using TaqMan PCR in independent cohorts of fresh frozen (n = 18 and FFPE serous ovarian tumours (n = 22. Concordance was observed on TaqMan analysis for miR-223 and miR-9 between the training cohort and the independent test cohorts. Target prediction analysis for the above miRNA "recurrent metastatic signature" identified genes previously validated in our transcriptome study. Common biological pathways well characterised in ovarian cancer were shared by miR-9 and miR-223 lists of predicted target genes. We provide strong evidence that miR-9 acts as a putative tumour suppressor gene in recurrent ovarian cancer. Components of the miRNA processing machinery, such as Dicer and Drosha are not responsible for miRNA deregulation in recurrent ovarian cancer, as deluded by TaqMan and immunohistochemistry. Conclusion We propose a miRNA model for the molecular pathogenesis of recurrent ovarian cancer. Some of the differentially deregulated miRNAs identified correlate with our previous transcriptome findings. Based on integrated transcriptome and miRNA analysis, miR-9 and miR-223 can be of potential importance as biomarkers in recurrent ovarian cancer.
Morphologic, Immunophenotypic, and Molecular Features of Epithelial Ovarian Cancer.
Ramalingam, Preetha
2016-02-01
Epithelial ovarian cancer comprises a heterogeneous group of tumors. The four most common subtypes are serous, endometrioid, clear cell, and mucinous carcinoma. Less common are transitional cell tumors, including transitional cell carcinoma and malignant Brenner tumor. While in the past these subtypes were grouped together and designated as epithelial ovarian tumors, these tumor types are now known to be separate entities with distinct clinical and biologic behaviors. From a therapeutic standpoint, current regimens employ standard chemotherapy based on stage and grade rather than histotype. However, this landscape may change in the era of personalized therapy, given that most subtypes (with the exception of high-grade serous carcinoma) are relatively resistant to chemotherapy. It is now well-accepted that high-grade and low-grade serous carcinomas represent distinct entities rather than a spectrum of the same tumor type. While they are similar in that patients present with advanced-stage disease, their histologic and molecular features are entirely different. High-grade serous carcinoma is associated with TP53 mutations, whereas low-grade serous carcinomas are associated with BRAF and KRAS mutations. Endometrioid and clear cell carcinomas typically present as early-stage disease and are frequently associated with endometriosis. Mucinous carcinomas typically present as large unilateral masses and often show areas of mucinous cystadenoma and mucinous borderline tumor. It must be emphasized that primary mucinous carcinomas are uncommon tumors, and metastasis from other sites such as the appendix, colon, stomach, and pancreaticobiliary tract must always be considered in the differential diagnosis. Lastly, transitional cell tumors of the ovary, specifically malignant Brenner tumors, are quite uncommon. High-grade serous carcinoma often has a transitional cell pattern, and adequate sampling in most cases shows more typical areas of serous carcinoma. Immunohistochemical
Iron addiction: a novel therapeutic target in ovarian cancer
International Nuclear Information System (INIS)
Basuli, D.
2017-01-01
Ovarian cancer is a lethal malignancy that has not seen a major therapeutic advance in over 30 years. We demonstrate that ovarian cancer exhibits a targetable alteration in iron metabolism. Ferroportin (FPN), the iron efflux pump, is decreased, and transferrin receptor (TFR1), the iron importer, is increased in tumor tissue from patients with high grade but not low grade serous ovarian cancer. A similar profile of decreased FPN and increased TFR1 is observed in a genetic model of ovarian cancer tumor-initiating cells (TICs). The net result of these changes is an accumulation of excess intracellular iron and an augmented dependence on iron for proliferation. A forced reduction in intracellular iron reduces the proliferation of ovarian cancer TICs in vitro, and inhibits both tumor growth and intraperitoneal dissemination of tumor cells in vivo. Some mechanistic studies demonstrate that iron increases metastatic spread by facilitating invasion through expression of matrix metalloproteases and synthesis of interleukin 6 (IL-6). Here, we show that the iron dependence of ovarian cancer TICs renders them exquisitely sensitive in vivo to agents that induce iron-dependent cell death (ferroptosis) as well as iron chelators, and thus creates a metabolic vulnerability that can be exploited therapeutically.
Seidman, Jeffrey D
2015-03-01
which STIC was absent (P not significant). It is concluded that serous tubal intraepithelial carcinoma occurs at and in the immediate vicinity of the TPJ. In combination with the findings that STICs are present in a majority of cases when the TPJ is present, that flat STICs are smaller than papillary STICs, and that lamina propria invasion is more frequent in the presence of STIC, these data support STIC as the precursor of extrauterine high-grade serous carcinoma, they provide important clues to the site of origin of high-grade serous carcinoma (ovarian cancer), and can guide further research.
DEFF Research Database (Denmark)
Doherty, Jennifer A; Rossing, Mary Anne; Cushing-Haugen, Kara L
2010-01-01
, respectively. A SNP 19 kb downstream of ESR1 (rs2295190, G-to-T change) was associated with invasive ovarian cancer risk, with a per-T-allele odds ratio (OR) of 1.24 [95% confidence interval (CI), 1.06-1.44, P = 0.006]. rs2295190 is a nonsynonymous coding SNP in a neighboring gene called spectrin repeat...... through the Ovarian Cancer Association Consortium, with 5,279 invasive epithelial cases and 7,450 controls. The per-T-allele OR for this 12-study set was 1.09 (95% CI, 1.02-1.17; P = 0.017). Results for the serous subtype in the 15 combined studies were similar to those overall (n = 3,545; OR, 1.09; 95......% CI, 1.01-1.18; P = 0.025), and our findings were strongest for the mucinous subtype (n = 447; OR, 1.32; 95% CI, 1.11-1.58; P = 0.002). No association was observed for the endometrioid subtype. In an additional analysis of 1,459 borderline ovarian cancer cases and 7,370 controls, rs2295190...
Therapeutic Strategies Against Cyclin E1 Amplified Ovarian Cancers
2017-10-01
13-14 ( References ) 1. INTRODUCTION: Approximately 20% of high grade serous ovarian cancers harbor Cyclin E1 (CCNE1) amplification and are associated... Harvard Medical School and was named Director of Translational Research in the Gynecologic Oncology Program at Dana-Farber Cancer Institute. How...on HDAC6 activity. Nat Cell Biol 19:962-973. PMID: 28737768. PMC5541905. Books or other non-periodical, one-time publications. “Nothing to Report
Phelan, Catherine M.; Kuchenbaecker, Karoline B.; Tyrer, Jonathan P.; Kar, Siddhartha P.; Lawrenson, Kate; Winham, Stacey J.; Dennis, Joe; Pirie, Ailith; Riggan, Marjorie; Chornokur, Ganna; Earp, Madalene A.; Lyra, Paulo C.; Lee, Janet M.; Coetzee, Simon; Beesley, Jonathan; McGuffog, Lesley; Soucy, Penny; Dicks, Ed; Lee, Andrew; Barrowdale, Daniel; Lecarpentier, Julie; Leslie, Goska; Aalfs, Cora M.; Aben, Katja K.H.; Adams, Marcia; Adlard, Julian; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia; Aravantinos, Gerasimos; Arnold, Norbert; Arun, Banu K.; Arver, Brita; Azzollini, Jacopo; Balmaña, Judith; Banerjee, Susana N.; Barjhoux, Laure; Barkardottir, Rosa B.; Bean, Yukie; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Bernardini, Marcus Q.; Birrer, Michael J.; Bjorge, Line; Black, Amanda; Blankstein, Kenneth; Blok, Marinus J.; Bodelon, Clara; Bogdanova, Natalia; Bojesen, Anders; Bonanni, Bernardo; Borg, Åke; Bradbury, Angela R.; Brenton, James D.; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Bruinsma, Fiona; Brunet, Joan; Buecher, Bruno; Butzow, Ralf; Buys, Saundra S.; Caldes, Trinidad; Caligo, Maria A.; Campbell, Ian; Cannioto, Rikki; Carney, Michael E.; Cescon, Terence; Chan, Salina B.; Chang-Claude, Jenny; Chanock, Stephen; Chen, Xiao Qing; Chiew, Yoke-Eng; Chiquette, Jocelyne; Chung, Wendy K.; Claes, Kathleen B.M.; Conner, Thomas; Cook, Linda S.; Cook, Jackie; Cramer, Daniel W.; Cunningham, Julie M.; D’Aloisio, Aimee A.; Daly, Mary B.; Damiola, Francesca; Damirovna, Sakaeva Dina; Dansonka-Mieszkowska, Agnieszka; Dao, Fanny; Davidson, Rosemarie; DeFazio, Anna; Delnatte, Capucine; Doheny, Kimberly F.; Diez, Orland; Ding, Yuan Chun; Doherty, Jennifer Anne; Domchek, Susan M.; Dorfling, Cecilia M.; Dörk, Thilo; Dossus, Laure; Duran, Mercedes; Dürst, Matthias; Dworniczak, Bernd; Eccles, Diana; Edwards, Todd; Eeles, Ros; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B.; Ellis, Steve; Elvira, Mingajeva; Eng, Kevin H.; Engel, Christoph; Evans, D. Gareth; Fasching, Peter A.; Ferguson, Sarah; Ferrer, Sandra Fert; Flanagan, James M.; Fogarty, Zachary C.; Fortner, Renée T.; Fostira, Florentia; Foulkes, William D.; Fountzilas, George; Fridley, Brooke L.; Friebel, Tara M.; Friedman, Eitan; Frost, Debra; Ganz, Patricia A.; Garber, Judy; García, María J.; Garcia-Barberan, Vanesa; Gehrig, Andrea; Gentry-Maharaj, Aleksandra; Gerdes, Anne-Marie; Giles, Graham G.; Glasspool, Rosalind; Glendon, Gord; Godwin, Andrew K.; Goldgar, David E.; Goranova, Teodora; Gore, Martin; Greene, Mark H.; Gronwald, Jacek; Gruber, Stephen; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hamann, Ute; Hansen, Thomas V.O.; Harrington, Patricia A.; Harris, Holly R; Hauke, Jan; Hein, Alexander; Henderson, Alex; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hodgson, Shirley; Høgdall, Claus K.; Høgdall, Estrid; Hogervorst, Frans B.L.; Holland, Helene; Hooning, Maartje J.; Hosking, Karen; Huang, Ruea-Yea; Hulick, Peter J.; Hung, Jillian; Hunter, David J.; Huntsman, David G.; Huzarski, Tomasz; Imyanitov, Evgeny N.; Isaacs, Claudine; Iversen, Edwin S.; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jernetz, Mats; Jensen, Allan; Jensen, Uffe Birk; John, Esther M.; Johnatty, Sharon; Jones, Michael E.; Kannisto, Päivi; Karlan, Beth Y.; Karnezis, Anthony; Kast, Karin; Kennedy, Catherine J.; Khusnutdinova, Elza; Kiemeney, Lambertus A.; Kiiski, Johanna I.; Kim, Sung-Won; Kjaer, Susanne K.; Köbel, Martin; Kopperud, Reidun K.; Kruse, Torben A.; Kupryjanczyk, Jolanta; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Larrañaga, Nerea; Larson, Melissa C.; Lazaro, Conxi; Le, Nhu D.; Le Marchand, Loic; Lee, Jong Won; Lele, Shashikant B.; Leminen, Arto; Leroux, Dominique; Lester, Jenny; Lesueur, Fabienne; Levine, Douglas A.; Liang, Dong; Liebrich, Clemens; Lilyquist, Jenna; Lipworth, Loren; Lissowska, Jolanta; Lu, Karen H.; Lubiński, Jan; Luccarini, Craig; Lundvall, Lene; Mai, Phuong L.; Mendoza-Fandiño, Gustavo; Manoukian, Siranoush; Massuger, Leon F.A.G.; May, Taymaa; Mazoyer, Sylvie; McAlpine, Jessica N.; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain; Meijers-Heijboer, Hanne; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R.; Merritt, Melissa A.; Milne, Roger L.; Mitchell, Gillian; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moffitt, Melissa; Montagna, Marco; Moysich, Kirsten B.; Mulligan, Anna Marie; Musinsky, Jacob; Nathanson, Katherine L.; Nedergaard, Lotte; Ness, Roberta B.; Neuhausen, Susan L.; Nevanlinna, Heli; Niederacher, Dieter; Nussbaum, Robert L.; Odunsi, Kunle; Olah, Edith; Olopade, Olufunmilayo I.; Olsson, Håkan; Olswold, Curtis; O’Malley, David M.; Ong, Kai-ren; Onland-Moret, N. Charlotte; Orr, Nicholas; Orsulic, Sandra; Osorio, Ana; Palli, Domenico; Papi, Laura; Park-Simon, Tjoung-Won; Paul, James; Pearce, Celeste L.; Pedersen, Inge Søkilde; Peeters, Petra H.M.; Peissel, Bernard; Peixoto, Ana; Pejovic, Tanja; Pelttari, Liisa M.; Permuth, Jennifer B.; Peterlongo, Paolo; Pezzani, Lidia; Pfeiler, Georg; Phillips, Kelly-Anne; Piedmonte, Marion; Pike, Malcolm C.; Piskorz, Anna M.; Poblete, Samantha R.; Pocza, Timea; Poole, Elizabeth M.; Poppe, Bruce; Porteous, Mary E.; Prieur, Fabienne; Prokofyeva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pujol, Pascal; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rhiem, Kerstin; Rice, Patricia; Richardson, Andrea; Robson, Mark; Rodriguez, Gustavo C.; Rodríguez-Antona, Cristina; Romm, Jane; Rookus, Matti A.; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Salvesen, Helga B.; Sandler, Dale P.; Schoemaker, Minouk J.; Senter, Leigha; Setiawan, V. Wendy; Severi, Gianluca; Sharma, Priyanka; Shelford, Tameka; Siddiqui, Nadeem; Side, Lucy E.; Sieh, Weiva; Singer, Christian F.; Sobol, Hagay; Song, Honglin; Southey, Melissa C.; Spurdle, Amanda B.; Stadler, Zsofia; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sucheston-Campbell, Lara E.; Sukiennicki, Grzegorz; Sutphen, Rebecca; Sutter, Christian; Swerdlow, Anthony J.; Szabo, Csilla I.; Szafron, Lukasz; Tan, Yen Y.; Taylor, Jack A.; Tea, Muy-Kheng; Teixeira, Manuel R.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Thomsen, Liv Cecilie Vestrheim; Thull, Darcy L.; Tihomirova, Laima; Tinker, Anna V.; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Tone, Alicia; Trabert, Britton; Travis, Ruth C.; Trichopoulou, Antonia; Tung, Nadine; Tworoger, Shelley S.; van Altena, Anne M.; Van Den Berg, David; van der Hout, Annemarie H.; van der Luijt, Rob B.; Van Heetvelde, Mattias; Van Nieuwenhuysen, Els; van Rensburg, Elizabeth J.; Vanderstichele, Adriaan; Varon-Mateeva, Raymonda; Ana, Vega; Edwards, Digna Velez; Vergote, Ignace; Vierkant, Robert A.; Vijai, Joseph; Vratimos, Athanassios; Walker, Lisa; Walsh, Christine; Wand, Dorothea; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Webb, Penelope M.; Weinberg, Clarice R.; Weitzel, Jeffrey N.; Wentzensen, Nicolas; Whittemore, Alice S.; Wijnen, Juul T.; Wilkens, Lynne R.; Wolk, Alicja; Woo, Michelle; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Yannoukakos, Drakoulis; Ziogas, Argyrios; Zorn, Kristin K.; Narod, Steven A.; Easton, Douglas F.; Amos, Christopher I.; Schildkraut, Joellen M.; Ramus, Susan J.; Ottini, Laura; Goodman, Marc T.; Park, Sue K.; Kelemen, Linda E.; Risch, Harvey A.; Thomassen, Mads; Offit, Kenneth; Simard, Jacques; Schmutzler, Rita Katharina; Hazelett, Dennis; Monteiro, Alvaro N.; Couch, Fergus J.; Berchuck, Andrew; Chenevix-Trench, Georgia; Goode, Ellen L.; Sellers, Thomas A.; Gayther, Simon A.; Antoniou, Antonis C.; Pharoah, Paul D.P.
2017-01-01
To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3, 9q31.1) and one for endometrioid EOC (5q12.3). We then meta-analysed the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified an additional three loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a novel susceptibility gene for low grade/borderline serous EOC. PMID:28346442
Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.
Phelan, Catherine M; Kuchenbaecker, Karoline B; Tyrer, Jonathan P; Kar, Siddhartha P; Lawrenson, Kate; Winham, Stacey J; Dennis, Joe; Pirie, Ailith; Riggan, Marjorie J; Chornokur, Ganna; Earp, Madalene A; Lyra, Paulo C; Lee, Janet M; Coetzee, Simon; Beesley, Jonathan; McGuffog, Lesley; Soucy, Penny; Dicks, Ed; Lee, Andrew; Barrowdale, Daniel; Lecarpentier, Julie; Leslie, Goska; Aalfs, Cora M; Aben, Katja K H; Adams, Marcia; Adlard, Julian; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia; Aravantinos, Gerasimos; Arnold, Norbert; Arun, Banu K; Arver, Brita; Azzollini, Jacopo; Balmaña, Judith; Banerjee, Susana N; Barjhoux, Laure; Barkardottir, Rosa B; Bean, Yukie; Beckmann, Matthias W; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Bernardini, Marcus Q; Birrer, Michael J; Bjorge, Line; Black, Amanda; Blankstein, Kenneth; Blok, Marinus J; Bodelon, Clara; Bogdanova, Natalia; Bojesen, Anders; Bonanni, Bernardo; Borg, Åke; Bradbury, Angela R; Brenton, James D; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Bruinsma, Fiona; Brunet, Joan; Buecher, Bruno; Butzow, Ralf; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Campbell, Ian; Cannioto, Rikki; Carney, Michael E; Cescon, Terence; Chan, Salina B; Chang-Claude, Jenny; Chanock, Stephen; Chen, Xiao Qing; Chiew, Yoke-Eng; Chiquette, Jocelyne; Chung, Wendy K; Claes, Kathleen B M; Conner, Thomas; Cook, Linda S; Cook, Jackie; Cramer, Daniel W; Cunningham, Julie M; D'Aloisio, Aimee A; Daly, Mary B; Damiola, Francesca; Damirovna, Sakaeva Dina; Dansonka-Mieszkowska, Agnieszka; Dao, Fanny; Davidson, Rosemarie; DeFazio, Anna; Delnatte, Capucine; Doheny, Kimberly F; Diez, Orland; Ding, Yuan Chun; Doherty, Jennifer Anne; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; Dossus, Laure; Duran, Mercedes; Dürst, Matthias; Dworniczak, Bernd; Eccles, Diana; Edwards, Todd; Eeles, Ros; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B; Ellis, Steve; Elvira, Mingajeva; Eng, Kevin H; Engel, Christoph; Evans, D Gareth; Fasching, Peter A; Ferguson, Sarah; Ferrer, Sandra Fert; Flanagan, James M; Fogarty, Zachary C; Fortner, Renée T; Fostira, Florentia; Foulkes, William D; Fountzilas, George; Fridley, Brooke L; Friebel, Tara M; Friedman, Eitan; Frost, Debra; Ganz, Patricia A; Garber, Judy; García, María J; Garcia-Barberan, Vanesa; Gehrig, Andrea; Gentry-Maharaj, Aleksandra; Gerdes, Anne-Marie; Giles, Graham G; Glasspool, Rosalind; Glendon, Gord; Godwin, Andrew K; Goldgar, David E; Goranova, Teodora; Gore, Martin; Greene, Mark H; Gronwald, Jacek; Gruber, Stephen; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hamann, Ute; Hansen, Thomas V O; Harrington, Patricia A; Harris, Holly R; Hauke, Jan; Hein, Alexander; Henderson, Alex; Hildebrandt, Michelle A T; Hillemanns, Peter; Hodgson, Shirley; Høgdall, Claus K; Høgdall, Estrid; Hogervorst, Frans B L; Holland, Helene; Hooning, Maartje J; Hosking, Karen; Huang, Ruea-Yea; Hulick, Peter J; Hung, Jillian; Hunter, David J; Huntsman, David G; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Iversen, Edwin S; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jernetz, Mats; Jensen, Allan; Jensen, Uffe Birk; John, Esther M; Johnatty, Sharon; Jones, Michael E; Kannisto, Päivi; Karlan, Beth Y; Karnezis, Anthony; Kast, Karin; Kennedy, Catherine J; Khusnutdinova, Elza; Kiemeney, Lambertus A; Kiiski, Johanna I; Kim, Sung-Won; Kjaer, Susanne K; Köbel, Martin; Kopperud, Reidun K; Kruse, Torben A; Kupryjanczyk, Jolanta; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Larrañaga, Nerea; Larson, Melissa C; Lazaro, Conxi; Le, Nhu D; Le Marchand, Loic; Lee, Jong Won; Lele, Shashikant B; Leminen, Arto; Leroux, Dominique; Lester, Jenny; Lesueur, Fabienne; Levine, Douglas A; Liang, Dong; Liebrich, Clemens; Lilyquist, Jenna; Lipworth, Loren; Lissowska, Jolanta; Lu, Karen H; Lubinński, Jan; Luccarini, Craig; Lundvall, Lene; Mai, Phuong L; Mendoza-Fandiño, Gustavo; Manoukian, Siranoush; Massuger, Leon F A G; May, Taymaa; Mazoyer, Sylvie; McAlpine, Jessica N; McGuire, Valerie; McLaughlin, John R; McNeish, Iain; Meijers-Heijboer, Hanne; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R; Merritt, Melissa A; Milne, Roger L; Mitchell, Gillian; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moffitt, Melissa; Montagna, Marco; Moysich, Kirsten B; Mulligan, Anna Marie; Musinsky, Jacob; Nathanson, Katherine L; Nedergaard, Lotte; Ness, Roberta B; Neuhausen, Susan L; Nevanlinna, Heli; Niederacher, Dieter; Nussbaum, Robert L; Odunsi, Kunle; Olah, Edith; Olopade, Olufunmilayo I; Olsson, Håkan; Olswold, Curtis; O'Malley, David M; Ong, Kai-Ren; Onland-Moret, N Charlotte; Orr, Nicholas; Orsulic, Sandra; Osorio, Ana; Palli, Domenico; Papi, Laura; Park-Simon, Tjoung-Won; Paul, James; Pearce, Celeste L; Pedersen, Inge Søkilde; Peeters, Petra H M; Peissel, Bernard; Peixoto, Ana; Pejovic, Tanja; Pelttari, Liisa M; Permuth, Jennifer B; Peterlongo, Paolo; Pezzani, Lidia; Pfeiler, Georg; Phillips, Kelly-Anne; Piedmonte, Marion; Pike, Malcolm C; Piskorz, Anna M; Poblete, Samantha R; Pocza, Timea; Poole, Elizabeth M; Poppe, Bruce; Porteous, Mary E; Prieur, Fabienne; Prokofyeva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pujol, Pascal; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rhiem, Kerstin; Rice, Patricia; Richardson, Andrea; Robson, Mark; Rodriguez, Gustavo C; Rodríguez-Antona, Cristina; Romm, Jane; Rookus, Matti A; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Salvesen, Helga B; Sandler, Dale P; Schoemaker, Minouk J; Senter, Leigha; Setiawan, V Wendy; Severi, Gianluca; Sharma, Priyanka; Shelford, Tameka; Siddiqui, Nadeem; Side, Lucy E; Sieh, Weiva; Singer, Christian F; Sobol, Hagay; Song, Honglin; Southey, Melissa C; Spurdle, Amanda B; Stadler, Zsofia; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sucheston-Campbell, Lara E; Sukiennicki, Grzegorz; Sutphen, Rebecca; Sutter, Christian; Swerdlow, Anthony J; Szabo, Csilla I; Szafron, Lukasz; Tan, Yen Y; Taylor, Jack A; Tea, Muy-Kheng; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Thomsen, Liv Cecilie Vestrheim; Thull, Darcy L; Tihomirova, Laima; Tinker, Anna V; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Tone, Alicia; Trabert, Britton; Travis, Ruth C; Trichopoulou, Antonia; Tung, Nadine; Tworoger, Shelley S; van Altena, Anne M; Van Den Berg, David; van der Hout, Annemarie H; van der Luijt, Rob B; Van Heetvelde, Mattias; Van Nieuwenhuysen, Els; van Rensburg, Elizabeth J; Vanderstichele, Adriaan; Varon-Mateeva, Raymonda; Vega, Ana; Edwards, Digna Velez; Vergote, Ignace; Vierkant, Robert A; Vijai, Joseph; Vratimos, Athanassios; Walker, Lisa; Walsh, Christine; Wand, Dorothea; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Webb, Penelope M; Weinberg, Clarice R; Weitzel, Jeffrey N; Wentzensen, Nicolas; Whittemore, Alice S; Wijnen, Juul T; Wilkens, Lynne R; Wolk, Alicja; Woo, Michelle; Wu, Xifeng; Wu, Anna H; Yang, Hannah; Yannoukakos, Drakoulis; Ziogas, Argyrios; Zorn, Kristin K; Narod, Steven A; Easton, Douglas F; Amos, Christopher I; Schildkraut, Joellen M; Ramus, Susan J; Ottini, Laura; Goodman, Marc T; Park, Sue K; Kelemen, Linda E; Risch, Harvey A; Thomassen, Mads; Offit, Kenneth; Simard, Jacques; Schmutzler, Rita Katharina; Hazelett, Dennis; Monteiro, Alvaro N; Couch, Fergus J; Berchuck, Andrew; Chenevix-Trench, Georgia; Goode, Ellen L; Sellers, Thomas A; Gayther, Simon A; Antoniou, Antonis C; Pharoah, Paul D P
2017-05-01
To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Hypermethylated APC in serous carcinoma based on a meta-analysis of ovarian cancer.
Shen, Chunyan; Sheng, Qifang; Zhang, Xiaojie; Fu, Yuling; Zhu, Kemiao
2016-09-26
The reduced expression of the Adenomatous polyposis coli (APC) gene, a tumor suppressor gene, through promoter hypermethylation has been reported to play a key role in the carcinogenesis. However, the correlation between APC promoter hypermethylation and ovarian cancer (OC) remains to be clarified. A comprehensive literature search was carried out in related research databases. The overall odds ratio (OR) and corresponding 95 % confidence interval (CI) were used to evaluate the effects of APC promoter hypermethylation on OC and clinicopathological characteristics. Ultimately, 12 eligible studies were used in our study, including 806 OC samples, 429 normal controls, 109 benign lesions and 75 LMP samples. The pooled OR showed that APC promoter hypermethylation was significantly higher in OC than in normal and benign controls (OR = 6.18 and OR = 3.26, respectively). No significant correlation was observed between OC and low malignant potential (LMP) tumors (P = 0.436). In the comparison of OC and normal controls, subgroup analysis based on race showed that the overall OR of APC promoter hypermethylation was significant and similar in Asians and Caucasians (OR = 8.34 and OR = 5.39, respectively). A subgroup analysis based on sample type found that the pooled OR was significantly higher in blood than in tissue (OR = 18.71 and OR = 5.74, respectively). A significant association was not observed between APC promoter hypermethylation and tumor grade or tumor stage. The pooled OR indicated that APC promoter hypermethylation was significantly lower in serous carcinoma than in non-serous carcinoma (OR = 0.56, P = 0.02). No obvious publication bias was detected by Egger's test (all P > 0.05). APC promoter hypermethylation may be linked to the increased risk of OC. It was associated with histological type, but not with tumor grade or tumor stage. Moreover, hypermethylated APC may be a noninvasive biomarker using blood samples. Future
LENUS (Irish Health Repository)
Furlong, Fiona
2012-04-01
Epithelial ovarian cancer (EOC) has an innate susceptibility to become chemoresistant. Up to 30% of patients do not respond to conventional chemotherapy [paclitaxel (Taxol®) in combination with carboplatin] and, of those who have an initial response, many patients relapse. Therefore, an understanding of the molecular mechanisms that regulate cellular chemotherapeutic responses in EOC cells has the potential to impact significantly on patient outcome. The mitotic arrest deficiency protein 2 (MAD2), is a centrally important mediator of the cellular response to paclitaxel. MAD2 immunohistochemical analysis was performed on 82 high-grade serous EOC samples. A multivariate Cox regression analysis of nuclear MAD2 IHC intensity adjusting for stage, tumour grade and optimum surgical debulking revealed that low MAD2 IHC staining intensity was significantly associated with reduced progression-free survival (PFS) (p = 0.0003), with a hazard ratio of 4.689. The in vitro analyses of five ovarian cancer cell lines demonstrated that cells with low MAD2 expression were less sensitive to paclitaxel. Furthermore, paclitaxel-induced activation of the spindle assembly checkpoint (SAC) and apoptotic cell death was abrogated in cells transfected with MAD2 siRNA. In silico analysis identified a miR-433 binding domain in the MAD2 3\\' UTR, which was verified in a series of experiments. Firstly, MAD2 protein expression levels were down-regulated in pre-miR-433 transfected A2780 cells. Secondly, pre-miR-433 suppressed the activity of a reporter construct containing the 3\\'-UTR of MAD2. Thirdly, blocking miR-433 binding to the MAD2 3\\' UTR protected MAD2 from miR-433 induced protein down-regulation. Importantly, reduced MAD2 protein expression in pre-miR-433-transfected A2780 cells rendered these cells less sensitive to paclitaxel. In conclusion, loss of MAD2 protein expression results in increased resistance to paclitaxel in EOC cells. Measuring MAD2 IHC staining intensity may predict
Gupta, Mamta; Babic, Ana; Beck, Andrew H.; Terry, Kathryn
2016-01-01
Inflammatory cytokines, like tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), are elevated in ovarian cancer. Differences in cytokine expression by histologic subytpe or ovarian cancer risk factors can provide useful insight into ovarian cancer risk and etiology. We used ribonucleic acid (RNA) in-situ hybridization to assess TNF-α and IL-6 expression on tissue microarray slides from 78 epithelial ovarian carcinomas (51 serous, 12 endometrioid, 7 clear cell, 2 mucinous, 6 other) from a population-based case control study. Cytokine expression was scored semi-quantitatively and odds ratios (OR) and 95% confidence intervals (CI) were calculated using polytomous logistic regression. TNF-α was expressed in 46% of the tumors while sparse IL-6 expression was seen only 18% of the tumors. For both markers, expression was most common in high grade serous carcinomas followed by endometrioid carcinomas. Parity was associated with a reduced risk of TNF-α positive (OR=0.3, 95% CI: 0.1-0.7 for 3 or more children versus none) but not TNF-α negative tumors (p-heterogeneity=0.02). In contrast, current smoking was associated with a nearly three fold increase in risk of TNF-α negative (OR=2.8, 95% CI: 1.2, 6.6) but not TNF-α positive tumors (p-heterogeneity = 0.06). Our data suggests that TNF-α expression in ovarian carcinoma varies by histologic subtype and provides some support for the role of inflammation in ovarian carcinogenesis. The novel associations detected in our study need to be validated in a larger cohort of patients in future studies. PMID:27068525
Gapstur, Susan M; Patel, Alpa V; Diver, W Ryan; Hildebrand, Janet S; Gaudet, Mia M; Jacobs, Eric J; Campbell, Peter T
2012-11-01
Despite consistent associations of type II diabetes mellitus with hormonally related cancers such as breast and endometrium, the relation between type II diabetes mellitus and ovarian cancer risk is unclear. Associations of type II diabetes mellitus status, duration, and insulin use with epithelial ovarian cancer overall, and with serous and nonserous histologic subtypes were examined in the Cancer Prevention Study-II Nutrition Cohort, a prospective study of U.S. men and women predominantly aged 50 years and older. Between 1992 and 2007, 524 incident epithelial ovarian cancer cases were identified among 63,440 postmenopausal women. Multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI) were computed using extended Cox regression to update diabetes status and bilateral oophorectomy status during follow-up. Type II diabetes mellitus status (RR = 1.05; 95% CI, 0.75-1.46) and duration were not associated with epithelial ovarian cancer risk. Although not statistically significantly different (P(difference) = 0.39), the RR was higher for type II diabetes mellitus with insulin use (RR = 1.28; 95% CI, 0.74-2.24) than for type II diabetes mellitus without insulin use (RR = 0.96; 95% CI, 0.64-1.43). Diabetes seemed to be more strongly associated with nonserous (RR = 1.41; 95% CI, 0.70-2.85) than serous (RR = 0.71; 95% CI, 0.41-1.23) histologic subtypes. Type II diabetes mellitus was not associated with risk of epithelial ovarian cancer, although higher risks with nonserous subtypes and among insulin users cannot be ruled out. Larger studies are needed to clarify associations of type II diabetes mellitus with or without insulin use with risk of ovarian cancer overall and by histologic subtypes. ©2012 AACR.
de Boo, Leonora Wijnandina; Vulink, Annelie Johanna Elisabeth; Bos, Monique Elisabeth Martina Maria
2017-12-01
Metronomic oral cyclophosphamide has gained increasing interest in recent years as a promising maintenance therapy in advanced, platinum-sensitive, high-grade serous ovarian cancer (HGSOC). Metronomic treatment with cyclophosphamide refers to the frequent, usually daily, administration of a low (oral) dose of cyclophosphamide with no prolonged drug-free breaks. Main advantages of this treatment are the effective reduction of tumour activity, oral administration in an outpatient setting, low cost and the low toxicity profile. Metronomic oral cyclophosphamide can benefit patients suffering from types of cancer known to be sensitive to alkylating agents, such as platinum-sensitive HGSOC. In recent years, several publications have underlined the advantage of this regimen and possible explanations were explored. We here present a patient with multiple recurrences of metastasized HGSOC, platinum-sensitive, with an on-going complete response to monotherapy with oral cyclophosphamide. This observation supports that patients with relapsing HGSOC who responded to platinum-based chemotherapy and cannot continue platinum-based chemotherapy because of toxicity, can be offered a course of metronomic cyclophosphamide. This case may serve as a reminder that old drugs can be used successfully even in the age of new upcoming therapy such as anti-angiogenic agents (VEGF inhibitors) and poly-ADP-ribose polymerase (PARP) inhibitors.
Development of A Mouse Model of Menopausal Ovarian Cancer
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Elizabeth R. Smith
2014-02-01
Full Text Available Despite significant understanding of the genetic mutations involved in ovarian epithelial cancer and advances in genomic approaches for expression and mutation profiling of tumor tissues, several key questions in ovarian cancer biology remain enigmatic: the mechanism for the well-established impact of reproductive factors on ovarian cancer risk remains obscure; questions of the cell of origin of ovarian cancer continue to be debated; and the precursor lesion, sequence, or events in progression remain to be defined. Suitable mouse models should complement the analysis of human tumor tissues and may provide clues to these questions currently perplexing ovarian cancer biology.A potentially useful model is the germ cell-deficient Wv (white spotting variant mutant mouse line, which may be used to study the impact of menopausal physiology on the increased risk of ovarian cancer. The Wv mice harbor a point mutation in c-Kit that reduces the receptor tyrosine kinase activity to about 1-5% (it is not a null mutation. Homozygous Wv mutant females have a reduced ovarian germ cell reservoir at birth and the follicles are rapidly depleted upon reaching reproductive maturity, but other biological phenotypes are minimal and the mice have a normal life span. The loss of ovarian function precipitates changes in hormonal and metabolic activity that model features of menopause in humans. As a consequence of follicle depletion, the Wv ovaries develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis that mark human ovarian aging. Ongoing work will test the possibility of converting the benign epithelial tubular adenomas into neoplastic tumors by addition of an oncogenic mutation, such as of Tp53, to model the genotype and biology of serous ovarian cancer.Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention.
Directory of Open Access Journals (Sweden)
Virant-Klun Irma
2011-08-01
Full Text Available Abstract Introduction The presence of oocytes in the ovarian surface epithelium has already been confirmed in the fetal ovaries. We report the presence of SSEA-4, SOX-2, VASA and ZP2-positive primitive oocyte-like cells in the adult ovarian surface epithelium of a patient with serous papillary adenocarcinoma. Case presentation Ovarian tissue was surgically retrieved from a 67-year old patient. Histological analysis revealed serous papillary adenocarcinoma. A proportion of ovarian cortex sections was deparaffinized and immunohistochemically stained for the expression of markers of pluripotency SSEA-4 and SOX-2 and oocyte-specific markers VASA and ZP2. The analysis confirmed the presence of round, SSEA-4, SOX-2, VASA and ZP2-positive primitive oocyte-like cells in the ovarian surface epithelium. These cells were possibly related to the necrotic malignant tissue. Conclusion Primitive oocyte-like cells present in the adult ovarian surface epithelium persisting probably from the fetal period of life or developed from putative stem cells are a pathological condition which is not observed in healthy adult ovaries, and might be related to serous papillary adenocarcinoma manifestation in the adult ovarian surface epithelium. This observation needs attention to be further investigated.
Singh, Garima; Roy, Jyoti; Rout, Pratiti; Mallick, Bibekanand
2018-01-01
PIWI-interacting (piRNAs), ~23-36 nucleotide-long small non-coding RNAs (sncRNAs), earlier believed to be germline-specific, have now been identified in somatic cells, including cancer cells. These sncRNAs impact critical biological processes by fine-tuning gene expression at post-transcriptional and epigenetic levels. The expression of piRNAs in ovarian cancer, the most lethal gynecologic cancer is largely uncharted. In this study, we investigated the expression of PIWILs by qRT-PCR and western blotting and then identified piRNA transcriptomes in tissues of normal ovary and two most prevalent epithelial ovarian cancer subtypes, serous and endometrioid by small RNA sequencing. We detected 219, 256 and 234 piRNAs in normal ovary, endometrioid and serous ovarian cancer samples respectively. We observed piRNAs are encoded from various genomic regions, among which introns harbor the majority of them. Surprisingly, piRNAs originated from different genomic contexts showed the varied level of conservations across vertebrates. The functional analysis of predicted targets of differentially expressed piRNAs revealed these could modulate key processes and pathways involved in ovarian oncogenesis. Our study provides the first comprehensive piRNA landscape in these samples and a useful resource for further functional studies to decipher new mechanistic views of piRNA-mediated gene regulatory networks affecting ovarian oncogenesis. The RNA-seq data is submitted to GEO database (GSE83794).
Alsop, Kathryn; Fereday, Sian; Meldrum, Cliff; deFazio, Anna; Emmanuel, Catherine; George, Joshy; Dobrovic, Alexander; Birrer, Michael J.; Webb, Penelope M.; Stewart, Colin; Friedlander, Michael; Fox, Stephen; Bowtell, David; Mitchell, Gillian
2012-01-01
Purpose The frequency of BRCA1 and BRCA2 germ-line mutations in women with ovarian cancer is unclear; reports vary from 3% to 27%. The impact of germ-line mutation on response requires further investigation to understand its impact on treatment planning and clinical trial design. Patients and Methods Women with nonmucinous ovarian carcinoma (n = 1,001) enrolled onto a population-based, case-control study were screened for point mutations and large deletions in both genes. Survival outcomes and responses to multiple lines of chemotherapy were assessed. Results Germ-line mutations were found in 14.1% of patients overall, including 16.6% of serous cancer patients (high-grade serous, 22.6%); 44% had no reported family history of breast or ovarian cancer. Patients carrying germ-line mutations had improved rates of progression-free and overall survival. In the relapse setting, patients carrying mutations more frequently responded to both platin- and nonplatin-based regimens than mutation-negative patients, even in patients with early relapse after primary treatment. Mutation-negative patients who responded to multiple cycles of platin-based treatment were more likely to carry somatic BRCA1/2 mutations. Conclusion BRCA mutation status has a major influence on survival in ovarian cancer patients and should be an additional stratification factor in clinical trials. Treatment outcomes in BRCA1/2 carriers challenge conventional definitions of platin resistance, and mutation status may be able to contribute to decision making and systemic therapy selection in the relapse setting. Our data, together with the advent of poly(ADP-ribose) polymerase inhibitor trials, supports the recommendation that germ-line BRCA1/2 testing should be offered to all women diagnosed with nonmucinous, ovarian carcinoma, regardless of family history. PMID:22711857
2018-04-27
Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Clear Cell Tumor; Malignant Ovarian Endometrioid Tumor; Malignant Ovarian Serous Tumor; Ovarian Seromucinous Carcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma
Functional role and prognostic significance of CD157 in ovarian carcinoma.
Ortolan, Erika; Arisio, Riccardo; Morone, Simona; Bovino, Paola; Lo-Buono, Nicola; Nacci, Giulia; Parrotta, Rossella; Katsaros, Dionyssios; Rapa, Ida; Migliaretti, Giuseppe; Ferrero, Enza; Volante, Marco; Funaro, Ada
2010-08-04
CD157, an ADP-ribosyl cyclase-related cell surface molecule, regulates leukocyte diapedesis during inflammation. Because CD157 is expressed in mesothelial cells and diapedesis resembles tumor cell migration, we investigated the role of CD157 in ovarian carcinoma. We assayed surgically obtained ovarian cancer and mesothelial cells and both native and engineered ovarian cancer cell lines for CD157 expression using flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR), and for adhesion to extracellular matrices, migration, and invasion using cell-based assays. We investigated invasion of human peritoneal mesothelial cells by serous ovarian cancer cells with a three-dimensional coculture model. Experiments were performed with or without CD157-blocking antibodies. CD157 expression in tissue sections from ovarian cancer patients (n = 88) was examined by immunohistochemistry, quantified by histological score (H score), and categorized as at or above or below the median value of 60, and compared with clinical parameters. Statistical tests were two-sided. CD157 was expressed by ovarian cancer cells and mesothelium, and it potentiated the adhesion, migration, and invasion of serous ovarian cancer cells through different extracellular matrices. CD157-transfected ovarian cancer cells migrated twice as much as CD157-negative control cells (P = .001). Blockage of CD157 inhibited mesothelial invasion by serous ovarian cancer cells in a three-dimensional model. CD157 was expressed in 82 (93%) of the 88 epithelial ovarian cancer tissue specimens. In serous ovarian cancer, patients with CD157 H scores of 60 or greater had statistically significantly shorter disease-free survival and overall survival than patients with lower CD157 H scores (CD157 H score > or =60 vs or =60 vs <60: median overall survival = 45 months, 95% CI = 21.21 to 68.79 vs unreached, P = .024). Multivariable Cox regression showed that CD157 is an independent prognostic factor for recurrence
Nakatsuka, Erika; Sawada, Kenjiro; Nakamura, Koji; Yoshimura, Akihito; Kinose, Yasuto; Kodama, Michiko; Hashimoto, Kae; Mabuchi, Seiji; Makino, Hiroshi; Morii, Eiichi; Yamaguchi, Yoichi; Yanase, Takeshi; Itai, Akiko; Morishige, Ken-Ichirou; Kimura, Tadashi
2017-10-27
In the present study, the therapeutic potential of targeting plasminogen activator inhibitor-1 (PAI-1) in ovarian cancer was tested. Tissues samples from 154 cases of ovarian carcinoma were immunostained with anti-PAI-1 antibody, and the prognostic value was analyzed. Among the samples, 67% (104/154) showed strong PAI-1 expression; this was significantly associated with poor prognosis (progression-free survival: 20 vs. 31 months, P = 0.0033). In particular, among patients with stage II-IV serous adenocarcinoma, PAI-1 expression was an independent prognostic factor. The effect of a novel PAI-1 inhibitor, IMD-4482, on ovarian cancer cell lines was assessed and its therapeutic potential was examined using a xenograft mouse model of ovarian cancer. IMD-4482 inhibited in vitro cell adhesion to vitronectin in PAI-1-positive ovarian cancer cells, followed by the inhibition of extracellular signal-regulated kinase and focal adhesion kinase phosphorylation through dissociation of the PAI-urokinase receptor complex from integrin αVβ3. IMD-4482 caused G0/G1 cell arrest and inhibited the proliferation of PAI-1-positive ovarian cancer cells. In the xenograft model, IMD-4482 significantly inhibited peritoneal dissemination with the reduction of PAI-1 expression and the inhibition of focal adhesion kinase phosphorylation. Collectively, the functional inhibition of PAI-1 significantly inhibited ovarian cancer progression, and targeting PAI-1 may be a potential therapeutic strategy in ovarian cancer.
Directory of Open Access Journals (Sweden)
Nash Guy F
2007-09-01
Full Text Available Abstract Background Women that carry germ-line mutations for BRCA1 or BRCA2 genes are at an increased risk of developing breast, ovarian and peritoneal cancer. Primary peritoneal carcinoma is a rare tumour histologically identical to papillary serous ovarian carcinoma. Risk-reducing surgery in the form of mastectomy and oophorectomy in premenopausal women has been recommended to prevent breast and ovarian cancer occurrence and decrease the risk of developing primary peritoneal cancer. Case presentation We present a case report of a woman with a strong family history of breast cancer who underwent risk-reducing surgery in the form of bilateral salpingo-oophorectomy following a mastectomy for a right-sided breast tumour. Following the finding of a BRCA1 mutation, a prophylactic left-sided mastectomy was performed. After remaining well for twenty-seven years, she presented with rectal bleeding and altered bowel habit, and was found to have a secondary cancer of the sigmoid colon. She was finally diagnosed with primary papillary serous carcinoma of the peritoneum (PSCP. Conclusion PSCP can present many years after risk-reducing surgery and be difficult to detect. Surveillance remains the best course of management for patients with known BRCA mutations.
YY1 modulates taxane response in epithelial ovarian cancer
Energy Technology Data Exchange (ETDEWEB)
Matsumura, Noriomi; Huang, Zhiqing; Baba, Tsukasa; Lee, Paula S.; Barnett, Jason C.; Mori, Seiichi; Chang, Jeffrey T.; Kuo, Wen-Lin; Gusberg, Alison H.; Whitaker, Regina S.; Gray, JoeW.; Fujii, Shingo; Berchuck, Andrew; Murphy, Susan K.
2008-10-10
The results of this study show that a high YY1 gene signature (characterized by coordinate elevated expression of transcription factor YY1 and putative YY1 target genes) within serous epithelial ovarian cancers is associated with enhanced response to taxane-based chemotherapy and improved survival. If confirmed in a prospective study, these results have important implications for the potential future use of individualized therapy in treating patients with ovarian cancer. Identification of the YY1 gene signature profile within a tumor prior to initiation of chemotherapy may provide valuable information about the anticipated response of these tumors to taxane-based drugs, leading to better informed decisions regarding chemotherapeutic choice. Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer (SEOC) were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary SEOC and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using siRNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in SEOC and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA crosslinking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1
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Nanjundan, Meera; Cheng, Kwai Wa; Zhang, Fan; Lahad, John; Kuo, Wen-Lin; Schmandt, Rosemarie; Smith-McCune, Karen; Fishman, David; Gray, Joe W.; Mills, Gordon B.
2008-07-18
High-resolution array comparative genomic hybridization of 235 serous epithelial ovarian cancers demonstrated a regional increase at 3q26.2 encompassing SnoN/SkiL, a coregulator of SMAD/TGF{beta} signaling. SnoN RNA transcripts were elevated in {approx}80% of advanced stage serous epithelial ovarian cancers. In both immortalized normal (TIOSE) and ovarian carcinoma cell lines (OVCA), SnoN RNA levels were increased by TGF{beta} stimulation and altered by LY294002 and JNK II inhibitor treatment suggesting that the PI3K and JNK signaling pathways may regulate TGF{beta}-induced increases in SnoN RNA. In TIOSE, SnoN protein levels were reduced 15min post TGF{beta}-stimulation, likely by proteosome-mediated degradation. In contrast, in OVCA, SnoN levels were elevated 3h post-stimulation potentially as a result of inhibition of the proteosome. To elucidate the role of SnoN in ovarian tumorigenesis, we explored the effects of both increasing and decreasing SnoN levels. In both TIOSE and OVCA, SnoN siRNA decreased cell growth between 20 and 50% concurrent with increased p21 levels. In TIOSE, transient expression of SnoN repressed TGF{beta} induction of PAI-1 promoters with little effect on the p21 promoter or resultant cell growth. In contrast to the effects of transient expression, stable expression of SnoN in TIOSE led to growth arrest through induction of senescence. Collectively, these results implicate SnoN levels in multiple roles during ovarian carcinogenesis: promoting cellular proliferation in ovarian cancer cells and as a positive mediator of cell cycle arrest and senescence in non-transformed ovarian epithelial cells.
Creighton, Chad J; Hernandez-Herrera, Anadulce; Jacobsen, Anders; Levine, Douglas A; Mankoo, Parminder; Schultz, Nikolaus; Du, Ying; Zhang, Yiqun; Larsson, Erik; Sheridan, Robert; Xiao, Weimin; Spellman, Paul T; Getz, Gad; Wheeler, David A; Perou, Charles M; Gibbs, Richard A; Sander, Chris; Hayes, D Neil; Gunaratne, Preethi H
2012-01-01
The Cancer Genome Atlas (TCGA) Network recently comprehensively catalogued the molecular aberrations in 487 high-grade serous ovarian cancers, with much remaining to be elucidated regarding the microRNAs (miRNAs). Here, using TCGA ovarian data, we surveyed the miRNAs, in the context of their predicted gene targets. Integration of miRNA and gene patterns yielded evidence that proximal pairs of miRNAs are processed from polycistronic primary transcripts, and that intronic miRNAs and their host gene mRNAs derive from common transcripts. Patterns of miRNA expression revealed multiple tumor subtypes and a set of 34 miRNAs predictive of overall patient survival. In a global analysis, miRNA:mRNA pairs anti-correlated in expression across tumors showed a higher frequency of in silico predicted target sites in the mRNA 3'-untranslated region (with less frequency observed for coding sequence and 5'-untranslated regions). The miR-29 family and predicted target genes were among the most strongly anti-correlated miRNA:mRNA pairs; over-expression of miR-29a in vitro repressed several anti-correlated genes (including DNMT3A and DNMT3B) and substantially decreased ovarian cancer cell viability. This study establishes miRNAs as having a widespread impact on gene expression programs in ovarian cancer, further strengthening our understanding of miRNA biology as it applies to human cancer. As with gene transcripts, miRNAs exhibit high diversity reflecting the genomic heterogeneity within a clinically homogeneous disease population. Putative miRNA:mRNA interactions, as identified using integrative analysis, can be validated. TCGA data are a valuable resource for the identification of novel tumor suppressive miRNAs in ovarian as well as other cancers.
Dynamics of the Intratumoral Immune Response during Progression of High-Grade Serous Ovarian Cancer
Directory of Open Access Journals (Sweden)
Mandy Stanske
2018-03-01
Full Text Available PURPOSE: Tumor-infiltrating lymphocytes (TILs have an established impact on the prognosis of high-grade serous ovarian carcinoma (HGSOC, however, their role in recurrent ovarian cancer is largely unknown. We therefore systematically investigated TIL densities and MHC class I and II (MHC1, 2 expression in the progression of HGSOC. EXPERIMENTAL DESIGN: CD3+, CD4+, CD8+ TILs and MHC1, 2 expression were evaluated by immunohistochemistry on tissue microarrays in 113 paired primary and recurrent HGSOC. TILs were quantified by image analysis. All patients had been included to the EU-funded OCTIPS FP7 project. RESULTS: CD3+, CD4+, CD8+ TILs and MHC1 and MHC2 expression showed significant correlations between primary and recurrent tumor levels (Spearman rho 0.427, 0.533, 0.361, 0.456, 0.526 respectively; P<.0001 each. Paired testing revealed higher CD4+ densities and MHC1 expression in recurrent tumors (Wilcoxon P=.034 and P=.018. There was also a shift towards higher CD3+ TILs levels in recurrent carcinomas when analyzing platinum-sensitive tumors only (Wilcoxon P=.026 and in pairs with recurrent tumor tissue from first relapse only (Wilcoxon P=.031. High MHC2 expression was the only parameter to be significantly linked to prolonged progression-free survival after first relapse (PFS2, log-rank P=.012. CONCLUSIONS: This is the first study that analyzed the development of TILs density and MHC expression in paired primary and recurrent HGSOC. The level of the antitumoral immune response in recurrent tumors was clearly dependent on the one in the primary tumor. Our data contribute to the understanding of temporal heterogeneity of HGSOC immune microenvironment and have implications for selection of samples for biomarker testing in the setting of immune-targeting therapeutics.
The role of appendectomy in surgical procedures for ovarian cancer.
Fontanelli, R; Paladini, D; Raspagliesi, F; di Re, E
1992-07-01
To assess the role of appendectomy in the surgical procedures for ovarian cancer, we evaluated retrospectively the clinical charts of 435 patients who underwent surgery after diagnosis of ovarian cancer. The appendix was removed in 160 cases and pathological examination revealed 37 with metastatic implants (23%). All the patients with appendiceal metastases showed advanced disease (stages III-IV) with an incidence of 43%. Ninety-one percent (31/34) of the tumors with appendiceal involvement at the staging operation were of the serous cell type and grade II or III. No case with early stage, right ovary carcinoma showed appendiceal metastatic foci, denying the existence of a preferential lymphatic pathway. Microscopic involvement was found only in 4 patients with advanced disease (11.7%). No intra- or postoperative complication directly related to the appendectomy was recorded. We conclude, with these results, that appendectomy should be part of the cytoreductive operation for ovarian cancer.
Role of the immune system in the peritoneal tumor spread of high grade serous ovarian cancer.
Auer, Katharina; Bachmayr-Heyda, Anna; Sukhbaatar, Nyamdelger; Aust, Stefanie; Schmetterer, Klaus G; Meier, Samuel M; Gerner, Christopher; Grimm, Christoph; Horvat, Reinhard; Pils, Dietmar
2016-09-20
The immune system plays a critical role in cancer progression and overall survival. Still, it is unclear if differences in the immune response are associated with different patterns of tumor spread apparent in high grade serous ovarian cancer patients and previously described by us. In this study we aimed to assess the role of the immune system in miliary (widespread, millet-sized lesions) and non-miliary (bigger, exophytically growing implants) tumor spread. To achieve this we comprehensively analyzed tumor tissues, blood, and ascites from 41 patients using immunofluorescence, flow cytometry, RNA sequencing, multiplexed immunoassays, and immunohistochemistry. Results showed that inflammation markers were systemically higher in miliary. In contrast, in non-miliary lymphocyte and monocyte/macrophage infiltration into the ascites was higher as well as the levels of PD-1 expression in tumor associated cytotoxic T-lymphocytes and PD-L1 expression in tumor cells. Furthermore, in ascites of miliary patients more epithelial tumor cells were present compared to non-miliary, possibly due to the active down-regulation of anti-tumor responses by B-cells and regulatory T-cells. Summarizing, adaptive immune responses prevailed in patients with non-miliary spread, whereas in patients with miliary spread a higher involvement of the innate immune system was apparent while adaptive responses were counteracted by immune suppressive cells and factors.
A novel serum microRNA panel to discriminate benign from malignant ovarian disease.
LENUS (Irish Health Repository)
Langhe, Ream
2015-01-28
Ovarian cancer is the seventh most common cancer in women and the most frequent cause of gynaecological malignancy-related mortality in women. Currently, no standardized reliable screening test exists. MicroRNA profiling has allowed the identification of signatures associated with diagnosis, prognosis and response to treatment of human tumours. The aim of this study was to determine if a microRNA signature could distinguish between malignant and benign ovarian disease. A training set of 5 serous ovarian carcinomas and 5 benign serous cystadenomas were selected for the initial experiments. The validation set included 20 serous ovarian carcinomas and 20 benign serous cystadenomas. The serum\\/plasma focus microRNA Exiqon panel was used for the training set. For the validation set a pick and mix Exiqon panel, which focuses on microRNAs of interest was used. A panel of 4 microRNAs (let-7i-5p, miR-122, miR-152-5p and miR-25-3p) was significantly down regulated in cancer patients. These microRNAs target WNT signalling, AKT\\/mTOR and TLR-4\\/MyD88, which have previously been found to play a role in ovarian carcinogenesis and chemoresistance. let-7i-5p, miR-122, miR-152-5p and miR-25-3p could act as diagnostic biomarkers in ovarian cancer.
Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer
Phelan, Catherine M.; Kuchenbaecker, Karoline B.; Tyrer, Jonathan P.; Kar, Siddhartha P.; Lawrenson, Kate; Winham, Stacey J.; Dennis, Joe; Pirie, Ailith; Riggan, Marjorie J.; Chornokur, Ganna; Earp, Madalene A.; Lyra, Paulo C.; Lee, Janet M.; Coetzee, Simon; Beesley, Jonathan; McGuffog, Lesley; Soucy, Penny; Dicks, Ed; Lee, Andrew; Barrowdale, Daniel; Lecarpentier, Julie; Leslie, Goska; Aalfs, Cora M.; Aben, Katja K. H.; Adams, Marcia; Adlard, Julian; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia; Aravantinos, Gerasimos; Arnold, Norbert; Arun, Banu K.; Arver, Brita; Azzollini, Jacopo; Balmaña, Judith; Banerjee, Susana N.; Barjhoux, Laure; Barkardottir, Rosa B.; Bean, Yukie; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Bernardini, Marcus Q.; Birrer, Michael J.; Bjorge, Line; Black, Amanda; Blankstein, Kenneth; Blok, Marinus J.; Bodelon, Clara; Bogdanova, Natalia; Bojesen, Anders; Bonanni, Bernardo; Borg, Åke; Bradbury, Angela R.; Brenton, James D.; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Bruinsma, Fiona; Brunet, Joan; Buecher, Bruno; Butzow, Ralf; Buys, Saundra S.; Caldes, Trinidad; Caligo, Maria A.; Campbell, Ian; Cannioto, Rikki; Carney, Michael E.; Cescon, Terence; Chan, Salina B.; Chang-Claude, Jenny; Chanock, Stephen; Chen, Xiao Qing; Chiew, Yoke-Eng; Chiquette, Jocelyne; Chung, Wendy K.; Claes, Kathleen B. M.; Conner, Thomas; Cook, Linda S.; Cook, Jackie; Cramer, Daniel W.; Cunningham, Julie M.; D'Aloisio, Aimee A.; Daly, Mary B.; Damiola, Francesca; Damirovna, Sakaeva Dina; Dansonka-Mieszkowska, Agnieszka; Dao, Fanny; Davidson, Rosemarie; Defazio, Anna; Delnatte, Capucine; Doheny, Kimberly F.; Diez, Orland; Ding, Yuan Chun; Doherty, Jennifer Anne; Domchek, Susan M.; Dorfling, Cecilia M.; Dörk, Thilo; Dossus, Laure; Duran, Mercedes; Dürst, Matthias; Dworniczak, Bernd; Eccles, Diana; Edwards, Todd; Eeles, Ros; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B.; Ellis, Steve; Elvira, Mingajeva; Eng, Kevin H.; Engel, Christoph; Evans, D. Gareth; Fasching, Peter A.; Ferguson, Sarah; Ferrer, Sandra Fert; Flanagan, James M.; Fogarty, Zachary C.; Fortner, Renée T.; Fostira, Florentia; Foulkes, William D.; Fountzilas, George; Fridley, Brooke L.; Friebel, Tara M.; Friedman, Eitan; Frost, Debra; Ganz, Patricia A.; Garber, Judy; García, María J.; Garcia-Barberan, Vanesa; Gehrig, Andrea; Gentry-Maharaj, Aleksandra; Gerdes, Anne-Marie; Giles, Graham G.; Glasspool, Rosalind; Glendon, Gord; Godwin, Andrew K.; Goldgar, David E.; Goranova, Teodora; Gore, Martin; Greene, Mark H.; Gronwald, Jacek; Gruber, Stephen; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hamann, Ute; Hansen, Thomas V. O.; Harrington, Patricia A.; Harris, Holly R.; Hauke, Jan; Hein, Alexander; Henderson, Alex; Hildebrandt, Michelle A. T.; Hillemanns, Peter; Hodgson, Shirley; Høgdall, Claus K.; Høgdall, Estrid; Hogervorst, Frans B. L.; Holland, Helene; Hooning, Maartje J.; Hosking, Karen; Huang, Ruea-Yea; Hulick, Peter J.; Hung, Jillian; Hunter, David J.; Huntsman, David G.; Huzarski, Tomasz; Imyanitov, Evgeny N.; Isaacs, Claudine; Iversen, Edwin S.; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jernetz, Mats; Jensen, Allan; Jensen, Uffe Birk; John, Esther M.; Johnatty, Sharon; Jones, Michael E.; Kannisto, Päivi; Karlan, Beth Y.; Karnezis, Anthony; Kast, Karin; Kennedy, Catherine J.; Khusnutdinova, Elza; Kiemeney, Lambertus A.; Kiiski, Johanna I.; Kim, Sung-Won; Kjaer, Susanne K.; Köbel, Martin; Kopperud, Reidun K.; Kruse, Torben A.; Kupryjanczyk, Jolanta; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Larrañaga, Nerea; Larson, Melissa C.; Lazaro, Conxi; Le, Nhu D.; Le Marchand, Loic; Lee, Jong Won; Lele, Shashikant B.; Leminen, Arto; Leroux, Dominique; Lester, Jenny; Lesueur, Fabienne; Levine, Douglas A.; Liang, Dong; Liebrich, Clemens; Lilyquist, Jenna; Lipworth, Loren; Lissowska, Jolanta; Lu, Karen H.; Lubinński, Jan; Luccarini, Craig; Lundvall, Lene; Mai, Phuong L.; Mendoza-Fandiño, Gustavo; Manoukian, Siranoush; Massuger, Leon F. A. G.; May, Taymaa; Mazoyer, Sylvie; McAlpine, Jessica N.; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain; Meijers-Heijboer, Hanne; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R.; Merritt, Melissa A.; Milne, Roger L.; Mitchell, Gillian; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moffitt, Melissa; Montagna, Marco; Moysich, Kirsten B.; Mulligan, Anna Marie; Musinsky, Jacob; Nathanson, Katherine L.; Nedergaard, Lotte; Ness, Roberta B.; Neuhausen, Susan L.; Nevanlinna, Heli; Niederacher, Dieter; Nussbaum, Robert L.; Odunsi, Kunle; Olah, Edith; Olopade, Olufunmilayo I.; Olsson, Håkan; Olswold, Curtis; O'Malley, David M.; Ong, Kai-Ren; Onland-Moret, N. Charlotte; Orr, Nicholas; Orsulic, Sandra; Osorio, Ana; Palli, Domenico; Papi, Laura; Park-Simon, Tjoung-Won; Paul, James; Pearce, Celeste L.; Pedersen, Inge Søkilde; Peeters, Petra H. M.; Peissel, Bernard; Peixoto, Ana; Pejovic, Tanja; Pelttari, Liisa M.; Permuth, Jennifer B.; Peterlongo, Paolo; Pezzani, Lidia; Pfeiler, Georg; Phillips, Kelly-Anne; Piedmonte, Marion; Pike, Malcolm C.; Piskorz, Anna M.; Poblete, Samantha R.; Pocza, Timea; Poole, Elizabeth M.; Poppe, Bruce; Porteous, Mary E.; Prieur, Fabienne; Prokofyeva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pujol, Pascal; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rhiem, Kerstin; Rice, Patricia; Richardson, Andrea; Robson, Mark; Rodriguez, Gustavo C.; Rodríguez-Antona, Cristina; Romm, Jane; Rookus, Matti A.; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Salvesen, Helga B.; Sandler, Dale P.; Schoemaker, Minouk J.; Senter, Leigha; Setiawan, V. Wendy; Severi, Gianluca; Sharma, Priyanka; Shelford, Tameka; Siddiqui, Nadeem; Side, Lucy E.; Sieh, Weiva; Singer, Christian F.; Sobol, Hagay; Song, Honglin; Southey, Melissa C.; Spurdle, Amanda B.; Stadler, Zsofia; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sucheston-Campbell, Lara E.; Sukiennicki, Grzegorz; Sutphen, Rebecca; Sutter, Christian; Swerdlow, Anthony J.; Szabo, Csilla I.; Szafron, Lukasz; Tan, Yen Y.; Taylor, Jack A.; tea, Muy-Kheng; Teixeira, Manuel R.; teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Thomsen, Liv Cecilie Vestrheim; Thull, Darcy L.; Tihomirova, Laima; Tinker, Anna V.; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Tone, Alicia; Trabert, Britton; Travis, Ruth C.; Trichopoulou, Antonia; Tung, Nadine; Tworoger, Shelley S.; van Altena, Anne M.; van den Berg, David; van der Hout, Annemarie H.; van der Luijt, Rob B.; van Heetvelde, Mattias; van Nieuwenhuysen, Els; van Rensburg, Elizabeth J.; Vanderstichele, Adriaan; Varon-Mateeva, Raymonda; Vega, Ana; Edwards, Digna Velez; Vergote, Ignace; Vierkant, Robert A.; Vijai, Joseph; Vratimos, Athanassios; Walker, Lisa; Walsh, Christine; Wand, Dorothea; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Webb, Penelope M.; Weinberg, Clarice R.; Weitzel, Jeffrey N.; Wentzensen, Nicolas; Whittemore, Alice S.; Wijnen, Juul T.; Wilkens, Lynne R.; Wolk, Alicja; Woo, Michelle; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Yannoukakos, Drakoulis; Ziogas, Argyrios; Zorn, Kristin K.; Narod, Steven A.; Easton, Douglas F.; Amos, Christopher I.; Schildkraut, Joellen M.; Ramus, Susan J.; Ottini, Laura; Goodman, Marc T.; Park, Sue K.; Kelemen, Linda E.; Risch, Harvey A.; Thomassen, Mads; Offit, Kenneth; Simard, Jacques; Schmutzler, Rita Katharina; Hazelett, Dennis; Monteiro, Alvaro N.; Couch, Fergus J.; Berchuck, Andrew; Chenevix-Trench, Georgia; Goode, Ellen L.; Sellers, Thomas A.; Gayther, Simon A.; Antoniou, Antonis C.; Pharoah, Paul D. P.
2017-01-01
To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC
Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer
DEFF Research Database (Denmark)
Phelan, Catherine M; Kuchenbaecker, Karoline B; Tyrer, Jonathan P
2017-01-01
To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous E...
Directory of Open Access Journals (Sweden)
Katy Milne
Full Text Available BACKGROUND: Tumor-infiltrating T cells are associated with survival in epithelial ovarian cancer (EOC, but their functional status is poorly understood, especially relative to the different risk categories and histological subtypes of EOC. METHODOLOGY/PRINCIPAL FINDINGS: Tissue microarrays containing high-grade serous, endometrioid, mucinous and clear cell tumors were analyzed immunohistochemically for the presence of lymphocytes, dendritic cells, neutrophils, macrophages, MHC class I and II, and various markers of activation and inflammation. In high-grade serous tumors from optimally debulked patients, positive associations were seen between intraepithelial cells expressing CD3, CD4, CD8, CD45RO, CD25, TIA-1, Granzyme B, FoxP3, CD20, and CD68, as well as expression of MHC class I and II by tumor cells. Disease-specific survival was positively associated with the markers CD8, CD3, FoxP3, TIA-1, CD20, MHC class I and class II. In other histological subtypes, immune infiltrates were less prevalent, and the only markers associated with survival were MHC class II (positive association in endometrioid cases and myeloperoxidase (negative association in clear cell cases. CONCLUSIONS/SIGNIFICANCE: Host immune responses to EOC vary widely according to histological subtype and the extent of residual disease. TIA-1, FoxP3 and CD20 emerge as new positive prognostic factors in high-grade serous EOC from optimally debulked patients.
Rucaparib: a new treatment option for ovarian cancer.
Sabatucci, Ilaria; Maltese, Giuseppa; Lepori, Stefano; Tripodi, Elisa; Bogani, Giorgio; Lorusso, Domenica
2018-05-01
Approximately 50% of high-grade serous ovarian cancers present a deficiency in the pathways involved in homologous recombination (HR). PARP inhibitors prevent single-strand DNA damage repair and determine a progression of the defect towards double-strand breaks, which results in a process known as 'synthetic lethality'. Areas covered: In this review, the authors discuss the efficacy and toxicity of rucaparib either as a single agent or as a maintenance treatment for ovarian cancer. This includes the NGS Foundation Medicine evaluation of the role of this drug in the treatment algorithm of ovarian cancer. Moreover, perspectives on the future development of this drug are presented. Expert opinion: The FDA has approved this drug for the treatment of recurrent BRCA-mutated ovarian cancers, which were previously treated with at least two chemotherapies and has accepted the supplemental new drug application for maintenance use in patients who respond to platinum-based chemotherapy via the Prescription Drug User Fee Act (PDUFA) on 6 April 2018. European Medicines Agency (EMA) approval in the same setting is awaited. The possibility of using PARP inhibitors as a maintenance therapy, as a front-line therapy to combat recurrence, and in combination with anti-angiogenic agents and immune-therapies appears to be of particular interest.
Ducie, Jennifer; Dao, Fanny; Considine, Michael; Olvera, Narciso; Shaw, Patricia A; Kurman, Robert J; Shih, Ie-Ming; Soslow, Robert A; Cope, Leslie; Levine, Douglas A
2017-10-17
Many high-grade serous carcinomas (HGSCs) of the pelvis are thought to originate in the distal portion of the fallopian tube. Serous tubal intra-epithelial carcinoma (STIC) lesions are the putative precursor to HGSC and identifiable in ~ 50% of advanced stage cases. To better understand the molecular etiology of HGSCs, we report a multi-center integrated genomic analysis of advanced stage tumors with and without STIC lesions and normal tissues. The most significant focal DNA SCNAs were shared between cases with and without STIC lesions. The RNA sequence and the miRNA data did not identify any clear separation between cases with and without STIC lesions. HGSCs had molecular profiles more similar to normal fallopian tube epithelium than ovarian surface epithelium or peritoneum. The data suggest that the molecular features of HGSCs with and without associated STIC lesions are mostly shared, indicating a common biologic origin, likely to be the distal fallopian tube among all cases.High-grade serous carcinomas (HGSCs) are associated with precursor lesions (STICs) in the fallopian epithelium in only half of the cases. Here the authors report the molecular analysis of HGSCs with and without associated STICs and show similar profiles supporting a common origin for all HGSCs.
Lycopene Protects Against Spontaneous Ovarian Cancer Formation in Laying Hens.
Sahin, Kazim; Yenice, Engin; Tuzcu, Mehmet; Orhan, Cemal; Mizrak, Cengizhan; Ozercan, Ibrahim H; Sahin, Nurhan; Yilmaz, Bahiddin; Bilir, Birdal; Ozpolat, Bulent; Kucuk, Omer
2018-03-01
Dietary intake of lycopene has been associated with a reduced risk of ovarian cancer, suggesting its chemopreventive potential against ovarian carcinogenesis. Lycopene's molecular mechanisms of action in ovarian cancer have not been fully understood. Therefore, in the present study, we investigated the effects of lycopene on the ovarian cancer formation using the laying hen model, a biologically relevant animal model of spontaneous ovarian carcinogenesis due to high incidence rates similar to humans. In this study, a total of 150 laying hens at age of 102 weeks were randomized into groups of 50: a control group (0 mg of lycopene per kg of diet) and two treatment groups (200 mg or 400 mg of lycopene per kg of diet, or ~26 and 52 mg/d/hen, respectively). At the end of 12 months, blood, ovarian tissues and tumors were collected. We observed that lycopene supplementation significantly reduced the overall ovarian tumor incidence ( P Lycopene also significantly decreased the rate of adenocarcinoma, including serous and mucinous subtypes ( P lycopene-fed hens compared to control birds ( P lycopene reduced the expression of NF-κB while increasing the expression of nuclear factor erythroid 2 and its major target protein, heme oxygenase 1. In addition, lycopene supplementation decreased the expression of STAT3 by inducing the protein inhibitor of activated STAT3 expression in the ovarian tissues. Taken together, our findings strongly support the potential of lycopene in the chemoprevention of ovarian cancer through antioxidant and anti-inflammatory mechanisms.
DEFF Research Database (Denmark)
Rasmussen, Emma L Kaderly; Hannibal, Charlotte Gerd; Dehlendorff, Christian
2017-01-01
OBJECTIVE: Few studies have examined the risk of an ovarian serous borderline tumor (SBT) associated with parity, infertility, oral contraceptives (OCs), or hormone replacement therapy (HRT), which was the study aim. METHODS: This nationwide case-control study included all women with an SBT...... diagnosis in Denmark, 1978-2002. SBTs were confirmed by centralized expert pathology review. For each case, 15 age-matched female controls were randomly selected using risk-set sampling. Cases and controls with previous cancer (except for non-melanoma skin cancer) and controls with bilateral oophorectomy...... or salpingo-oophorectomy were excluded. Conditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We found a strongly decreased risk of SBTs among parous women which decreased with increasing number of children (p
Directory of Open Access Journals (Sweden)
Mun-Kun Hong
2015-04-01
Conclusion: The patient had serous carcinoma of the ovary with tubal STIC, which presented as dermatomyositis. The AGC-FN identified from a Pap smear hinted at a diagnosis of ovarian carcinoma. These presentations point to an occult malignancy in the genital tract and demand careful diagnostic workup.
Mittal, Neha; Srinivasan, Radhika; Gupta, Nalini; Rajwanshi, Arvind; Nijhawan, Raje; Gautam, Upasana; Sood, Swati; Dhaliwal, Lakhbir
2016-01-01
High-grade serous carcinomas of ovarian, tubal, and peritoneal origin are together referred as pelvic serous carcinoma. The fallopian tubes, ovarian surface epithelium, and the tuboperitoneal junctional epithelium are all implicated in pelvic serous carcinogenesis. The aim of this study is to identify putative precursor lesions of serous carcinoma including secretory cell outgrowths (SCOUTs), serous tubal intraepithelial carcinoma (STIC), and p53 signatures and assign its probable site of origin. Prospective case-control study of consecutive specimen comprising 32 serous carcinomas and 31 controls (10 normal adnexa, 10 benign and 6 atypically proliferative surface epithelial tumors, and 5 other carcinomas). Sectioning and extensive examination of the fimbrial end (SEE-FIM) protocol along with immunohistochemistry for Bcl-2, p53, and Ki-67 was employed for evaluating invasive carcinoma and precursor lesions in cases versus controls. SCOUT, p53 signatures, and STIC were most frequent in the serous carcinomas. p53 signatures and STIC were always seen in the fimbrial end. STICs were exclusively present in serous carcinomas, more common in ipsilateral tubes of cases with dominant ovarian mass. Multifocal p53 signatures with STIC were seen in 7 (21.9%) cases. STIC was present with or without an invasive carcinoma in 25% and in 6.25% of cases of pelvic serous carcinomas, respectively. The junctional epithelia did not show any lesion in any group. SEE-FIM protocol is recommended for evaluation of sporadicpelvic (ovarian/tubal/peritoneal) serous carcinoma. Based on the presence of STIC or invasive carcinoma, nearly 60% of all pelvic serous carcinomas are of fallopian tubal origin.
Directory of Open Access Journals (Sweden)
Wouter Wegdam
Full Text Available PURPOSE: To identify proteins and (molecular/biological pathways associated with differences between benign and malignant epithelial ovarian tumors. EXPERIMENTAL PROCEDURES: Serum of six patients with a serous adenocarcinoma of the ovary was collected before treatment, with a control group consisting of six matched patients with a serous cystadenoma. In addition to the serum, homogeneous regions of cells exhibiting uniform histology were isolated from benign and cancerous tissue by laser microdissection. We subsequently employed label-free liquid chromatography tandem mass spectrometry (LC-MSe to identify proteins in these serum and tissues samples. Analyses of differential expression between samples were performed using Bioconductor packages and in-house scripts in the statistical software package R. Hierarchical clustering and pathway enrichment analyses were performed, as well as network enrichment and interactome analysis using MetaCore. RESULTS: In total, we identified 20 and 71 proteins that were significantly differentially expressed between benign and malignant serum and tissue samples, respectively. The differentially expressed protein sets in serum and tissue largely differed with only 2 proteins in common. MetaCore network analysis, however inferred GCR-alpha and Sp1 as common transcriptional regulators. Interactome analysis highlighted 14-3-3 zeta/delta, 14-3-3 beta/alpha, Alpha-actinin 4, HSP60, and PCBP1 as critical proteins in the tumor proteome signature based on their relative overconnectivity. The data have been deposited to the ProteomeXchange with identifier PXD001084. DISCUSSION: Our analysis identified proteins with both novel and previously known associations to ovarian cancer biology. Despite the small overlap between differentially expressed protein sets in serum and tissue, APOA1 and Serotransferrin were significantly lower expressed in both serum and cancer tissue samples, suggesting a tissue-derived effect in serum
Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)
DEFF Research Database (Denmark)
Jim, Heather S L; Lin, Hui-Yi; Tyrer, Jonathan P
2015-01-01
where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine...... single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2......,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant...
Discovery of dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer
Directory of Open Access Journals (Sweden)
Nodin Björn
2012-01-01
Full Text Available Abstract Background The Dachshund homolog 2 (DACH2 gene has been implicated in development of the female genital tract in mouse models and premature ovarian failure syndrome, but to date, its expression in human normal and cancerous tissue remains unexplored. Using the Human Protein Atlas as a tool for cancer biomarker discovery, DACH2 protein was found to be differentially expressed in epithelial ovarian cancer (EOC. Here, the expression and prognostic significance of DACH2 was further evaluated in ovarian cancer cell lines and human EOC samples. Methods Immunohistochemical expression of DACH2 was examined in tissue microarrays with 143 incident EOC cases from two prospective, population-based cohorts, including a subset of benign-appearing fallopian tubes (n = 32. A nuclear score (NS, i.e. multiplier of staining fraction and intensity, was calculated. For survival analyses, cases were dichotomized into low (NS 3 using classification and regression tree analysis. Kaplan Meier analysis and Cox proportional hazards modelling were used to assess the impact of DACH2 expression on survival. DACH2 expression was analysed in the cisplatin sensitive ovarian cancer cell line A2780 and its cisplatin resistant derivative A2780-Cp70. The specificity of the DACH2 antibody was tested using siRNA-mediated silencing of DACH2 in A2780-Cp70 cells. Results DACH2 expression was considerably higher in the cisplatin resistant A2780-Cp70 cells compared to the cisplatin-sensitive A2780 cells. While present in all sampled fallopian tubes, DACH2 expression ranged from negative to strong in EOC. In EOC, DACH2 expression correlated with several proteins involved in DNA integrity and repair, and proliferation. DACH2 expression was significantly higher in carcinoma of the serous subtype compared to non-serous carcinoma. In the full cohort, high DACH2 expression was significantly associated with poor prognosis in univariable analysis, and in carcinoma of the serous subtype
Termination of Pregnancy in a Patient with Advanced Ovarian Cancer
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Suna Özdemir
2010-04-01
Full Text Available Ovarian cancer during pregnancy is a rare entity and the management of the disease can be challenging for the patient and the clinician. In this case, we report a case of advanced ovarian carcinoma diagnosed during pregnancy, which was managed with termination of pregnancy and chemotheraphy. The patient was underwent exploratory laparatomy including the right ovarian cystectomy, omentectomy, appendectomy, pelvic and para-aortic lymphadenectomy after frozen section of borderline serous cystadenocarcinoma at the 14 week of gestation. After final histopathology, the patient was staged as having FIGO stage IIIC disease. The pregnancy was termineted with the decision of patient and her family. The patient was treated with chemotheraphy.
Histological and molecular analysis of Fallopian tube precursors in pelvic serous carcinogenesis
Bijron, J.G.
2012-01-01
Epithelial ovarian cancer is the second most common gynaecological cancer, but has the highest fatality-to-case rate, which can be primarily attributed to diagnosis delay due to rapid disease progression and location. This is especially true for the serous subtype, which shows some form of pelvic
International Nuclear Information System (INIS)
Mesquita, Bárbara; Veiga, Isabel; Pereira, Deolinda; Tavares, Ana; Pinto, Isabel M; Pinto, Carla; Teixeira, Manuel R; Castedo, Sérgio
2005-01-01
The mechanisms of chemoresistance in ovarian cancer patients remain largely to be elucidated. Paclitaxel/cisplatin combination is the standard chemotherapeutic treatment for this disease, although some patients do not respond to therapy. Our goals were to investigate whether TUBB mutations and mismatch repair defects underlie paclitaxel and cisplatin resistance. Thirty-four patients with primary ovarian carcinomas (26 serous and eight clear cell carcinomas) treated with paclitaxel/cisplatin were analysed. TUBB exon 4 was analysed by nested PCR after a first round PCR using intronic primers. Microsatellite analysis was performed with the quasimonomorphic markers BAT 26 and BAT 34. Twenty-two of the 34 ovarian cancers (64.7%) presented residual tumour after surgery, seven of which (7/22; 31.8%) were shown to be chemoresistant (five serous and two clear cell tumours). Sequence analysis did not find any mutation in TUBB exon 4. Microsatellite instability was not detected in any of the ovarian carcinomas. We conclude that TUBB exon 4 mutations and mismatch repair defects do not play a significant role in paclitaxel/cisplatin resistance
Recent technological advances in using mouse models to study ovarian cancer.
House, Carrie Danielle; Hernandez, Lidia; Annunziata, Christina Messineo
2014-01-01
Serous epithelial ovarian cancer (SEOC) is the most lethal gynecological cancer in the United States with disease recurrence being the major cause of morbidity and mortality. Despite recent advances in our understanding of the molecular mechanisms responsible for the development of SEOC, the survival rate for women with this disease has remained relatively unchanged in the last two decades. Preclinical mouse models of ovarian cancer, including xenograft, syngeneic, and genetically engineered mice, have been developed to provide a mechanism for studying the development and progression of SEOC. Such models strive to increase our understanding of the etiology and dissemination of ovarian cancer in order to overcome barriers to early detection and resistance to standard chemotherapy. Although there is not a single model that is most suitable for studying ovarian cancer, improvements have led to current models that more closely mimic human disease in their genotype and phenotype. Other advances in the field, such as live animal imaging techniques, allow effective monitoring of the microenvironment and therapeutic efficacy. New and improved preclinical mouse models, combined with technological advances to study such models, will undoubtedly render success of future human clinical trials for patients with SEOC.
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Neha Mittal
2016-01-01
Full Text Available Context: High-grade serous carcinomas of ovarian, tubal, and peritoneal origin are together referred as pelvic serous carcinoma. The fallopian tubes, ovarian surface epithelium, and the tuboperitoneal junctional epithelium are all implicated in pelvic serous carcinogenesis. Aims: The aim of this study is to identify putative precursor lesions of serous carcinoma including secretory cell outgrowths (SCOUTs, serous tubal intraepithelial carcinoma (STIC, and p53 signatures and assign its probable site of origin. Settings and Design: Prospective case-control study of consecutive specimen comprising 32 serous carcinomas and 31 controls (10 normal adnexa, 10 benign and 6 atypically proliferative surface epithelial tumors, and 5 other carcinomas. Subjects and Methods: Sectioning and extensive examination of the fimbrial end (SEE-FIM protocol along with immunohistochemistry for Bcl-2, p53, and Ki-67 was employed for evaluating invasive carcinoma and precursor lesions in cases versus controls. Results: SCOUT, p53 signatures, and STIC were most frequent in the serous carcinomas. p53 signatures and STIC were always seen in the fimbrial end. STICs were exclusively present in serous carcinomas, more common in ipsilateral tubes of cases with dominant ovarian mass. Multifocal p53 signatures with STIC were seen in 7 (21.9% cases. STIC was present with or without an invasive carcinoma in 25% and in 6.25% of cases of pelvic serous carcinomas, respectively. The junctional epithelia did not show any lesion in any group. Conclusions: SEE-FIM protocol is recommended for evaluation of sporadicpelvic (ovarian/tubal/peritoneal serous carcinoma. Based on the presence of STIC or invasive carcinoma, nearly 60% of all pelvic serous carcinomas are of fallopian tubal origin.
A nationwide study of serous “borderline” ovarian tumors in Denmark 1978–2002
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Hannibal, Charlotte Gerd; Vang, Russell; Junge, Jette
2014-01-01
OBJECTIVE: To describe the study population and estimate overall survival of women with a serous "borderline" ovarian tumor (SBT) in Denmark over 25 years relative to the general population. METHODS: The Danish Pathology Data Bank and the Danish Cancer Registry were used to identify 1487 women...... as noninvasive or invasive. Medical records were collected from hospital departments and reviewed. Data were analyzed using Kaplan-Meier and relative survival was estimated with follow-up through September 2, 2013. RESULTS: A cohort of 1042 women with a confirmed SBT diagnosis was identified. Women with stage I...... had an overall survival similar to the overall survival expected from the general population (p=0.3), whereas women with advanced stage disease had a poorer one (pwomen with noninvasive (pwomen with advanced stage...
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Ernest K Amankwah
Full Text Available Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN and lumican (LUM show reduced stromal expression in serous epithelial ovarian cancer (sEOC. We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR among 397 cases and 920 controls in two U.S.-based studies (discovery set, 436 cases and 1,098 controls in Australia (replication set 1 and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2. The discovery set and replication set 1 (833 cases and 2,013 controls showed statistically homogeneous (P(heterogeneity≥0.48 decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; P(trend = 0.001 to 0.03. Results from replication set 2 were statistically homogeneous (P(heterogeneity≥0.13 and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; P(trend≤0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (P(heterogeneity≤0.03, which precluded combining. In post-hoc analyses, interactions were observed between each variant and recruitment period (P(interaction≤0.003, age at diagnosis (P(interaction = 0.04, and year of diagnosis (P(interaction = 0.05 in the five studies with available information (1,044 cases, 2,469 controls. We conclude that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required.
Tumor-associated auto-antibodies as early detection markers for ovarian cancer?
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Kaaks, Rudolf; Fortner, Renée Turzanski; Hüsing, Anika
2018-01-01
.08-0.40] for CTAG1A, CTAG2 and NUDT1 to 0.23 [0.10-0.44] for P53 (0.33 [0.11-0.68] for high-grade serous tumors). However, at longer lead-times the ability of these AAb markers to distinguish future ovarian cancer cases from controls declined rapidly; at lead times >1 year, SE98 estimates were close to zero (all...... invasive cases, range: 0.01-0.11). Compared to CA125 alone, combined logistic regression scores of AAbs and CA125 did not improve detection sensitivity at equal level of specificity. The added value of these selected AAbs as markers for ovarian cancer beyond CA125 for early detection is therefore limited...
DEFF Research Database (Denmark)
Lawrenson, Kate; Kar, Siddhartha; McCue, Karen
2016-01-01
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER......'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk....
Bogani, Giorgio; Tagliabue, Elena; Ditto, Antonino; Signorelli, Mauro; Martinelli, Fabio; Casarin, Jvan; Chiappa, Valentina; Dondi, Giulia; Leone Roberti Maggiore, Umberto; Scaffa, Cono; Borghi, Chiara; Montanelli, Luca; Lorusso, Domenica; Raspagliesi, Francesco
2017-10-01
To estimate the prevalence of lymph node involvement in early-stage epithelial ovarian cancer in order to assess the prognostic value of lymph node dissection. Data of consecutive patients undergoing staging for early-stage epithelial ovarian cancer were retrospectively evaluated. Logistic regression and a nomogram-based analysis were used to assess the risk of lymph node involvement. Overall, 290 patients were included. All patients had lymph node dissection including pelvic and para-aortic lymphadenectomy. Forty-two (14.5%) patients were upstaged due to lymph node metastatic disease. Pelvic and para-aortic nodal metastases were observed in 22 (7.6%) and 42 (14.5%) patients. Lymph node involvement was observed in 18/95 (18.9%), 1/37 (2.7%), 4/29 (13.8%), 11/63 (17.4%), 3/41 (7.3%) and 5/24 (20.8%) patients with high-grade serous, low-grade-serous, endometrioid G1, endometrioid G2&3, clear cell and undifferentiated, histology, respectively (p=0.12, Chi-square test). We observed that high-grade serous histology was associated with an increased risk of pelvic node involvement; while, histology rather than low-grade serous and bilateral tumors were independently associated with para-aortic lymph node involvement (p<0.05). Nomograms displaying the risk of nodal involvement in the pelvic and para-aortic areas were built. High-grade serous histology and bilateral tumors are the main characteristics suggesting lymph node positivity. Our data suggested that high-grade serous and bilateral early-stage epithelial ovarian cancer are at high risk of having disease harboring in the lymphatic tissues of both pelvic and para-aortic area. After receiving external validation, our data will help to identify patients deserving comprehensive retroperitoneal staging. Copyright © 2017 Elsevier Inc. All rights reserved.
Grandi, Giovanni; Toss, Angela; Cortesi, Laura; Botticelli, Laura; Volpe, Annibale; Cagnacci, Angelo
2015-01-01
Although endometriosis frequently involves multiple sites in the pelvis, malignancies associated with this disease are mostly confined to the ovaries, evolving from an endometrioma. Endometriomas present a 2-3-fold increased risk of transformation in clear-cell, endometrioid, and possibly low-grade serous ovarian cancers, but not in mucinous ovarian cancers. These last cancers are, in some aspects, different from the other epithelial ovarian cancers, as they do not appear to be decreased by the inhibition of ovulation and menstruation. The step by step process of transformation from typical endometrioma, through atypical endometrioma, finally to ovarian cancer seems mainly related to oxidative stress, inflammation, hyperestrogenism, and specific molecular alterations. Particularly, activation of oncogenic KRAS and PI3K pathways and inactivation of tumor suppressor genes PTEN and ARID1A are suggested as major pathogenic mechanisms for endometriosis associated clear-cell and endometrioid ovarian cancer. Both the risk for endometriomas and their associated ovarian cancers seems to be highly and similarly decreased by the inhibition of ovulation and retrograde menstruation, suggesting a common pathogenetic mechanism and common possible preventive strategies during reproductive life.
Conservative management of epithelial ovarian cancer.
Dexeus, S; Labastida, R; Dexeus, D
2005-01-01
We are currently faced with a progressive delay in the age at which women conceive for the first time. This raises the possibility of the appearance of gynecologic disorders that may affect fertility, including neoplasms of the ovary. Fertility-sparing surgery is defined as the preservation of ovarian tissue in one or both adnexa and/or the uterus. Borderline ovarian tumor should be treated with conservative surgery. Salpingo-oophorectomy, or even ovarian cystectomy, are the procedures of choice, with recurrence rates of 2-3% and up to 20% if a simple cystectomy is performed. Cystectomy is indicated in patients with bilateral borderline tumors or in patients with a residual ovary. Borderline tumors with invasive peritoneal implants behave as an invasive cancer in 10-30% of cases with a survival rate of 10-66% compared with 100% in borderline tumors without invasive implants. Prophylactic oophorectomy is recommended when desire of conception has been accomplished. Conservative surgery in invasive epithelial ovarian cancer is limited to Stage IA, grade 1 tumor, and in some highly selected grade 2 tumors of serous, mucinous or endometrioid type, well-encapsulated and free of adhesions. The standard oncological surgical procedure with preservation of the uterus and normal appearing ovary is recommended. This includes salpingo-oophorectomy, excision of any suspicious peritoneal lesion, multiple peritoneal biopsies, appendectomy (particularly in mucinous tumors), and pelvic and paraaortic lymphadenectomy.
New perspectives on targeted therapy in ovarian cancer
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Coward JIG
2015-02-01
Full Text Available Jermaine IG Coward,1–3 Kathryn Middleton,1 Felicity Murphy1 1Mater Health Services, Raymond Terrace, South Brisbane, QLD, Australia; 2Inflammtion and Cancer Therapeutics Group, Mater Research, University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, Australia; 3School of Medicine, University of Queensland, Brisbane, QLD, Australia Abstract: Epithelial ovarian cancer remains the most lethal gynecologic malignancy. During the last 15 years, there has been only marginal improvement in 5 year overall survival. These daunting statistics are compounded by the fact that despite all subtypes exhibiting striking heterogeneity, their systemic management remains identical. Although changes to the scheduling and administration of chemotherapy have improved outcomes to a degree, a therapeutic ceiling is being reached with this approach, resulting in a number of trials investigating the efficacy of targeted therapies alongside standard treatment algorithms. Furthermore, there is an urge to develop subtype-specific studies in an attempt to improve outcomes, which currently remain poor. This review summarizes the key studies with antiangiogenic agents, poly(adenosine diphosphate [ADP]-ribose inhibitors, and epidermal growth factor receptor/human epidermal growth factor receptor family targeting, in addition to folate receptor antagonists and insulin growth factor receptor inhibitors. The efficacy of treatment paradigms used in non-ovarian malignancies for type I tumors is also highlighted, in addition to recent advances in appropriate patient stratification for targeted therapies in epithelial ovarian cancer. Keywords: antiangiogenic therapy, high-grade serous, low grade ovarian cancer, PARP inhibition, cancer-related inflammation
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Ditzel, Helena M; Strickland, Kyle C; Meserve, Emily E
2018-01-01
A chemotherapy response score (CRS) system was recently described to assess the histopathologic response and prognosis of patients with tubo-ovarian high-grade serous carcinoma (HGSC) receiving neoadjuvant chemotherapy. The current study was performed as an independent assessment of this CRS syst...
International Nuclear Information System (INIS)
Nykopp, Timo K; Anttila, Maarit; Rilla, Kirsi; Sironen, Reijo; Tammi, Markku I; Tammi, Raija H; Hämäläinen, Kirsi; Heikkinen, Anna-Mari; Komulainen, Marja; Kosma, Veli-Matti
2009-01-01
Hyaluronan, a tumor promoting extracellular matrix polysaccharide, is elevated in malignant epithelial ovarian tumors, and associates with an unfavorable prognosis. To explore possible contributors to the accumulation of hyaluronan, we examined the expression of hyaluronan synthases (HAS1, HAS2 and HAS3) and hyaluronidases (HYAL1 and HYAL2), correlated with hyaluronidase enzyme activity hyaluronan content and HAS1–3 immunoreactivity. Normal ovaries (n = 5) and 34 serous epithelial ovarian tumors, divided into 4 groups: malignant grades 1+2 (n = 10); malignant grade 3 (n = 10); borderline (n = 4) and benign epithelial tumors (n = 10), were analyzed for mRNA by real-time RT-PCR and compared to hyaluronidase activity, hyaluronan staining, and HAS1–3 immunoreactivity in tissue sections of the same specimens. The levels of HAS2 and HAS3 mRNA (HAS1 was low or absent), were not consistently increased in the carcinomas, and were not significantly correlated with HAS protein or hyaluronan accumulation in individual samples. Instead, the median of HYAL1 mRNA level was 69% lower in grade 3 serous ovarian cancers compared to normal ovaries (P = 0.01). The expression of HYAL1, but not HYAL2, significantly correlated with the enzymatic activity of tissue hyaluronidases (r = 0.5; P = 0.006). An inverse correlation was noted between HYAL1 mRNA and the intensity of hyaluronan staining of the corresponding tissue sections (r = -0.4; P = 0.025). The results indicate that in serous epithelial ovarian malignancies HAS expression is not consistently elevated but HYAL1 expression is significantly reduced and correlates with the accumulation of hyaluronan. (233 words)
Coalition of Oct4A and β1 integrins in facilitating metastasis in ovarian cancer
International Nuclear Information System (INIS)
Samardzija, Chantel; Luwor, Rodney B.; Quinn, Michael A.; Kannourakis, George; Findlay, Jock K.; Ahmed, Nuzhat
2016-01-01
Ovarian cancer is a metastatic disease and one of the leading causes of gynaecology malignancy-related deaths in women. Cancer stem cells (CSCs) are key contributors of cancer metastasis and relapse. Integrins are a family of cell surface receptors which allow interactions between cells and their surrounding microenvironment and play a fundamental role in promoting metastasis. This study investigates the molecular mechanism which associates CSCs and integrins in ovarian cancer metastasis. The expression of Oct4A in high-grade serous ovarian tumors and normal ovaries was determined by immunofluorescence analysis. The functional role of Oct4A was evaluated by generating stable knockdown (KD) of Oct4A clones in an established ovarian cancer cell line HEY using shRNA-mediated silencing. The expression of integrins in cell lines was evaluated by flow cytometry. Spheroid forming ability, adhesion and the activities of matrix metalloproteinases 9/2 (MMP-9/2) was measured by in vitro functional assays and gelatin zymography. These observations were further validated in in vivo mouse models using Balb/c nu/nu mice. We report significantly elevated expression of Oct4A in high-grade serous ovarian tumors compared to normal ovarian tissues. The expression of Oct4A in ovarian cancer cell lines correlated with their CSC-related sphere forming abilities. The suppression of Oct4A in HEY cells resulted in a significant diminution of integrin β1 expression and associated α5 and α2 subunits compared to vector control cells. This was associated with a reduced adhesive ability on collagen and fibronectin and decreased secretion of pro-MMP2 in Oct4A KD cells compared to vector control cells. In vivo, Oct4A knock down (KD) cells produced tumors which were significantly smaller in size and weight compared to tumors derived from vector control cells. Immunohistochemical analyses of Oct4A KD tumor xenografts demonstrated a significant loss of cytokeratin 7 (CK7), Glut-1 as well as CD34
Harris, H R; Titus, L J; Cramer, D W; Terry, K L
2017-01-15
Long and irregular menstrual cycles, a hallmark of polycystic ovary syndrome (PCOS), have been associated with higher androgen and lower sex hormone binding globulin levels and this altered hormonal environment may increase the risk of specific histologic subtypes of ovarian cancer. We investigated whether menstrual cycle characteristics and self-reported PCOS were associated with ovarian cancer risk among 2,041 women with epithelial ovarian cancer and 2,100 controls in the New England Case-Control Study (1992-2008). Menstrual cycle irregularity, menstrual cycle length, and PCOS were collected through in-person interview. Unconditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) for ovarian cancer risk overall, and polytomous logistic regression to evaluate whether risk differed between histologic subtypes. Overall, we observed no elevation in ovarian cancer risk for women who reported periods that were never regular or for those reporting a menstrual cycle length of >35 days with ORs of 0.87 (95% CI = 0.69-1.10) and 0.83 (95% CI = 0.44-1.54), respectively. We observed no overall association between self-reported PCOS and ovarian cancer (OR = 0.97; 95% CI = 0.61-1.56). However, we observed significant differences in the association with menstrual cycle irregularity and risk of ovarian cancer subtypes (p heterogeneity = 0.03) as well as by BMI and OC use (p interaction < 0.01). Most notable, menstrual cycle irregularity was associated with a decreased risk of high grade serous tumors but an increased risk of serous borderline tumors among women who had never used OCs and those who were overweight. Future research in a large collaborative consortium may help clarify these associations. © 2016 UICC.
Appendiceal pathology at the time of oophorectomy for ovarian neoplasms.
Timofeev, Julia; Galgano, Mary T; Stoler, Mark H; Lachance, Jason A; Modesitt, Susan C; Jazaeri, Amir A
2010-12-01
To investigate the prevalence of appendiceal pathology in women undergoing surgery for a suspected ovarian neoplasm and the predictive value of intraoperative findings to determine the need for appendectomy at the time of surgery. Retrospective analysis of patients who underwent oophorectomy and appendectomy during the same surgical procedures at the University of Virginia Health System from 1992 to 2007. Observations were stratified based on the nature (benign, borderline, or malignant) and histology (serous compared with mucinous) of the ovarian neoplasm, frozen compared with final pathological diagnosis, and the gross appearance of the appendix. Among the 191 patients identified, frozen section was consistent with seven mucinous and 35 serous carcinomas, 16 serous and 33 mucinous borderline tumors, 71 mucinous and serous cystadenomas, and 29 cases of suspected metastatic tumor from a gastrointestinal primary. The highest rates of coexisting appendiceal pathology were associated with serous ovarian cancers (94.4% of grossly abnormal and 35.3% of normal appendices) and ovarian tumors suspected to be of primary gastrointestinal origin (83.3% grossly abnormal and 60.0% normal appendices harbored coexisting mucinous neoplasms). Linear regression analysis revealed that appearance of the appendix and frozen section diagnosis of the ovarian pathology were statistically significant predictors of coexisting appendiceal pathology, but the latter was more important. The prevalence of coexisting, clinically significant appendiceal pathology is low with a frozen section diagnosis of serous or mucinous cystadenoma. Appendectomy is recommended when frozen section diagnosis is mucinous or serous ovarian carcinoma, borderline tumor or metastatic carcinoma of suspected gastrointestinal origin.
Xu, Xia; Deng, Fei; Lv, Mengmeng; Chen, Xiaoxiang
2017-02-01
No consensus exists on the number of chemotherapy cycles to be administered before and after interval debulking surgery (IDS) in patients with advanced stage epithelial ovarian cancer. The present study aims to explore the optimal number of cycles of neoadjuvant chemotherapy (NAC) and post-operation chemotherapy to treat the International Federation of Gynecology and Obstetrics stage IIIc-IV high-grade serous ovarian cancer (HG-SOC). A total of 129 IIIc-IV stage HG-SOC cases were retrospectively analyzed. Cases were comprised of patients who underwent NAC followed by IDS and who achieved clinical complete response (CCR) at the end of primary therapy. Patients were recruited from the Jiangsu Institute of Cancer Research between 1993 and 2013. Optimal IDS-associated factors were explored with logistic regression. The association between progression-free survival (PFS), overall survival (OS) duration, and covariates was assessed by Cox proportional hazards model and log-rank test. The median number of NAC cycle was 3 (range 1-8). CA-125 decreasing kinetics (p = 0.01) was independently associated with optimal IDS. CA-125 decreasing kinetics, optimal IDS, and NAC cycles was independently associated with OS (p cycles was shorter than those of patients who underwent cycles (12.3 versus 17.2 months). The PFS and OS of patients who underwent cycles of adjuvant chemotherapy post-IDS were shorter than those of patients who underwent ≥5 cycles (14.2 and 20.3 versus 21.2 and 28.8 months). NAC cycles, CA-125 decreasing kinetics, and optimal debulking are independently associated with the prognosis of patients with advanced stage HG-SOC who underwent NAC/IDS and achieved CCR. The number of administered NAC cycles should not exceed 4.
Mingels, Marjanka J J M; Masadah, Rina; Geels, Yvette P; Otte-Höller, Irene; de Kievit, Ineke M; van der Laak, Jeroen A W M; van Ham, Maaike A P C; Bulten, Johan; Massuger, Leon F A G
2014-08-01
The aim of the present study is to determine the prevalence of endometrial premalignancies in women diagnosed with epithelial ovarian cancer (EOC). Endometrial and ovarian specimens of 186 patients with EOC were retrospectively selected using the nationwide pathology network and registry, and sections were comprehensively reviewed: 136 (73%) serous, 19 (10%) endometrioid, 15 (8%) mucinous, seven (4%) clear cell, and nine (5%) undifferentiated. Immunohistochemical phenotypes were compared for patients with serous EOC with concurrent endometrial pathology. In 31%, endometrial (pre)malignancy was found: carcinoma in 3%, endometrial intraepithelial carcinoma (EIC) in 4%, and atypical hyperplasia in 24%. Atypical hyperplasia was found in 47% of endometrioid EOCs but in 7% to 33% of other subtypes. Body mass index was higher concurrent to atypical hyperplasia (P=.001). Serous EOC and EIC immunophenotypes were comparable, whereas atypical hyperplasia was expressed differently. Apart from synchronous endometrial carcinoma, endometrial premalignancies should be taken into account when determining optimal treatment for women diagnosed with EOC. Copyright© by the American Society for Clinical Pathology.
Rasmussen, Christina B.; Kjaer, Susanne K.; Albieri, Vanna; Bandera, Elisa V.; Doherty, Jennifer A.; Høgdall, Estrid; Webb, Penelope M.; Jordan, Susan J.; Rossing, Mary Anne; Wicklund, Kristine G.; Goodman, Marc T.; Modugno, Francesmary; Moysich, Kirsten B.; Ness, Roberta B.; Edwards, Robert P.; Schildkraut, Joellen M.; Berchuck, Andrew; Olson, Sara H.; Kiemeney, Lambertus A.; Massuger, Leon F. A. G.; Narod, Steven A.; Phelan, Catherine M.; Anton-Culver, Hoda; Ziogas, Argyrios; Wu, Anna H.; Pearce, Celeste L.; Risch, Harvey A.; Jensen, Allan
2017-01-01
Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) = 1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR = 2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR = 0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR = 1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation. PMID:27941069
Carlson, Joseph W; Miron, Alexander; Jarboe, Elke A; Parast, Mana M; Hirsch, Michelle S; Lee, Yonghee; Muto, Michael G; Kindelberger, David; Crum, Christopher P
2008-09-01
A diagnosis of primary peritoneal serous carcinoma (PPSC) requires exclusion of a source in other reproductive organs. Serous tubal intraepithelial carcinoma (STIC; stage 0) has been described in asymptomatic women with BRCA mutations and linked to a serous cancer precursor in the fimbria. This study examined the frequency of STIC in PPSC and its clinical outcome in BRCA-positive women. Presence or absence of STIC was recorded in consecutive cases meeting the 2001 WHO criteria for PPSC, including 26 patients with nonuniform sampling of the fallopian tubes (group 1) and 19 patients with complete tubal examination (group 2; sectioning and extensively examining the fimbriated end, or SEE-FIM protocol). In selected cases, STIC or its putative precursor and the peritoneal tumor were analyzed for p53 mutations (exons 1 to 11). Outcome of STIC was ascertained by literature review. Thirteen (50%) of 26 PPSCs in group 1 involved the endosalpinx, with nine STICs (35%). Fifteen (79%) of 19 cases in group 2 contained endosalpingeal involvement, with nine STICs (47%). STIC was typically fimbrial and unifocal, with variable invasion of the tubal wall. In five of five cases, the peritoneal and tubal lesion shared an identical p53 mutation. Of 10 reported STICs in BRCA-positive women, all patients were without disease on follow-up. The fimbria is the source of nearly one half of PPSCs, suggesting serous malignancy originates in the tubal mucosa but grows preferentially at a remote peritoneal site. The generally low risk of recurrence in stage 0 (STIC) disease further underscores STIC as a possible target for early serous cancer detection and prevention.
Social support and ovarian cancer incidence - A Swedish prospective population-based study.
Idahl, Annika; Hermansson, Andrea; Lalos, Ann
2018-05-01
Low social support is associated with worse prognosis for epithelial ovarian cancer (EOC) patients. However, few studies have explored the relation between low social support and incidence of EOC. The aim of this prospective nested case-control study was to examine whether self-perceived low social support was associated with the incidence of EOC. The Swedish Cancer Registry was used to identify participants in the Västerbotten Intervention Programme (VIP) comprising 58,000 women, who later developed EOC. Each case was matched to four cancer free controls. The VIP uses the Social Support questionnaire, a modified version of the validated questionnaire "The Interview Schedule for Social Interaction" (ISSI) measuring quantitative (AVSI) and qualitative (AVAT) aspects of social support. The risk of EOC in relation to AVSI and AVAT was similar between the 239 cases and the 941 controls after adjustment for educational level, smoking, BMI, Cambridge Physical Activity Index and age (aOR 0.85, 95% CI 0.72-1.01 and aOR 0.54, 95% CI 0.16-1.81). Lagtime was found to have no impact. A decreased risk of serous ovarian cancer was seen in women with fewer persons available for informal socializing (aOR 0.75, 95% CI 0.59-0.95). Adjusted analyses showed non-significant odds ratios below 1.0 in the vast majority of histotypes. A general trend towards a decreased risk of ovarian cancer associated with low AVSI and AVAT was identified. Solely the serous subtype was significantly associated with low scores of AVSI. Prospective pathophysiological and epidemiological studies regarding social support are needed. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Histopathological Pattern and Age Distribution, of Malignant Ovarian Tumor among Sudanese Ladies
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Sumeya A. Khieri
2018-02-01
CONCLUSION: The incidence of different types of ovarian cancers in the present study is similar to worldwide incidence. The surface epithelial tumour is the commonest ovarian cancer, of which serous adenocarcinoma is the commonest and most of our patients present in late stages.
Recent Concepts of Ovarian Carcinogenesis: Type I and Type II
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Masafumi Koshiyama
2014-01-01
Full Text Available Type I ovarian tumors, where precursor lesions in the ovary have clearly been described, include endometrioid, clear cell, mucinous, low grade serous, and transitional cell carcinomas, while type II tumors, where such lesions have not been described clearly and tumors may develop de novo from the tubal and/or ovarian surface epithelium, comprise high grade serous carcinomas, undifferentiated carcinomas, and carcinosarcomas. The carcinogenesis of endometrioid and clear cell carcinoma (CCC arising from endometriotic cysts is significantly influenced by the free iron concentration, which is associated with cancer development through the induction of persistent oxidative stress. A subset of mucinous carcinomas develop in association with ovarian teratomas; however, the majority of these tumors do not harbor any teratomatous component. Other theories of their origin include mucinous metaplasia of surface epithelial inclusions, endometriosis, and Brenner tumors. Low grade serous carcinomas are thought to evolve in a stepwise fashion from benign serous cystadenoma to a serous borderline tumor (SBT. With regard to high grade serous carcinoma, the serous tubal intraepithelial carcinomas (STICs of the junction of the fallopian tube epithelium with the mesothelium of the tubal serosa, termed the “tubal peritoneal junction” (TPJ, undergo malignant transformation due to their location, and metastasize to the nearby ovary and surrounding pelvic peritoneum. Other theories of their origin include the ovarian hilum cells.
K. Lawrenson (Kate); S. Kar (Siddhartha); K. McCue (Karen); Kuchenbaeker, K. (Karoline); K. Michailidou (Kyriaki); J.P. Tyrer (Jonathan); J. Beesley (Jonathan); S.J. Ramus (Susan); Li, Q. (Qiyuan); Delgado, M.K. (Melissa K.); J.M. Lee (Janet M.); K. Aittomäki (Kristiina); I.L. Andrulis (Irene); H. Anton-Culver (Hoda); Arndt, V. (Volker); B.K. Arun (Banu); B. Arver (Brita Wasteson); E.V. Bandera (Elisa); M. Barile (Monica); Barkardottir, R.B. (Rosa B.); D. Barrowdale (Daniel); M.W. Beckmann (Matthias); J. Benítez (Javier); A. Berchuck (Andrew); M. Bisogna (Maria); L. Bjorge (Line); C. Blomqvist (Carl); W.J. Blot (William); N.V. Bogdanova (Natalia); Bojesen, A. (Anders); S.E. Bojesen (Stig); M.K. Bolla (Manjeet K.); B. Bonnani (Bernardo); A.-L. Borresen-Dale (Anne-Lise); H. Brauch (Hiltrud); P. Brennan (Paul); H. Brenner (Hermann); F. Bruinsma (Fiona); J. Brunet (Joan); S.A.B.S. Buhari (Shaik Ahmad Bin Syed); B. Burwinkel (Barbara); R. Butzow (Ralf); S.S. Buys (Saundra); Q. Cai (Qiuyin); T. Caldes (Trinidad); I. Campbell (Ian); Canniotto, R. (Rikki); J. Chang-Claude (Jenny); Chiquette, J. (Jocelyne); Choi, J.-Y. (Ji-Yeob); K.B.M. Claes (Kathleen B.M.); L.S. Cook (Linda S.); A. Cox (Angela); D.W. Cramer (Daniel); S.S. Cross (Simon); C. Cybulski (Cezary); K. Czene (Kamila); M.B. Daly (Mary B.); F. Damiola (Francesca); A. Dansonka-Mieszkowska (Agnieszka); H. Darabi (Hatef); J. Dennis (Joe); P. Devilee (Peter); O. Díez (Orland); J.A. Doherty (Jennifer A.); S.M. Domchek (Susan); C.M. Dorfling (Cecilia); T. Dörk (Thilo); M. Dumont (Martine); H. Ehrencrona (Hans); B. Ejlertsen (Bent); S.D. Ellis (Steve); C. Engel (Christoph); E. Lee (Eunjung); Evans, D.G. (D. Gareth); P.A. Fasching (Peter); L. Feliubadaló (L.); J.D. Figueroa (Jonine); D. Flesch-Janys (Dieter); O. Fletcher (Olivia); H. Flyger (Henrik); L. Foretova (Lenka); F. Fostira (Florentia); W.D. Foulkes (William); B.L. Fridley (Brooke); E. Friedman (Eitan); D. Frost (Debra); Gambino, G. (Gaetana); P.A. Ganz (Patricia A.); J. Garber (Judy); M. García-Closas (Montserrat); A. Gentry-Maharaj (Aleksandra); M. Ghoussaini (Maya); G.G. Giles (Graham); R. Glasspool (Rosalind); A.K. Godwin (Andrew K.); M.S. Goldberg (Mark); D. Goldgar (David); A. González-Neira (Anna); E.L. Goode (Ellen); M.T. Goodman (Marc); M.H. Greene (Mark H.); J. Gronwald (Jacek); P. Guénel (Pascal); C.A. Haiman (Christopher A.); P. Hall (Per); Hallberg, E. (Emily); U. Hamann (Ute); T.V.O. Hansen (Thomas); P. harrington (Patricia); J.M. Hartman (Joost); N. Hassan (Norhashimah); S. Healey (Sue); P.U. Heitz; J. Herzog (Josef); E. Høgdall (Estrid); C.K. Høgdall (Claus); F.B.L. Hogervorst (Frans); A. Hollestelle (Antoinette); J.L. Hopper (John); P.J. Hulick (Peter); T. Huzarski (Tomasz); E.N. Imyanitov (Evgeny); C. Isaacs (Claudine); H. Ito (Hidemi); A. Jakubowska (Anna); R. Janavicius (Ramunas); A. Jensen (Allan); E.M. John (Esther); Johnson, N. (Nichola); M. Kabisch (Maria); D. Kang (Daehee); M.K. Kapuscinski (Miroslav K.); Karlan, B.Y. (Beth Y.); S. Khan (Sofia); L.A.L.M. Kiemeney (Bart); M. Kjaer (Michael); J.A. Knight (Julia); I. Konstantopoulou (I.); V-M. Kosma (Veli-Matti); V. Kristensen (Vessela); J. Kupryjanczyk (Jolanta); A. Kwong (Ava); M. de La Hoya (Miguel); Y. Laitman (Yael); Lambrechts, D. (Diether); N.D. Le (Nhu D.); K. De Leeneer (Kim); K.J. Lester (Kathryn); D.A. Levine (Douglas); J. Li (Jingmei); A. Lindblom (Annika); J. Long (Jirong); A. Lophatananon (Artitaya); J.T. Loud (Jennifer); K.H. Lu (Karen); J. Lubinski (Jan); A. Mannermaa (Arto); S. Manoukian (Siranoush); L. Le Marchand (Loic); S. Margolin (Sara); F. Marme (Frederick); L.F. Massuger (Leon); K. Matsuo (Keitaro); S. Mazoyer (Sylvie); L. McGuffog (Lesley); C.A. McLean (Catriona Ann); I. McNeish (Iain); A. Meindl (Alfons); U. Menon (Usha); Mensenkamp, A.R. (Arjen R.); R.L. Milne (Roger); M. Montagna (Marco); K.B. Moysich (Kirsten); K.R. Muir (K.); A.-M. Mulligan (Anna-Marie); K.L. Nathanson (Katherine); R.B. Ness (Roberta); S.L. Neuhausen (Susan); H. Nevanlinna (Heli); S. Nord (Silje); R.L. Nussbaum (Robert L.); K. Odunsi (Kunle); K. Offit (Kenneth); E. Olah; O.I. Olopade (Olufunmilayo I.); J.E. Olson (Janet); C. Olswold (Curtis); D.M. O'Malley (David M.); I. Orlow (Irene); N. Orr (Nick); A. Osorio (Ana); Park, S.K. (Sue Kyung); C.L. Pearce (Celeste); T. Pejovic (Tanja); P. Peterlongo (Paolo); G. Pfeiler (Georg); C. Phelan (Catherine); E.M. Poole (Elizabeth); K. Pykäs (Katri); P. Radice (Paolo); J. Rantala (Johanna); M.U. Rashid (Muhammad); G. Rennert (Gad); V. Rhenius (Valerie); K. Rhiem (Kerstin); H. Risch (Harvey); G.C. Rodriguez (Gustavo); M.A. Rossing (Mary Anne); Rudolph, A. (Anja); H.B. Salvesen (Helga); Sangrajrang, S. (Suleeporn); Sawyer, E.J. (Elinor J.); J.M. Schildkraut (Joellen); M.K. Schmidt (Marjanka); R.K. Schmutzler (Rita); T.A. Sellers (Thomas A.); C.M. Seynaeve (Caroline); Shah, M. (Mitul); C.-Y. Shen (Chen-Yang); X.-O. Shu (Xiao-Ou); W. Sieh (Weiva); C.F. Singer (Christian); O. Sinilnikova (Olga); S. Slager (Susan); H. Song (Honglin); Soucy, P. (Penny); M.C. Southey (Melissa); M. Stenmark-Askmalm (Marie); D. Stoppa-Lyonnet (Dominique); C. Sutter (Christian); A.J. Swerdlow (Anthony ); Tchatchou, S. (Sandrine); P.J. Teixeira; S.-H. Teo (Soo-Hwang); K.L. Terry (Kathryn); M.B. Terry (Mary Beth); M. Thomassen (Mads); M.G. Tibiletti (Maria Grazia); L. Tihomirova (Laima); S. Tognazzo (Silvia); A.E. Toland (Amanda); I.P. Tomlinson (Ian); D. Torres (Diana); T. Truong (Thérèse); C.-C. Tseng (Chiu-Chen); N. Tung (Nadine); Tworoger, S.S. (Shelley S.); C. Vachon (Celine); Van Den Ouweland, A.M.W. (Ans M.W.); Van Doorn, H.C. (Helena C.); E.J. van Rensburg (Elizabeth); L.J. van 't Veer (Laura); A. Vanderstichele (Adriaan); I. Vergote (Ignace); J. Vijai (Joseph); Wang, Q. (Qin); S. Wang-Gohrke (Shan); J.N. Weitzel (Jeffrey); N. Wentzensen (N.); A.S. Whittemore (Alice); H. Wildiers (Hans); R. Winqvist (Robert); A.H. Wu (Anna); Yannoukakos, D. (Drakoulis); S.-Y. Yoon (Sook-Yee); J-C. Yu (Jyh-Cherng); W. Zheng (Wei); Y. Zheng (Ying); Khanna, K.K. (Kum Kum); J. Simard (Jacques); A.N.A. Monteiro (Alvaro N.); J.D. French (Juliet); F.J. Couch (Fergus); M. Freedman (Matthew); D.F. Easton (Douglas F.); A.M. Dunning (Alison); P.D.P. Pharoah (Paul); S.L. Edwards (Stacey); G. Chenevix-Trench (Georgia); A.C. Antoniou (Antonis C.); S.A. Gayther (Simon); D. Bowtell (David); A. DeFazio (Anna); P. Webb (Penny); M.-A. Collonge-Rame; Damette, A. (Alexandre); E. Barouk-Simonet (Emmanuelle); F. Bonnet (Françoise); V. Bubien (Virginie); N. Sevenet (Nicolas); M. Longy (Michel); P. Berthet (Pascaline); D. Vaur (Dominique); L. Castera (Laurent); S.F. Ferrer; Y.-J. Bignon (Yves-Jean); N. Uhrhammer (Nancy); F. Coron (Fanny); L. Faivre (Laurence); Baurand, A. (Amandine); Jacquot, C. (Caroline); Bertolone, G. (Geoffrey); Lizard, S. (Sarab); D. Leroux (Dominique); H. Dreyfus (Hélène); C. Rebischung (Christine); Peysselon, M. (Magalie); J.-P. Peyrat; J. Fournier (Joëlle); F. Révillion (Françoise); C. Adenis (Claude); L. Vénat-Bouvet (Laurence); M. Léone (Mélanie); N. Boutry-Kryza (N.); A. Calender (Alain); S. Giraud (Sophie); C. Verny-Pierre (Carole); C. Lasset (Christine); V. Bonadona (Valérie); Barjhoux, L. (Laure); H. Sobol (Hagay); V. Bourdon (Violaine); Noguchi, T. (Tetsuro); A. Remenieras (Audrey); I. Coupier (Isabelle); P. Pujol (Pascal); J. Sokolowska (Johanna); M. Bronner (Myriam); C.D. Delnatte (Capucine); Bézieau, S. (Stéphane); Mari, V. (Véronique); M. Gauthier-Villars (Marion); B. Buecher (Bruno); E. Rouleau (Etienne); L. Golmard (Lisa); V. Moncoutier (Virginie); M. Belotti (Muriel); A. de Pauw (Antoine); Elan, C. (Camille); Fourme, E. (Emmanuelle); Birot, A.-M. (Anne-Marie); Saule, C. (Claire); Laurent, M. (Maïté); C. Houdayer (Claude); F. Lesueur (Fabienne); N. Mebirouk (Noura); F. Coulet (Florence); C. Colas (Chrystelle); F. Soubrier; Warcoin, M. (Mathilde); F. Prieur (Fabienne); M. Lebrun (Marine); C. Kientz (Caroline); D.W. Muller (Danièle); J.P. Fricker (Jean Pierre); C. Toulas (Christine); R. Guimbaud (Rosine); L. Gladieff (Laurence); V. Feillel (Viviane); I. Mortemousque (Isabelle); B. Bressac-de Paillerets (Brigitte); O. Caron (Olivier); M. Guillaud-Bataille (Marine); H. Gregory (Helen); Z. Miedzybrodzka (Zosia); P.J. Morrison (Patrick); A. Donaldson (Alan); M.T. Rogers (Mark); M.J. Kennedy (John); M.E. Porteous (Mary); A. Brady (A.); J. Barwell (Julian); Foo, C. (Claire); F. Lalloo (Fiona); L. Side (Lucy); J. Eason (Jacqueline); Henderson, A. (Alex); L.J. Walker (Lisa); J. Cook (Jackie); Snape, K. (Katie); A. Murray (Alexandra); E. McCann (Emma); M.A. Rookus (Matti); F.E. van Leeuwen (F.); L. van der Kolk (Lizet); M.K. Schmidt (Marjanka); N.S. Russell (Nicola); J.L. de Lange (J.); Wijnands, R.; J.M. Collée (Margriet); M.J. Hooning (Maartje); Seynaeve, C.; C.H.M. van Deurzen (Carolien); A.I.M. Obdeijn (Inge-Marie); C.J. van Asperen (Christi); R.A.E.M. Tollenaar (Rob); T.C.T.E.F. van Cronenburg; C.M. Kets; M.G.E.M. Ausems (Margreet); C. van der Pol (Carmen); T.A.M. van Os (Theo); Q. Waisfisz (Quinten); E.J. Meijers-Heijboer (Hanne); E.B. Gómez García (Encarna); J.C. Oosterwijk (Jan); M.J. Mourits (Marjan); G.H. de Bock (Geertruida); H. Vasen (Hans); Siesling, S.; Verloop, J.; L.I.H. Overbeek (Lucy); S.B. Fox (Stephen); J. Kirk (Judy); G.J. Lindeman; M. Price (Melanie)
2016-01-01
textabstractA locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 ×
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Zhiqing eHuang
2013-05-01
Full Text Available Overexpression of insulin-like growth factor-II (IGF2 is a prominent characteristic of many epithelial ovarian malignancies. IGF2 imprinting and transcription are regulated in part through DNA methylation, which in turn regulates binding of the insulator protein, CTCF, within the IGF2/H19 imprint center. We have shown that IGF2 overexpression in ovarian cancer is associated with hypermethylation of CTCF binding sites within the IGF2/H19 imprint center. The aim of this study was to investigate the methylation and binding capacity of a novel putative CTCF binding motif located intragenic to IGF2 and determine how this relates to IGF2 expression. In 35 primary serous epithelial ovarian cancer specimens, methylation of two CpGs, including one within the core binding motif and another adjacent to this motif, was higher in the 18 cancers with elevated IGF2 expression versus 10 with low expression (avg. 68.2% vs. 38.5%; p<0.0001. We also found that the CpG site within the CTCF binding motif is hypermethylated in male gametes (>92%; avg. 93.2%; N=16. We confirmed binding of CTCF to this region in ovarian cancer cells, as well as the paralog of CTCF, BORIS, which is frequently overexpressed in cancers. The unmethylated CTCF binding motif has insulator activity in cells that express CTCF or BORIS, but not in cells that express both CTCF and BORIS. These intragenic CpG dinucleotides comprise a novel paternal germline imprint mark and are located in a binding motif for the insulator protein CTCF. Methylation of the CpG dinucleotides is positively correlated with IGF2 transcription, supporting that increased methylation represses insulator function. These combined results suggest that methylation and CTCF binding at this region play important roles in regulating the level of IGF2 transcription. Our data have revealed a novel epigenetic regulatory element within the IGF2/H19 imprinted domain that is highly relevant to aberrant IGF2 expression in ovarian
Będkowska, Grażyna Ewa; Ławicki, Sławomir; Gacuta, Ewa; Pawłowski, Przemysław; Szmitkowski, Maciej
2015-05-03
We investigated plasma levels of M-CSF and conventional tumor markers (HE4 and CA 125) in epithelial ovarian cancer patients as compared to control groups: benign ovarian tumor patients (cysts) and healthy subjects. M-CSF levels were determined by ELISA, HE4 and CA 125 levels - by CMIA method. Our results have demonstrated significant differences in the concentration levels of M-CSF, CA 125 and HE4 between the groups of ovarian cancer patients, cysts patients and the healthy controls. In the groups tested M-CSF demonstrated equal to or higher values than both CA 125 and HE4 in diagnostic sensitivity (SE), positive and negative predictive values (PPV, NPV), and in the area under the ROC curve (AUC), particularly in the group with the serous epithelial sub-type of OC. Moreover, CA 125 showed better results of the aforementioned diagnostic criteria than HE4. The combined use of the parameters studied resulted in a further, significant increase in the value of the diagnostic indicators and in the value of the diagnostic power (AUC), especially in the early stages of ovarian cancer. These findings suggest a high usefulness of M-CSF in diagnosing the serous sub-type of epithelial ovarian cancer and in discriminating between cancer and non-carcinoma lesions, particularly in new diagnostic panels in combination with CA 125 and HE4 for the detection of EOC in the early stages.
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Lane, Denis; Matte, Isabelle; Garde-Granger, Perrine; Laplante, Claude; Carignan, Alex; Rancourt, Claudine; Piché, Alain
2015-01-01
Platinum-based combination therapy is the standard first-line treatment for women with advanced serous epithelial ovarian carcinoma (EOC). However, about 20 % will not respond and are considered clinically resistant. The availability of biomarkers to predict responses to the initial therapy would provide a practical approach to identify women who would benefit from a more appropriate first-line treatment. Ascites is an attractive inflammatory fluid for biomarker discovery as it is easy and minimally invasive to obtain. The aim of this study was to evaluate whether six selected inflammation-regulating factors in ascites could serve as diagnostic or drug resistance biomarkers in patients with advanced serous EOC. A total of 53 women with stage III/IV serous EOC and 10 women with benign conditions were enrolled in this study. Eleven of the 53 women with serous EOC were considered clinically resistant to treatment with progression-free survival < 6 months. Ascites were collected at the time of the debulking surgery and the levels of cytokines were measured by ELISA. The six selected cytokines were evaluated for their ability to discriminate serous EOC from benign controls, and to discriminate platinum resistant from platinum sensitive patients. Median ascites levels of IL-6, IL-10 and osteoprotegerin (OPG) were significantly higher in women with advanced serous EOC than in controls (P ≤ 0.012). There were no significant difference in the median ascites levels of leptin, soluble urokinase plasminogen activator receptor (suPAR) and CCL18 among serous EOC women and controls. In Receiver Operator curve (ROC) analysis, IL-6, IL-10 and OPG had a high area under the curve value of 0.905, 0.832 and 0.825 respectively for distinguishing EOC from benign controls. ROC analysis of individual cytokines revealed low discriminating potential to stratify patients according to their sensitivity to first-line treatment. The combination of biomarkers with the highest discriminating
Targeting TBP-associated factors in ovarian cancer
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Jennifer R Ribeiro
2014-03-01
Full Text Available As ovarian tumors progress, they undergo a process of dedifferentiation, allowing adaptive changes in growth and morphology that promote metastasis and chemoresistance. Herein, we outline a hypothesis that TATA-box binding protein (TBP associated factors (TAFs, which compose the RNA Polymerase II initiation factor, TFIID, contribute to regulation of dedifferentiation states in ovarian cancer. Numerous studies demonstrate that TAFs regulate differentiation and proliferation states; their expression is typically high in pluripotent cells and reduced upon differentiation. Strikingly, TAF2 exhibits copy number increases or mRNA overexpression in 73% of high grade serous ovarian cancers (HGSC. At the biochemical level, TAF2 directs TFIID to TATA-less promoters by contact with an Initiator element, which may lead to the deregulation of the transcriptional output of these tumor cells. TAF4, which is altered in 66% of HGSC, is crucial for the stability of the TFIID complex and helps drive dedifferentiation of mouse embryonic fibroblasts to induced pluripotent stem cells. Its ovary-enriched paralog, TAF4B, is altered in 26% of HGSC. Here, we show that Taf4b mRNA correlates with Cyclin D2 mRNA expression in human granulosa cell tumors. TAF4B may also contribute to regulation of tumor microenvironment due to its estrogen-responsiveness and ability to act as a cofactor for NFκB. Conversely, TAF9, a cofactor for p53 in regulating apoptosis, may act as a tumor suppressor in ovarian cancer, since it is downregulated or deleted in 98% of HGSC. We conclude that a greater understanding of mechanisms of transcriptional regulation that execute signals from oncogenic signaling cascades is needed in order to expand our understanding of the etiology and progression of ovarian cancer, and most importantly to identify novel targets for therapeutic intervention.
[Expressions of Ras and Sos1 in epithelial ovarian cancer tissues and their clinical significance].
Xiao, Zheng-Hua; Linghu, Hua; Liu, Qian-Fen
2016-11-20
To detect the expressions of Ras and Sos1 proteins in human epithelial ovarian cancer (EOC) tissues and explore their correlation with the clinicopathological features of the patients. The expressions of Ras and Sos1 proteins were detected immunohistochemically in 62 EOC tissues, 5 borderline ovarian cancer tissues, 15 benign epithelial ovarian neoplasm tissues, and 18 normal ovarian tissues. The EOC tissues showed significantly higher expression levels of both Ras and Sos1 than the other tissues tested (Ptissues, Ras and Sos1 proteins were expressed mostly on the cell membrane and in the cytoplasm. The expression level of Ras was correlated with pathological types of the tumor (Ptissue-specific variation of Ras expression can lend support to a specific diagnosis of ovarian serous adenocarcinoma. The association of Ras and Sos1 protein expression with the tumor-free survival time of the patients awaits further investigation with a larger sample size.
REG4 Is Highly Expressed in Mucinous Ovarian Cancer: A Potential Novel Serum Biomarker.
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Laura Lehtinen
Full Text Available Preoperative diagnostics of ovarian neoplasms rely on ultrasound imaging and the serum biomarkers CA125 and HE4. However, these markers may be elevated in non-neoplastic conditions and may fail to identify most non-serous epithelial cancer subtypes. The objective of this study was to identify histotype-specific serum biomarkers for mucinous ovarian cancer. The candidate genes with mucinous histotype specific expression profile were identified from publicly available gene-expression databases and further in silico data mining was performed utilizing the MediSapiens database. Candidate biomarker validation was done using qRT-PCR, western blotting and immunohistochemical staining of tumor tissue microarrays. The expression level of the candidate gene in serum was compared to the serum CA125 and HE4 levels in a patient cohort of prospectively collected advanced ovarian cancer. Database searches identified REG4 as a potential biomarker with specificity for the mucinous ovarian cancer subtype. The specific expression within epithelial ovarian tumors was further confirmed by mRNA analysis. Immunohistochemical staining of ovarian tumor tissue arrays showed distinctive cytoplasmic expression pattern only in mucinous carcinomas and suggested differential expression between benign and malignant mucinous neoplasms. Finally, an ELISA based serum biomarker assay demonstrated increased expression only in patients with mucinous ovarian cancer. This study identifies REG4 as a potential serum biomarker for histotype-specific detection of mucinous ovarian cancer and suggests serum REG4 measurement as a non-invasive diagnostic tool for postoperative follow-up of patients with mucinous ovarian cancer.
Wu, Miao; Yan, Chuanbo; Liu, Huiqiang; Liu, Qian
2018-06-29
Ovarian cancer is one of the most common gynecologic malignancies. Accurate classification of ovarian cancer types (serous carcinoma, mucous carcinoma, endometrioid carcinoma, transparent cell carcinoma) is an essential part in the different diagnosis. Computer-aided diagnosis (CADx) can provide useful advice for pathologists to determine the diagnosis correctly. In our study, we employed a Deep Convolutional Neural Networks (DCNN) based on AlexNet to automatically classify the different types of ovarian cancers from cytological images. The DCNN consists of five convolutional layers, three max pooling layers, and two full reconnect layers. Then we trained the model by two group input data separately, one was original image data and the other one was augmented image data including image enhancement and image rotation. The testing results are obtained by the method of 10-fold cross-validation, showing that the accuracy of classification models has been improved from 72.76 to 78.20% by using augmented images as training data. The developed scheme was useful for classifying ovarian cancers from cytological images. © 2018 The Author(s).
Kearse, K P; Smith, N L; Semer, D A; Eagles, L; Finley, J L; Kazmierczak, S; Kovacs, C J; Rodriguez, A A; Kellogg-Wennerberg, A E
2000-12-15
A newly developed murine monoclonal antibody, DS6, immunohistochemically reacts with an antigen, CA6, that is expressed by human serous ovarian carcinomas but not by normal ovarian surface epithelium or mesothelium. CA6 has a limited distribution in normal adult tissues and is most characteristically detected in fallopian tube epithelium, inner urothelium and type 2 pneumocytes. Pre-treatment of tissue sections with either periodic acid or neuraminidase from Vibrio cholerae abolishes immunoreactivity with DS6, indicating that CA6 is a neuraminidase-sensitive and periodic acid-sensitive sialic acid glycoconjugate ("sialoglycotope"). SDS-PAGE of OVCAR5 cell lysates has revealed that the CA6 epitope is expressed on an 80 kDa non-disulfide-linked glycoprotein containing N-linked oligosaccharides. Two-dimensional non-equilibrium pH gradient gel electrophoresis indicates an isoelectric point of approximately 6.2 to 6.5. Comparison of the immunohistochemical distribution of CA6 in human serous ovarian adenocarcinomas has revealed similarities to that of CA125; however, distinct differences and some complementarity of antigen expression were revealed by double-label, 2-color immunohistochemical studies. The DS6-detected CA6 antigen appears to be distinct from other well-characterized tumor-associated antigens, including MUC1, CA125 and the histo-blood group-related antigens sLea, sLex and sTn. Copyright 2000 Wiley-Liss, Inc.
Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities
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Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray,Joe; Huntsman, David G.
2007-07-23
Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.
Resistance to first line platinum paclitaxel chemotherapy in serous epithelial ovarian cancer
DEFF Research Database (Denmark)
Steffensen, Karina Dahl; Smoter, Marta; Waldstrøm, Marianne
2014-01-01
of sensitivity to platinum/paclitaxel treatment. The primary aim of the study was to investigate whether ERCC1 and Tau protein expression correlates with patient outcome in newly diagnosed epithelial ovarian cancer (EOC) patients. Formalin-fixed, paraffin-embedded tissue sections from 227 newly diagnosed EOC...
DEFF Research Database (Denmark)
Lawrenson, Kate; Kar, Siddhartha; McCue, Karen
2016-01-01
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-n...
Nuclear COMMD1 Is Associated with Cisplatin Sensitivity in Ovarian Cancer.
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Alina Fedoseienko
Full Text Available Copper metabolism MURR1 domain 1 (COMMD1 protein is a multifunctional protein, and its expression has been correlated with patients' survival in different types of cancer. In vitro studies revealed that COMMD1 plays a role in sensitizing cancer cell lines to cisplatin, however, the mechanism and its role in platinum sensitivity in cancer has yet to be established. We evaluated the role of COMMD1 in cisplatin sensitivity in A2780 ovarian cancer cells and the relation between COMMD1 expression and response to platinum-based therapy in advanced stage high-grade serous ovarian cancer (HGSOC patients. We found that elevation of nuclear COMMD1 expression sensitized A2780 ovarian cancer cells to cisplatin-mediated cytotoxicity. This was accompanied by a more effective G2/M checkpoint, and decreased protein expression of the DNA repair gene BRCA1, and the apoptosis inhibitor BCL2. Furthermore, COMMD1 expression was immunohistochemically analyzed in two tissue micro-arrays (TMAs, representing a historical cohort and a randomized clinical trial-based cohort of advanced stage HGSOC tumor specimens. Expression of COMMD1 was observed in all ovarian cancer samples, however, specifically nuclear expression of COMMD1 was only observed in a subset of ovarian cancers. In our historical cohort, nuclear COMMD1 expression was associated with an improved response to chemotherapy (OR = 0.167; P = 0.038, although this association could not be confirmed in the second cohort, likely due to sample size. Taken together, these results suggest that nuclear expression of COMMD1 sensitize ovarian cancer to cisplatin, possibly by modulating the G2/M checkpoint and through controlling expression of genes involved in DNA repair and apoptosis.
2014-12-29
Fatigue; Malignant Ovarian Mixed Epithelial Tumor; Neuropathy; Neurotoxicity Syndrome; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Pain; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma
Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities
International Nuclear Information System (INIS)
Press, Joshua Z; Smith, Margaret; Spellman, Paul T; Wang, Yuker; Miller, Dianne M; Horsman, Doug; Faham, Malek; Gilks, C Blake; Gray, Joe; Huntsman, David G; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E; Blood, Katherine A
2008-01-01
Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways
Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities
Energy Technology Data Exchange (ETDEWEB)
Gilks, C. Blake; Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray, Joe; Huntsman, David G.
2008-05-02
Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n=5), clear cell (n=4), or low grade serous (n=2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.
Morrison, Jane C; Blanco, Luis Z; Vang, Russell; Ronnett, Brigitte M
2015-04-01
A precursor for invasive ovarian/pelvic high-grade serous carcinoma, termed serous tubal intraepithelial carcinoma (STIC), has been identified and characterized through careful analysis of the fallopian tubes in both prophylactic salpingo-oophorectomy specimens obtained from women with either a family history of breast and/or ovarian cancer or germline mutations of BRCA1 and BRCA2 and in cases of pelvic high-grade serous carcinoma. Data on incidental STICs and clinically occult microscopic invasive high-grade serous carcinomas are limited. We analyzed the clinicopathologic features of 22 cases, including 15 pure STICs and 7 STICs associated with microscopic invasive high-grade serous carcinomas, identified incidentally in fallopian tubes removed for nonprophylactic indications. Patient age ranged from 39 to 79 years (mean: 62.7; median: 61), with only 1 patient under the age of 50. No patients were known to carry BRCA1 or BRCA2 mutations. Of the 12 pure STICs for which the location in the fallopian tube could be established, 9 were in the fimbriated portion, 1 was at the junction of the fimbria and infundibulum, and 2 were in the nonfimbriated tube. Of the 7 STICs with associated invasive high-grade serous carcinoma, 3 were located in the fimbriated portion, 2 were at the junction of the fimbria and infundibulum, and 2 were in the nonfimbriated tube. The invasive components were in the fallopian tube in 6 cases, 4 in subepithelial stroma of tubal mucosa, and 2 as an intramucosal (exophytic) luminal lesion without invasion of underlying subepithelial stroma (size range: 1 to 4 mm). The remaining case had a microscopic focus of high-grade serous carcinoma within the ipsilateral ovary (1.3 mm cortical focus) identified only on deeper sections, without an associated invasive component in the fallopian tube. The preferential finding of atypical epithelium with the cytologic features of high-grade serous carcinoma, namely STIC, in the fallopian tubes rather than the
Early telomere shortening and genomic instability in tubo-ovarian preneoplastic lesions.
Chene, Gautier; Tchirkov, Andrei; Pierre-Eymard, Eleonore; Dauplat, Jacques; Raoelfils, Ines; Cayre, Anne; Watkin, Emmanuel; Vago, Philippe; Penault-Llorca, Frederique
2013-06-01
Genetic instability plays an important role in ovarian carcinogenesis. We investigated the level of telomere shortening and genomic instability in early and preinvasive stages of ovarian cancer, serous tubal intraepithelial carcinoma (STIC), and tubo-ovarian dysplasia (TOD). Fifty-one TOD from prophylactic salpingo-oophorectomies with BRCA1 or 2 mutation, 12 STICs, 53 tubo-ovarian high-grade serous carcinoma, and 36 noncancerous controls were laser capture microdissected from formalin-fixed, paraffin-embedded sections, analyzed by comparative genomic hybridization (array CGH) and for telomere length (using quantitative real-time PCR based on the Cawthon's method). TOD and STICs were defined by morphologic scores and immunohistochemical expressions of p53, Ki67, and γH2AX. TOD showed marked telomere shortening compared with noncancerous controls (P STICs had even shorter telomeres than TOD (P = 0.0008). Ovarian carcinoma had shorter telomeres than controls but longer than STICs and dysplasia. In TOD, telomeres were significantly shorter in those with BRCA1 mutation than in those with BRCA2 mutation (P = 0.005). In addition, γH2AX expression in TOD and STIC groups with short telomeres was significantly increased (P STICs. The total number of genetic alterations was the highest in ovarian cancers. These findings suggest that genetic instability occurs in early stages of ovarian tumorigenesis. STICs and noninvasive dysplasia are likely an important step in early serous ovarian neoplasia. ©2013 AACR
Increased oxidative stress mediates the antitumor effect of PARP inhibition in ovarian cancer
Directory of Open Access Journals (Sweden)
Dong Hou
2018-07-01
Full Text Available PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells. Inhibition or depletion of PARP leads to not only an increase in DNA damage, but also an elevation in the levels of reactive oxygen species (ROS. Importantly, antioxidant N-acetylcysteine (NAC significantly attenuated the induction of DNA damage and the perturbation of proliferation by PARP inhibition or depletion. We further showed that NADPH oxidases 1 and 4 were significantly upregulated by PARP inhibition and were partially responsible for the induction of oxidative stress. Depletion of NOX1 and NOX4 partially rescued the growth inhibition of PARP1-deficient tumor xenografts. Our findings suggest that in addition to compromising the repair of DNA damage, PARP inhibition or depletion may exert extra antitumor effect by elevating oxidative stress in ovarian cancer cells. Keywords: PARP1, Oxidative stress, NADPH oxidases, Ovarian cancer
Directory of Open Access Journals (Sweden)
Nishat Fatema
2018-01-01
Full Text Available Giant (>10 cm ovarian cyst is a rare finding. In the literature, a few cases of giant ovarian cysts have been mentioned sporadically, especially in elderly patients. We report a 57-year-old postmenopausal woman with a giant left ovarian cyst measuring 43 × 15 × 9 cm. She was referred to us from the local health center in view of palpable pelvic mass for six-month period. Considering the age and menopausal state, we performed a total abdominal hysterectomy and bilateral salpingo-oophorectomy with excision of the giant left ovarian cyst intact and successfully without any significant complication. On histopathological examination, the cyst was confirmed as benign serous cystadenoma of the ovary. During the management of these high-risk cases of multidisciplinary approach, intraoperative and postoperative strict vigilance is necessary to avoid unwanted complications.
Are all pelvic (nonuterine) serous carcinomas of tubal origin?
Przybycin, Christopher G; Kurman, Robert J; Ronnett, Brigitte M; Shih, Ie-Ming; Vang, Russell
2010-10-01
It has been proposed that the presence of tubal intraepithelial carcinoma (TIC), in association with one-third to nearly half of pelvic serous carcinomas, is evidence of fallopian tube origin for high-grade serous carcinomas that would have been otherwise classified as primary ovarian or peritoneal. To address this hypothesis, we evaluated a series of 114 consecutive pelvic (nonuterine) gynecologic carcinomas at our institution (2006 to 2008) to determine the frequency of TIC in 52 cases in which all the resected fallopian tube tissue was examined microscopically. These 52 cases were classified as ovarian (n=37), peritoneal (n=8), or fallopian tube (n=7) in origin as per conventional criteria based on disease distribution. The presence of TIC and its location and relationship to invasive carcinoma in the fallopian tubes and ovaries were assessed. Among the 45 cases of ovarian/peritoneal origin, carcinoma subtypes included 41 high-grade serous, 1 endometrioid, 1 mucinous, 1 high-grade, not otherwise specified, and 1 malignant mesodermal mixed tumor. TIC was identified in 24 cases (59%) of high-grade serous carcinoma but not among any of the other subtypes; therefore, the term serous TIC (STIC) is a more specific appellation. STICs were located in the fimbriated end of the tube in 22 cases (92%) and in the ampulla in 2 (8%); they were unilateral in 21 (88%) and bilateral in 3 (13%). STICs in the absence of an associated invasive carcinoma in the same tube were detected in 7 cases (30%) and with invasive carcinoma in the same tube in 17 (71%). Unilateral STICs were associated with bilateral ovarian involvement in 15 cases and unilateral (ipsilateral) ovarian involvement in 5 (the remaining case with a unilateral STIC had a primary peritoneal tumor with no ovarian involvement); the bilateral STICs were all associated with bilateral ovarian involvement. Six of the 7 primary tubal tumors were high-grade serous carcinomas, and 4 of these 6 (67%) had STICs. Based on
Assessment of moderate coffee consumption and risk of epithelial ovarian cancer
DEFF Research Database (Denmark)
Ong, Jue-Sheng; Hwang, Liang-Dar; Cuellar-Partida, Gabriel
2018-01-01
Background: Coffee consumption has been shown to be associated with various health outcomes in observational studies. However, evidence for its association with epithelial ovarian cancer (EOC) is inconsistent and it is unclear whether these associations are causal. Methods: We used single...... nucleotide polymorphisms associated with (i) coffee and (ii) caffeine consumption to perform Mendelian randomization (MR) on EOC risk. We conducted a two-sample MR using genetic data on 44 062 individuals of European ancestry from the Ovarian Cancer Association Consortium (OCAC), and combined instrumental...... variable estimates using a Wald-type ratio estimator. Results: For all EOC cases, the causal odds ratio (COR) for genetically predicted consumption of one additional cup of coffee per day was 0.92 [95% confidence interval (CI): 0.79, 1.06]. The COR was 0.90 (95% CI: 0.73, 1.10) for high-grade serous EOC...
Zervantonakis, Ioannis K; Iavarone, Claudia; Chen, Hsing-Yu; Selfors, Laura M; Palakurthi, Sangeetha; Liu, Joyce F; Drapkin, Ronny; Matulonis, Ursula; Leverson, Joel D; Sampath, Deepak; Mills, Gordon B; Brugge, Joan S
2017-08-28
The lack of effective chemotherapies for high-grade serous ovarian cancers (HGS-OvCa) has motivated a search for alternative treatment strategies. Here, we present an unbiased systems-approach to interrogate a panel of 14 well-annotated HGS-OvCa patient-derived xenografts for sensitivity to PI3K and PI3K/mTOR inhibitors and uncover cell death vulnerabilities. Proteomic analysis reveals that PI3K/mTOR inhibition in HGS-OvCa patient-derived xenografts induces both pro-apoptotic and anti-apoptotic signaling responses that limit cell killing, but also primes cells for inhibitors of anti-apoptotic proteins. In-depth quantitative analysis of BCL-2 family proteins and other apoptotic regulators, together with computational modeling and selective anti-apoptotic protein inhibitors, uncovers new mechanistic details about apoptotic regulators that are predictive of drug sensitivity (BIM, caspase-3, BCL-X L ) and resistance (MCL-1, XIAP). Our systems-approach presents a strategy for systematic analysis of the mechanisms that limit effective tumor cell killing and the identification of apoptotic vulnerabilities to overcome drug resistance in ovarian and other cancers.High-grade serous ovarian cancers (HGS-OvCa) frequently develop chemotherapy resistance. Here, the authors through a systematic analysis of proteomic and drug response data of 14 HGS-OvCa PDXs demonstrate that targeting apoptosis regulators can improve response of these tumors to inhibitors of the PI3K/mTOR pathway.
Ovarian Cancer and BRCA1/2 Testing: Opportunities to improve clinical care and disease prevention
Directory of Open Access Journals (Sweden)
Katherine eKarakasis
2016-05-01
Full Text Available Without prevention or screening options available, ovarian cancer is the most lethal malignancy of the female reproductive tract. High grade serous ovarian cancer (HGSOC is the most common histologic subtype, and the role of germline BRCA1/2 mutation in predisposition and prognosis is established. Given the targeted treatment opportunities with PARP inhibitors, a predictive role for BRCA1/2 mutation has emerged. Despite recommendations to provide BRCA1/2 testing to all women with histologically confirmed HGSOC, uniform implementation remains challenging. The opportunity to review and revise genetic screening and testing practices will identify opportunities where universal adoption of BRCA1/2 mutation testing will impact and improve treatment of women with ovarian cancer. Improving education and awareness of genetic testing for women with cancer, as well as the broader general community, will help focus much needed attention on opportunities to advance prevention and screening programs in ovarian cancer. This is imperative not only for women with cancer, those at risk of developing cancer, but also for their first-degree relatives. In addition, BRCA1/2 testing may have direct implications for patients with other types of cancers, many which are now being found to have BRCA1/2 involvement.
Melatonin Reduces Angiogenesis in Serous Papillary Ovarian Carcinoma of Ethanol-Preferring Rats
Zonta, Yohan Ricci; Martinez, Marcelo; Camargo, Isabel Cristina C.; Domeniconi, Raquel F.; Lupi Júnior, Luiz Antonio; Pinheiro, Patricia Fernanda F.; Reiter, Russel J.; Martinez, Francisco Eduardo; Chuffa, Luiz Gustavo A.
2017-01-01
Angiogenesis is a hallmark of ovarian cancer (OC); the ingrowth of blood vessels promotes rapid cell growth and the associated metastasis. Melatonin is a well-characterized indoleamine that possesses important anti-angiogenic properties in a set of aggressive solid tumors. Herein, we evaluated the role of melatonin therapy on the angiogenic signaling pathway in OC of an ethanol-preferring rat model that mimics the same pathophysiological conditions occurring in women. OC was chemically induced with a single injection of 7,12-dimethylbenz(a)anthracene (DMBA) under the ovarian bursa. After the rats developed serous papillary OC, half of the animals received intraperitoneal injections of melatonin (200 µg/100 g body weight/day) for 60 days. Melatonin-treated animals showed a significant reduction in OC size and microvessel density. Serum levels of melatonin were higher following therapy, and the expression of its receptor MT1 was significantly increased in OC-bearing rats, regardless of ethanol intake. TGFβ1, a transforming growth factor-beta1, was reduced only after melatonin treatment. Importantly, vascular endothelial growth factor (VEGF) was severely reduced after melatonin therapy in animals given or not given ethanol. Conversely, the levels of VEGF receptor 1 (VEGFR1) was diminished after ethanol consumption, regardless of melatonin therapy, and VEGFR2 was only reduced following melatonin. Hypoxia-inducible factor (HIF)-1α was augmented with ethanol consumption, and, notably, melatonin significantly reduced their levels. Collectively, our results suggest that melatonin attenuates angiogenesis in OC in an animal model of ethanol consumption; this provides a possible complementary therapeutic opportunity for concurrent OC chemotherapy. PMID:28398226
Is MRI a useful tool to distinguish between serous and mucinous borderline ovarian tumours?
International Nuclear Information System (INIS)
Bazot, M.; Haouy, D.; Daraï, E.; Cortez, A.; Dechoux-Vodovar, S.; Thomassin-Naggara, I.
2013-01-01
Aim: To analyse the morphological magnetic resonance imaging (MRI) features of borderline ovarian tumours (BOT) and to evaluate whether MRI can be used to distinguish serous from mucinous subtypes. Materials and methods: A retrospective study of 72 patients who underwent BOT resection was undertaken. MRI images were reviewed blindly by two radiologists to assess MRI features: size, tumour type, grouped and irregular thickened septa, number of septa, loculi of different signal intensity, vegetations, solid portion, signal intensity of vegetations, normal ovarian parenchyma, and pelvic ascites. Statistical analysis was performed using Mann–Whitney and Fisher's exact tests. Logistic regression analysis was used to assess the predictive value of the MRI findings for histological subtypes. Results: At histology, there were 33 serous BOT (SBOT) and 39 mucinous BOT (MBOT). Predictive MRI criteria for SBOT were bilaterality, predominantly solid tumour, and the presence of vegetations, especially exophytic or with a high T2 signal (p < 0.01), whereas predictive MRI criteria for MBOT were multilocularity, number of septa, loculi of different signal intensity, and grouped and irregular thickened septa (p < 0.01). Using multivariate analysis, vegetations were independently associated with SBOT [odds ratio (OR) = 29.5] and multilocularity with MBOT (OR = 3.9). Conclusion: Vegetations and multilocularity are two independent MRI features that can help to distinguish between SBOT and MBOT.
AA , Ovarian tumour, a common neoplasm in women, can present as ...
African Journals Online (AJOL)
definite screening program for ovarian tumours as obtained in cervical cancer. The cause of ... common benign primary ovarian tumour constituting. 54.7% of cases of benign tumours followed by serous cystadenoma comprising 19.6%. Mature cystic teratoma is ... Maiduguri, Nigeria where mature cystic teratoma was found ...
Genome-wide association study for ovarian cancer susceptibility using pooled DNA
DEFF Research Database (Denmark)
Lu, Yi; Chen, Xiaoqing; Beesley, Jonathan
2012-01-01
stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by less dense arrays. However, our study lacked power to make clear statements on the existence of hitherto untagged small......Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used...... in the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly associated...
Polycystic ovary syndrome and risk of endometrial, ovarian, and breast cancer: a systematic review.
Harris, Holly R; Terry, Kathryn L
2016-01-01
Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. The altered metabolic and hormonal environment among women with PCOS may increase their risk of some types of cancer. We performed a comprehensive review of the literature using numerous search terms for all studies examining the associations between polycystic ovary syndrome and related characteristics and cancer published in English through October 2016. This review summarizes the epidemiological findings on the associations between PCOS and endometrial, ovarian, and breast cancers and discusses the methodological issues, complexities, and underlying mechanisms of these associations. We identified 11 individual studies and 3 meta-analyses on the associations between PCOS and endometrial cancer, 8 studies and 1 meta-analysis for ovarian cancer, and 10 studies and 1 meta-analysis for breast cancer. Multiple studies reported that women with PCOS were at a higher risk for endometrial cancer; however, many did not take into account body mass index (BMI), a strong and well-established risk factor for endometrial cancer. The association with ovarian cancer was less clear, but a potentially increased risk of the borderline serous subtype was reported by two studies. No consistent association between PCOS risk and breast cancer was observed. The associations between PCOS and endometrial, ovarian, and breast cancer are complex, with the need to consider many methodological issues in future analyses. Larger well-designed studies, or pooled analyses, may help clarify these complex associations.
Wegdam, Wouter; Argmann, Carmen A.; Kramer, Gertjan; Vissers, Johannes P.; Buist, Marrije R.; Kenter, Gemma G.; Aerts, Johannes M. F. G.; Meijer, Danielle; Moerland, Perry D.
2014-01-01
To identify proteins and (molecular/biological) pathways associated with differences between benign and malignant epithelial ovarian tumors. Serum of six patients with a serous adenocarcinoma of the ovary was collected before treatment, with a control group consisting of six matched patients with a
Sharrow, Allison C; Perkins, Brandy; Collector, Michael I; Yu, Wayne; Simons, Brian W; Jones, Richard J
2016-08-01
The cancer stem cell (CSC) paradigm hypothesizes that successful clinical eradication of CSCs may lead to durable remission for patients with ovarian cancer. Despite mounting evidence in support of ovarian CSCs, their phenotype and clinical relevance remain unclear. We and others have found high aldehyde dehydrogenase 1 (ALDH(high)) expression in a variety of normal and malignant stem cells, and sought to better characterize ALDH(high) cells in ovarian cancer. We compared ALDH(high) to ALDH(low) cells in two ovarian cancer models representing distinct subtypes: FNAR-C1 cells, derived from a spontaneous rat endometrioid carcinoma, and the human SKOV3 cell line (described as both serous and clear cell subtypes). We assessed these populations for stem cell features then analyzed expression by microarray and qPCR. ALDH(high) cells displayed CSC properties, including: smaller size, quiescence, regenerating the phenotypic diversity of the cell lines in vitro, lack of contact inhibition, nonadherent growth, multi-drug resistance, and in vivo tumorigenicity. Microarray and qPCR analysis of the expression of markers reported by others to enrich for ovarian CSCs revealed that ALDH(high) cells of both models showed downregulation of CD24, but inconsistent expression of CD44, KIT and CD133. However, the following druggable targets were consistently expressed in the ALDH(high) cells from both models: mTOR signaling, her-2/neu, CD47 and FGF18/FGFR3. Based on functional characterization, ALDH(high) ovarian cancer cells represent an ovarian CSC population. Differential gene expression identified druggable targets that have the potential for therapeutic efficacy against ovarian CSCs from multiple subtypes. Copyright © 2016 Elsevier Inc. All rights reserved.
Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).
Jim, Heather S L; Lin, Hui-Yi; Tyrer, Jonathan P; Lawrenson, Kate; Dennis, Joe; Chornokur, Ganna; Chen, Zhihua; Chen, Ann Y; Permuth-Wey, Jennifer; Aben, Katja Kh; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V; Bean, Yukie T; Beckmann, Matthias W; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bunker, Clareann H; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Sieh, Weiva; Doherty, Jennifer A; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F; Eccles, Diana M; Edwards, Robert P; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goodman, Marc T; Gronwald, Jacek; Harter, Philipp; Hasmad, Hanis N; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Claus K; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kellar, Melissa; Kiemeney, Lambertus A; Krakstad, Camilla; Kjaer, Susanne K; Kupryjanczyk, Jolanta; Vierkant, Robert A; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; McNeish, Ian; Menon, Usha; Milne, Roger L; Modugno, Francesmary; Thomsen, Lotte; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Palmieri Weber, Rachel; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Pike, Malcolm C; Poole, Elizabeth M; Schernhammer, Eva; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Song, Honglin; Southey, Melissa C; Spiewankiewicz, Beata; Sucheston-Campbell, Lara; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Tangen, Ingvild L; Tworoger, Shelley S; van Altena, Anne M; Vergote, Ignace; Walsh, Christine S; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Wu, Anna H; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Amankwah, Ernest; Berchuck, Andrew; Schildkraut, Joellen M; Kelemen, Linda E; Ramus, Susan J; Monteiro, Alvaro N A; Goode, Ellen L; Narod, Steven A; Gayther, Simon A; Pharoah, Paul D P; Sellers, Thomas A; Phelan, Catherine M
Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10 -4 ]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1 , may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
Coffman, Lan G; Burgos-Ojeda, Daniela; Wu, Rong; Cho, Kathleen; Bai, Shoumei; Buckanovich, Ronald J
2016-09-01
Emerging evidence suggest that many high-grade serous "ovarian" cancers (HGSOC) start in the fallopian tube. Cancer cells are then recruited to the ovary and then spread diffusely through the abdomen. The mechanism of ovarian cancer spread was thought to be largely due to direct shedding of tumor cells into the peritoneal cavity with vascular spread being of limited importance. Recent work challenges this dogma, suggesting hematogenous spread of ovarian cancer may play a larger role in ovarian cancer cell metastasis than previously thought. One reason the role of vascular spread of ovarian cancer has not been fully elucidated is the lack of easily accessible models of vascular ovarian cancer metastasis. Here, we present 3 metastatic models of ovarian cancer which confirm the ability of ovarian cancer to hematogenously spread. Strikingly, we observe a high rate of metastasis to the ovary with the development of ascites in these models. Interestingly, oophorectomy resulted in a complete loss of peritoneal metastases and ascites. Taken together, our data indicate that hematogenously disseminated HGSOC cells have a unique tropism for the ovary and that hematogenous spread in ovarian cancer may be more common than appreciated. Furthermore, our studies support a critical role for the ovary in promoting HGSOC cell metastasis to the abdomen. The models developed here represent important new tools to evaluate both the mechanism of cancer cell recruitment to the ovary and understand and target key steps in ovarian cancer metastasis. Copyright © 2016 Elsevier Inc. All rights reserved.
Histones and their modifications in ovarian cancer - drivers of disease and therapeutic targets.
Marsh, Deborah J; Shah, Jaynish S; Cole, Alexander J
2014-01-01
Epithelial ovarian cancer has the highest mortality of the gynecological malignancies. High grade serous epithelial ovarian cancer (SEOC) is the most common subtype, with the majority of women presenting with advanced disease where 5-year survival is around 25%. Platinum-based chemotherapy in combination with paclitaxel remains the most effective treatment despite platinum therapies being introduced almost 40 years ago. Advances in molecular medicine are underpinning new strategies for the treatment of cancer. Major advances have been made by international initiatives to sequence cancer genomes. For SEOC, with the exception of TP53 that is mutated in virtually 100% of these tumors, there is no other gene mutated at high frequency. There is extensive copy number variation, as well as changes in methylation patterns that will influence gene expression. To date, the role of histones and their post-translational modifications in ovarian cancer is a relatively understudied field. Post-translational histone modifications play major roles in gene expression as they direct the configuration of chromatin and so access by transcription factors. Histone modifications include methylation, acetylation, and monoubiquitination, with involvement of enzymes including histone methyltransferases, histone acetyltransferases/deacetylases, and ubiquitin ligases/deubiquitinases, respectively. Complexes such as the Polycomb repressive complex also play roles in the control of histone modifications and more recently roles for long non-coding RNA and microRNAs are emerging. Epigenomic-based therapies targeting histone modifications are being developed and offer new approaches for the treatment of ovarian cancer. Here, we discuss histone modifications and their aberrant regulation in malignancy and specifically in ovarian cancer. We review current and upcoming histone-based therapies that have the potential to inform and improve treatment strategies for women with ovarian cancer.
Etter, John Lewis; Eng, Kevin; Cannioto, Rikki; Kaur, Jasmine; Almohanna, Hani; Alqassim, Emad; Szender, J Brian; Joseph, Janine M; Lele, Shashikant; Odunsi, Kunle; Moysich, Kirsten B
2018-04-01
Although family history of testicular cancer is well-established as a risk factor for testicular cancer, it is unknown whether family history of ovarian cancer is associated with risk of testicular cancer. Using data from the Familial Ovarian Cancer Registry on 2636 families with multiple cases of ovarian cancer, we systematically compared relative frequencies of ovarian cancer among relatives of men with testicular and non-testicular cancers. Thirty-one families with cases of both ovarian and testicular cancer were identified. We observed that, among men with cancer, those with testicular cancer were more likely to have a mother with ovarian cancer than those with non-testicular cancers (OR = 3.32, p = 0.004). Zero paternal grandmothers of men with testicular cancer had ovarian cancer. These observations provide compelling preliminary evidence for a familial association between ovarian and testicular cancers Future studies should be designed to further investigate this association and evaluate X-linkage. Copyright © 2018 Elsevier Ltd. All rights reserved.
Surrogates of Long-Term Vitamin D Exposure and Ovarian Cancer Risk in Two Prospective Cohort Studies
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Prescott, Jennifer; Bertrand, Kimberly A.; Poole, Elizabeth M.; Rosner, Bernard A.; Tworoger, Shelley S.
2013-01-01
Experimental evidence and ecologic studies suggest a protective role of vitamin D in ovarian carcinogenesis. However, epidemiologic studies using individual level data have been inconsistent. We evaluated ultraviolet (UV)-B radiation, vitamin D intake, and predicted plasma 25-hydroxyvitamin D [25(OH)D] levels as long-term surrogates of vitamin D exposure within the Nurses’ Health Study (NHS) and NHSII. We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) for risk of overall ovarian cancer and by histologic subtype using Cox proportional hazards models. Between 1976 and 2010 in NHS and 1989 and 2011 in NHSII, we identified a total of 1,225 incident epithelial ovarian cancer cases (NHS: 970, NHSII: 255) over 4,628,648 person-years of follow-up. Cumulative average UV-B exposure was not associated with ovarian cancer risk in NHS (P trend = 0.08), but was associated with reduced risk in NHSII (highest vs. lowest category RR = 0.67; 95% CI: 0.50, 0.89; P trend < 0.01). When stratified by histologic subtype, UV-B flux was positively associated with risk of serous tumors in NHS (P trend < 0.01), but inversely associated in NHSII (P trend = 0.01). Adjusted for confounders, ovarian cancer risk was not associated with vitamin D intake from food or supplements or with predicted 25(OH)D levels. Our study does not strongly support a protective role for vitamin D in ovarian cancer risk
Surrogates of Long-Term Vitamin D Exposure and Ovarian Cancer Risk in Two Prospective Cohort Studies
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Prescott, Jennifer, E-mail: jennifer.prescott@channing.harvard.edu; Bertrand, Kimberly A.; Poole, Elizabeth M.; Rosner, Bernard A.; Tworoger, Shelley S. [Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 181 Longwood Ave. Boston, MA 02115 (United States)
2013-11-22
Experimental evidence and ecologic studies suggest a protective role of vitamin D in ovarian carcinogenesis. However, epidemiologic studies using individual level data have been inconsistent. We evaluated ultraviolet (UV)-B radiation, vitamin D intake, and predicted plasma 25-hydroxyvitamin D [25(OH)D] levels as long-term surrogates of vitamin D exposure within the Nurses’ Health Study (NHS) and NHSII. We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) for risk of overall ovarian cancer and by histologic subtype using Cox proportional hazards models. Between 1976 and 2010 in NHS and 1989 and 2011 in NHSII, we identified a total of 1,225 incident epithelial ovarian cancer cases (NHS: 970, NHSII: 255) over 4,628,648 person-years of follow-up. Cumulative average UV-B exposure was not associated with ovarian cancer risk in NHS (P{sub trend} = 0.08), but was associated with reduced risk in NHSII (highest vs. lowest category RR = 0.67; 95% CI: 0.50, 0.89; P{sub trend} < 0.01). When stratified by histologic subtype, UV-B flux was positively associated with risk of serous tumors in NHS (P{sub trend} < 0.01), but inversely associated in NHSII (P{sub trend} = 0.01). Adjusted for confounders, ovarian cancer risk was not associated with vitamin D intake from food or supplements or with predicted 25(OH)D levels. Our study does not strongly support a protective role for vitamin D in ovarian cancer risk.
Surrogates of Long-Term Vitamin D Exposure and Ovarian Cancer Risk in Two Prospective Cohort Studies
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Jennifer Prescott
2013-11-01
Full Text Available Experimental evidence and ecologic studies suggest a protective role of vitamin D in ovarian carcinogenesis. However, epidemiologic studies using individual level data have been inconsistent. We evaluated ultraviolet (UV-B radiation, vitamin D intake, and predicted plasma 25-hydroxyvitamin D [25(OHD] levels as long-term surrogates of vitamin D exposure within the Nurses’ Health Study (NHS and NHSII. We estimated incidence rate ratios (RRs and 95% confidence intervals (CIs for risk of overall ovarian cancer and by histologic subtype using Cox proportional hazards models. Between 1976 and 2010 in NHS and 1989 and 2011 in NHSII, we identified a total of 1,225 incident epithelial ovarian cancer cases (NHS: 970, NHSII: 255 over 4,628,648 person-years of follow-up. Cumulative average UV-B exposure was not associated with ovarian cancer risk in NHS (Ptrend = 0.08, but was associated with reduced risk in NHSII (highest vs. lowest category RR = 0.67; 95% CI: 0.50, 0.89; Ptrend < 0.01. When stratified by histologic subtype, UV-B flux was positively associated with risk of serous tumors in NHS (Ptrend < 0.01, but inversely associated in NHSII (Ptrend = 0.01. Adjusted for confounders, ovarian cancer risk was not associated with vitamin D intake from food or supplements or with predicted 25(OHD levels. Our study does not strongly support a protective role for vitamin D in ovarian cancer risk.
GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer
Pharoah, Paul D. P.; Tsai, Ya-Yu; Ramus, Susan J.; Phelan, Catherine M.; Goode, Ellen L.; Lawrenson, Kate; Price, Melissa; Fridley, Brooke L.; Tyrer, Jonathan P.; Shen, Howard; Weber, Rachel; Karevan, Rod; Larson, Melissa C.; Song, Honglin; Tessier, Daniel C.; Bacot, François; Vincent, Daniel; Cunningham, Julie M.; Dennis, Joe; Dicks, Ed; Aben, Katja K.; Anton-Culver, Hoda; Antonenkova, Natalia; Armasu, Sebastian M.; Baglietto, Laura; Bandera, Elisa V.; Beckmann, Matthias W.; Birrer, Michael J.; Bloom, Greg; Bogdanova, Natalia; Brenton, James D.; Brinton, Louise A.; Brooks-Wilson, Angela; Brown, Robert; Butzow, Ralf; Campbell, Ian; Carney, Michael E; Carvalho, Renato S.; Chang-Claude, Jenny; Chen, Y. Anne; Chen, Zhihua; Chow, Wong-Ho; Cicek, Mine S.; Coetzee, Gerhard; Cook, Linda S.; Cramer, Daniel W.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Despierre, Evelyn; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Edwards, Robert; Ekici, Arif B.; Fasching, Peter A.; Fenstermacher, David; Flanagan, James; Gao, Yu-Tang; Garcia-Closas, Montserrat; Gentry-Maharaj, Aleksandra; Giles, Graham; Gjyshi, Anxhela; Gore, Martin; Gronwald, Jacek; Guo, Qi; Halle, Mari K; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hillemanns, Peter; Hoatlin, Maureen; Høgdall, Estrid; Høgdall, Claus K.; Hosono, Satoyo; Jakubowska, Anna; Jensen, Allan; Kalli, Kimberly R.; Karlan, Beth Y.; Kelemen, Linda E.; Kiemeney, Lambertus A.; Kjaer, Susanne Krüger; Konecny, Gottfried E.; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Nathan; Lee, Janet; Leminen, Arto; Lim, Boon Kiong; Lissowska, Jolanta; Lubiński, Jan; Lundvall, Lene; Lurie, Galina; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B.; Nakanishi, Toru; Narod, Steven A.; Ness, Roberta B.; Nevanlinna, Heli; Nickels, Stefan; Noushmehr, Houtan; Odunsi, Kunle; Olson, Sara; Orlow, Irene; Paul, James; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jenny; Pike, Malcolm C; Poole, Elizabeth M; Qu, Xiaotao; Risch, Harvey A.; Rodriguez-Rodriguez, Lorna; Rossing, Mary Anne; Rudolph, Anja; Runnebaum, Ingo; Rzepecka, Iwona K; Salvesen, Helga B.; Schwaab, Ira; Severi, Gianluca; Shen, Hui; Shridhar, Vijayalakshmi; Shu, Xiao-Ou; Sieh, Weiva; Southey, Melissa C.; Spellman, Paul; Tajima, Kazuo; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J; Timorek, Agnieszka; Tworoger, Shelley S.; van Altena, Anne M.; Berg, David Van Den; Vergote, Ignace; Vierkant, Robert A.; Vitonis, Allison F.; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wik, Elisabeth; Winterhoff, Boris; Woo, Yin Ling; Wu, Anna H; Yang, Hannah P.; Zheng, Wei; Ziogas, Argyrios; Zulkifli, Famida; Goodman, Marc T.; Hall, Per; Easton, Douglas F; Pearce, Celeste L; Berchuck, Andrew; Chenevix-Trench, Georgia; Iversen, Edwin; Monteiro, Alvaro N.A.; Gayther, Simon A.; Schildkraut, Joellen M.; Sellers, Thomas A.
2013-01-01
Genome wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC) with another two loci being close to genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the United Kingdom. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. Follow-up genotyping was carried out in 18,174 cases and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 previously near genome-wide significance and identified three novel loci associated with risk; two loci associated with all EOC subtypes, at 8q21 (rs11782652, P=5.5×10-9) and 10p12 (rs1243180; P=1.8×10-8), and another locus specific to the serous subtype at 17q12 (rs757210; P=8.1×10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility that implicates CHMP4C in the pathogenesis of ovarian cancer. PMID:23535730
Hu, Xiaoyu; Yang, Zhu; Zeng, Manman; Liu, Y I; Yang, Xiaotao; Li, Yanan; Li, X U; Yu, Qiubo
2016-07-01
The aim of the present study was to investigate the status of speckle-type POZ (pox virus and zinc finger protein) protein (SPOP) gene located on chromosome 17q21 in ovarian cancer (OC). The present study evaluated a tissue microarray, which contained 90 samples of ovarian cancer and 10 samples of normal ovarian tissue, using fluorescence in situ hybridization (FISH). FISH is a method where a SPOP-specific DNA red fluorescence probe was used for the experimental group and a centromere-specific DNA green fluorescence probe for chromosome 17 was used for the control group. The present study demonstrated that a deletion of the SPOP gene was observed in 52.27% (46/88) of the ovarian cancer tissues, but was not identified in normal ovarian tissues. Simultaneously, monosomy 17 was frequently identified in the ovarian cancer tissues, but not in the normal ovarian tissues. Furthermore, the present data revealed that the ovarian cancer histological subtype and grade were significantly associated with a deletion of the SPOP gene, which was assessed by the appearance of monosomy 17 in the ovarian cancer samples; the deletion of the SPOP gene was observed in a large proportion of serous epithelial ovarian cancer (41/61; 67.21%), particularly in grade 3 (31/37; 83.78%). In conclusion, deletion of the SPOP gene on chromosome 17 in ovarian cancer samples, which results from monosomy 17, indicates that the SPOP gene may serve as a tumor suppressor gene in ovarian cancer.
Pochechueva, Tatiana; Alam, Shahidul; Schötzau, Andreas; Chinarev, Alexander; Bovin, Nicolai V; Hacker, Neville F; Jacob, Francis; Heinzelmann-Schwarz, Viola
2017-02-10
Glycosphingolipids are important compounds of the plasma membrane of mammalian cells and a number of them have been associated with malignant transformation and progression, reinforcing tumour aggressiveness and metastasis. Here we investigated the levels of naturally occurring anti-glycan antibodies to Globo H in blood plasma obtained from high-grade serous ovarian cancer patients (SOC) and women without gynaecological malignancies (control) using suspension glycan array technology employing chemically synthesized glycans as antibody targets. We found that anti-human Globo H IgG antibodies were able to significantly discriminate SOC from controls (P anti-Globo H antibodies highly correlated (r = 0.992). The incubation of plasma-derived anti-glycan antibodies with chemically synthesized (presented on fluorescence microspheres) and native Globo H (expressed on Globo H-positive cell lines) revealed strong reactivity of naturally occurring human anti-Globo H antibodies towards its antigen expressed on ovarian cancer cells. Our data demonstrate that human plasma-derived antibodies to Globo H as well as the presence of the antigen might be considered as therapeutic option in ovarian cancer.
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Candido-dos-Reis, Francisco J; Song, Honglin; Goode, Ellen L
2015-01-01
greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer-specific mortality. CONCLUSIONS: BRCA1...
Hypoxia-Activated Alkylating Agents in BRCA1-Mutant Ovarian Serous Carcinoma.
Conroy, Michael; Borad, Mitesh J; Bryce, Alan H
2017-07-26
Breast cancer 1 antigen (BRCA 1) and breast cancer 2 antigen (BRCA2) genes play a significant role in deoxyribonucleic acid (DNA) repair by means of interstrand crosslink repair, and deleterious germline mutations of these are responsible for most hereditary breast and ovarian cancers. Therapeutic strategies which specifically target interstrand crosslink repair can therefore be helpful in patients with harmful mutations. We describe two patients with advanced ovarian cancer and deleterious BRCA1 mutations who were treated with TH-302, a hypoxia-activated alkylating agent.
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Feng, Qiang; Pei, Wei; Zheng, Zhao-Xu; Bi, Jian-Jun; Yuan, Xing-Hua
2013-01-01
This study aims to explore the clinicopathologic characteristics and prognostic factors of gastric cancer patients with metachronous ovarian metastasis. Clinicopathologic data were collected from 63 post-operative gastric cancer patients with metachronous ovarian metastasis. The patients were admitted to the Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College between January 1999 and December 2011. A log-rank test was conducted for survival analysis. Possible prognostic factors that affect survival were examined by univariate analysis. A Cox regression model was used for multivariate analysis. The incidence of ovarian metastasis was 3.4% with a mean age of 45 years. Up to 65.1% of the patients were pre-menopausal. The mean interval between ovarian metastasis and primary cancer was 16 months. Lowly differentiated carcinoma ranked first in the primary gastric cancers. The majority of lesions occurred in the serous membrane (87.3%). The metastatic sites included N 2-3 lymph nodes (68.3%), bilateral ovaries (85.7%), and peritoneal membrane (73%). Total resection of metastatic sites was performed (31.7%). The overall median survival was 13.6 months, whereas the overall 1-, 2-, and 3-year survival rates were 52.5%, 22.0%, and 9.8%, respectively. The 5-year survival rate was zero. Univariate analysis showed that the patient prognosis was correlated with metastatic peritoneal seeding, vascular tumor embolus, range of lesion excision, and mode of comprehensive treatment with adjuvant chemotherapy (P<0.05). Multivariate analysis indicated that metastatic peritoneal seeding was an independent prognostic factor for gastric cancer patients with ovarian metastasis (P<0.01). Effective control of peritoneal seeding—induced metastasis is important for improving the prognosis of gastric cancer patients with ovarian metastasis
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Ardighieri, Laura; Zeppernick, Felix; Hannibal, Charlotte G
2014-01-01
There is debate as to whether peritoneal implants associated with serous borderline tumours/atypical proliferative serous tumours (SBT/APSTs) of the ovary are derived from the primary ovarian tumour or arise independently in the peritoneum. We analysed 57 SBT/APSTs from 45 patients with advanced......), 34 (53.9%) had KRAS mutations and 14 (22%) had BRAF mutations, of which identical KRAS mutations were found in 34 (91%) of 37 SBT/APST-implant pairs and identical BRAF mutations in 14 (100%) of 14 SBT/APST-implant pairs. Wild-type KRAS and BRAF (at the loci investigated) were found in 11 (100%) of 11...... SBT/APST-implant pairs. Overall concordance of KRAS and BRAF mutations was 95% in 59 of 62 SBT/APST-implant (non-invasive and invasive) pairs (p identical KRAS or BRAF...
Directory of Open Access Journals (Sweden)
Higgins LeeAnn
2010-06-01
Full Text Available Abstract Background Ovarian cancer is the most lethal gynecologic malignancy, with the majority of cases diagnosed at an advanced stage when treatments are less successful. Novel serum protein markers are needed to detect ovarian cancer in its earliest stage; when detected early, survival rates are over 90%. The identification of new serum biomarkers is hindered by the presence of a small number of highly abundant proteins that comprise approximately 95% of serum total protein. In this study, we used pooled serum depleted of the most highly abundant proteins to reduce the dynamic range of proteins, and thereby enhance the identification of serum biomarkers using the quantitative proteomic method iTRAQ®. Results Medium and low abundance proteins from 6 serum pools of 10 patients each from women with serous ovarian carcinoma, and 6 non-cancer control pools were labeled with isobaric tags using iTRAQ® to determine the relative abundance of serum proteins identified by MS. A total of 220 unique proteins were identified and fourteen proteins were elevated in ovarian cancer compared to control serum pools, including several novel candidate ovarian cancer biomarkers: extracellular matrix protein-1, leucine-rich alpha-2 glycoprotein-1, lipopolysaccharide binding protein-1, and proteoglycan-4. Western immunoblotting validated the relative increases in serum protein levels for several of the proteins identified. Conclusions This study provides the first analysis of immunodepleted serum in combination with iTRAQ® to measure relative protein expression in ovarian cancer patients for the pursuit of serum biomarkers. Several candidate biomarkers were identified which warrant further development.
Vishnu, Prakash; Colon-Otero, Gerardo; Kennedy, Gregory T; Marlow, Laura A; Kennedy, William P; Wu, Kevin J; Santoso, Joseph T; Copland, John A
2012-03-01
The aim was to evaluate antitumor activity of the combination of ixabepilone and sunitinib in pre-clinical models of chemotherapy naïve and refractory epithelial ovarian tumors, and to investigate the mechanism of synergy of such drug combination. HOVTAX2 cell line was derived from a metastatic serous papillary epithelial ovarian tumor (EOC) and a paclitaxel-resistant derivative was established. Dose response curves for ixabepilone and sunitinib were generated and synergy was determined using combination indexes. The molecular mechanism of antitumor synergy was examined using shRNA silencing. The combination of ixabepilone and sunitinib demonstrated robust antitumor synergy in naïve and paclitaxel-resistant HOVTAX2 cell lines due to increased apoptosis. The GTPase, RhoB, was synergistically upregulated in cells treated with ixabepilone and sunitinib. Using shRNA, RhoB was demonstrated to mediate antitumor synergy. These results were validated in two other EOC cell lines. Ixabepilone plus sunitinib demonstrated antitumor synergy via RhoB in naïve and paclitaxel-resistant cells resulting in apoptosis. This study demonstrates a novel mechanism of action leading to antitumor synergy and provides 'proof-of-principle' for combining molecular targeted agents with cytotoxic chemotherapy to improve antitumor efficacy. RhoB could be envisioned as an early biomarker of response to therapy in a planned Phase II clinical trial to assess the efficacy of ixabepilone combined with a receptor tyrosine kinase inhibitor such as sunitinib. To the best of our knowledge, this is the first demonstration of antitumor synergy between these two classes of drugs in EOC and the pivotal role of RhoB in this synergy. Copyright © 2011 Elsevier Inc. All rights reserved.
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Markowska, A.
2007-01-01
Many different hypotheses and theories have been formulated regarding the development of sporadic ovarian cancer. The augmented risk is associated with nulliparity or low fecundity. Apart from changes in the genital system, leptin can be linked in several ways to infertility or low fecundity, from poor alimentation (severe dieting) and its effects on the hypothalamushypophysis-ovary axis to improper blastocyst implantation in the endometrium. Ovulation used to be regarded as representing one of the factors which promote the development of ovarian cancer due to the associated lesions of the ovarian epithelium and the development of inclusion cysts. The risk is reduced by the long-term use of contraceptive pills. However, it has been demonstrated, that hormonal contraception is linked to the stabilization of plasma leptin levels and that it, possibly, has less pronounced effects on target tissues. In view of the suggestions on leptin involvement, the hypothesis regarding the effects of HRT on ovarian cancer development remains unsupported since leptin levels during a course of HRT manifest no increases or decreases- they remain stable. The inflammatory theory of ovarian cancer development might also be linked to the potential involvement of leptin in the pathogenesis of endometriosis, promoting endometrioid and clarocellular ovarian cancers. Leptin has been shown to be linked to the development of endometriosis, particularly due to its mitogenic and angiogenic effects. Bilateral ovariectomy, aimed at preventing the development of ovarian cancer, induces a decrease in serum leptin levels, in contrast to the reversible effects of pharmacological gonadectomy. Ovarian cancer develops more frequently in women who have high living standards, which is significantly associated with increased BMI and augmented serum leptin levels. The described theory concerning the two pathways of ovarian cancer development, including one typical for more aggressive serous cancers, may
Coetzee, Simon G; Shen, Howard C; Hazelett, Dennis J; Lawrenson, Kate; Kuchenbaecker, Karoline; Tyrer, Jonathan; Rhie, Suhn K; Levanon, Keren; Karst, Alison; Drapkin, Ronny; Ramus, Susan J; Couch, Fergus J; Offit, Kenneth; Chenevix-Trench, Georgia; Monteiro, Alvaro N A; Antoniou, Antonis; Freedman, Matthew; Coetzee, Gerhard A; Pharoah, Paul D P; Noushmehr, Houtan; Gayther, Simon A
2015-07-01
Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single-nucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 × 10(-30)), OSECs (P = 2.4 × 10(-23)) and HMECs (P = 6.7 × 10(-15)) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Paul Michael Jones
2013-08-01
Full Text Available Recent developments in the study of epithelial ovarian cancer have called into question the traditional views regarding the site of tumor initiation. Histopathologic studies and genomic analyses suggest that extra-ovarian sites, like the fallopian tube, may harbor the coveted cell of origin and could therefore contribute significantly to the development of high-grade serous ovarian carcinoma (HG-SOC. Our ability to validate these emerging genomic and pathologic observations and characterize the early transformation events of HG-SOC hinges on the development of novel model systems. Currently, there are only a handful of new model systems that are addressing these concerns. This review will chronicle the convergent evolution of these ovarian cancer model systems in the context of the changing pathologic and genomic understanding of HG-SOC.
Fan, H-Y; Duan, D-M; Liu, Y-F
2017-09-01
To evaluate the value of three tumor markers serum Golgi phosphoprotein-3 (GOLPH3), cancer antigen 125 (CA125) and cancer antigen 19-9 (CA19.9) in the diagnosis and postoperative evaluation of ovarian cancer by detecting these three markers. A total of 187 patients were studied and included in the ovarian cancer group, benign pelvic mass group, and the normal control group. The levels of serum Golgi phosphoprotein-3 (GOLPH3), cancer antigen 125 (CA125) and cancer antigen 199 (CA19.9) were detected, respectively, and their effects on the diagnosis, evaluation, pathology typing and staging of ovarian cancer were measured. The sensitivity of the detection of ovarian cancer by GOLPH3 combined with CA125 and CA19.9 was higher than that by a single marker (pserum GOLPH3 in patients with serous and endometrioid carcinoma was significantly higher than that in patients with mucinous carcinoma, clear-cell carcinoma and germ cell tumor (pserum GOLPH3 level between patients with ovarian malignancies at stage III-IV and those at stage I-II (p>0.05). The levels of serum GOLPH3, CA125 and CA19.9 in patients with ovarian malignancies after surgery were significantly lower than those before surgery (p<0.05). The combined detection by GOLPH3, CA125, and CA19.9 may improve the diagnosis rate of ovarian epithelial cancer. GOLPH3, as a new ovarian cancer tumor marker used in clinical diagnosis, is expected to become an important indicator for the early diagnosis of ovarian cancer and the determination of clinical surgery efficacy.
International Nuclear Information System (INIS)
Davis, Sally J; Choong, David YH; Ramakrishna, Manasa; Ryland, Georgina L; Campbell, Ian G; Gorringe, Kylie L
2011-01-01
MAP2K4 is a putative tumor and metastasis suppressor gene frequently found to be deleted in various cancer types. We aimed to conduct a comprehensive analysis of this gene to assess its involvement in ovarian cancer. We screened for mutations in MAP2K4 using High Resolution Melt analysis of 149 primary ovarian tumors and methylation at the promoter using Methylation-Specific Single-Stranded Conformation Polymorphism analysis of 39 tumors. We also considered the clinical impact of changes in MAP2K4 using publicly available expression and copy number array data. Finally, we used siRNA to measure the effect of reducing MAP2K4 expression in cell lines. In addition to 4 previously detected homozygous deletions, we identified a homozygous 16 bp truncating deletion and a heterozygous 4 bp deletion, each in one ovarian tumor. No promoter methylation was detected. The frequency of MAP2K4 homozygous inactivation was 5.6% overall, and 9.8% in high-grade serous cases. Hemizygous deletion of MAP2K4 was observed in 38% of samples. There were significant correlations of copy number and expression in three microarray data sets. There was a significant correlation between MAP2K4 expression and overall survival in one expression array data set, but this was not confirmed in an independent set. Treatment of JAM and HOSE6.3 cell lines with MAP2K4 siRNA showed some reduction in proliferation. MAP2K4 is targeted by genetic inactivation in ovarian cancer and restricted to high grade serous and endometrioid carcinomas in our cohort
Sugio, Asuka; Iwasaki, Masahiro; Habata, Shutaro; Mariya, Tasuku; Suzuki, Miwa; Osogami, Hiroyuki; Tamate, Masato; Tanaka, Ryoichi; Saito, Tsuyoshi
2014-09-01
Ovarian cancer is the leading cause of death from gynecologic cancer, reflecting its often late diagnosis and its chemoresistance. We identified a set of microRNAs whose expression is altered upon BAG3 knockdown. Our primary objective was to examine the relationships between BAG3, miR-29b and Mcl-1, an antiapoptotic Bcl-2 family protein, in ovarian cancer cells. Ovarian cancer cells were cultured and their responsiveness to paclitaxel was tested. Microarray analysis was performed to identify microRNAs differentially expressed in ES2 BAG3 knockdown ovarian cancer cells and their control cells. Primary ovarian cancer tissues were obtained from 56 patients operated on for ovarian cancer. The patients' clinical and pathological data were obtained from their medical records. BAG3 knockdown increased the chemosensitivity to paclitaxel of ES2 ovarian clear cell carcinoma cells to a greater degree than AMOC2 serous adenocarcinoma cells. qRT-PCR analysis showed that miR-29b expression was significantly upregulated in primary cancer tissue expressing low levels of BAG3, as compared to tissue expressing high levels. Moreover, levels of miR-29b correlated significantly with progression-free survival. Upregulation of miR-29b also reduced levels of Mcl-1 and sensitized ES2 cells to low-dose paclitaxel. BAG3 knockdown appears to downregulate expression of Mcl-1 through upregulation of miR-29b, thereby increasing the chemosensitivity of ovarian clear cell carcinoma cells. This suggests that BAG3 is a key determinant of the responsiveness of ovarian cancer cells, especially clear cell carcinoma, to paclitaxel and that BAG3 may be a useful therapeutic target for the treatment of ovarian cancer. Copyright © 2014 Elsevier Inc. All rights reserved.
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Philipp Harter
Full Text Available Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated.Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53 were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history.In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16-93 and 406 patients (77.6% had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%, BRCA2 (5.5%, RAD51C (2.5% and PALB2 (1.1% genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes in patients <60 years was 30.2% (33.2% versus 10.6% (18.9% in patients ≥60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants
Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis.
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Roland F Schwarz
2015-02-01
Full Text Available The major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC is the development of progressive resistance to platinum-based chemotherapy. The objective of this study was to determine whether intra-tumour genetic heterogeneity resulting from clonal evolution and the emergence of subclonal tumour populations in HGSOC was associated with the development of resistant disease.Evolutionary inference and phylogenetic quantification of heterogeneity was performed using the MEDICC algorithm on high-resolution whole genome copy number profiles and selected genome-wide sequencing of 135 spatially and temporally separated samples from 14 patients with HGSOC who received platinum-based chemotherapy. Samples were obtained from the clinical CTCR-OV03/04 studies, and patients were enrolled between 20 July 2007 and 22 October 2009. Median follow-up of the cohort was 31 mo (interquartile range 22-46 mo, censored after 26 October 2013. Outcome measures were overall survival (OS and progression-free survival (PFS. There were marked differences in the degree of clonal expansion (CE between patients (median 0.74, interquartile range 0.66-1.15, and dichotimization by median CE showed worse survival in CE-high cases (PFS 12.7 versus 10.1 mo, p = 0.009; OS 42.6 versus 23.5 mo, p = 0.003. Bootstrap analysis with resampling showed that the 95% confidence intervals for the hazard ratios for PFS and OS in the CE-high group were greater than 1.0. These data support a relationship between heterogeneity and survival but do not precisely determine its effect size. Relapsed tissue was available for two patients in the CE-high group, and phylogenetic analysis showed that the prevalent clonal population at clinical recurrence arose from early divergence events. A subclonal population marked by a NF1 deletion showed a progressive increase in tumour allele fraction during chemotherapy.This study demonstrates that quantitative measures of intra
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Ester Rozenblum
Full Text Available A new ovarian near-diploid cell line, OVDM1, was derived from a highly aneuploid serous ovarian metastatic adenocarcinoma. A metastatic tumor was obtained from a 47-year-old Ashkenazi Jewish patient three years after the first surgery removed the primary tumor, both ovaries, and the remaining reproductive organs. OVDM1 was characterized by cell morphology, genotyping, tumorigenic assay, mycoplasma testing, spectral karyotyping (SKY, and molecular profiling of the whole genome by aCGH and gene expression microarray. Targeted sequencing of a panel of cancer-related genes was also performed. Hierarchical clustering of gene expression data clearly confirmed the ovarian origin of the cell line. OVDM1 has a near-diploid karyotype with a low-level aneuploidy, but samples of the original metastatic tumor were grossly aneuploid. A number of single nucleotide variations (SNVs/mutations were detected in OVDM1 and the metastatic tumor samples. Some of them were cancer-related according to COSMIC and HGMD databases (no founder mutations in BRCA1 and BRCA2 have been found. A large number of focal copy number alterations (FCNAs were detected, including homozygous deletions (HDs targeting WWOX and GATA4. Progression of OVDM1 from early to late passages was accompanied by preservation of the near-diploid status, acquisition of only few additional large chromosomal rearrangements and more than 100 new small FCNAs. Most of newly acquired FCNAs seem to be related to localized but massive DNA fragmentation (chromothripsis-like rearrangements. Newly developed near-diploid OVDM1 cell line offers an opportunity to evaluate tumorigenesis pathways/events in a minor clone of metastatic ovarian adenocarcinoma as well as mechanisms of chromothripsis.
Sehdev, Ann Smith; Kurman, Robert J; Kuhn, Elisabetta; Shih, Ie-Ming
2010-06-01
Serous tubal intraepithelial carcinoma (STIC) has been proposed as a precursor for many pelvic high-grade serous carcinomas. Our previous analysis of the ovarian cancer genome identified several genes with oncogenic potential that are amplified and/or overexpressed in the majority of high-grade serous carcinomas. Determining whether these genes are upregulated in STICs is important in further elucidating the relationship of STICs to high-grade serous carcinomas and is fundamental in understanding the molecular pathogenesis of high-grade serous carcinomas. In this study, 37 morphologically defined STICs were obtained from 23 patients with stage IIIC/IV high-grade serous carcinomas. Both STICs and the high-grade serous carcinomas were analyzed for expression of Rsf-1 (HBXAP), cyclin E, fatty acid synthase (FASN) and mucin-4. In addition, they were examined for expression of established markers including p53, Ki-67 and p16. We found that diffuse nuclear p53 and p16 immunoreactivity was observed in 27 (75%) of 36 and 18 (55%) of 33 STICs, respectively, whereas an elevated Ki-67 labeling index (>or=10%) was detected in 29 (78%) of 37 STICs. Cyclin E nuclear staining was seen in 24 (77%) of 35 STICs, whereas normal tubal epithelial cells were all negative. Increased Rsf-1 and FASN immunoreactivity occurred in 63%, and 62% of STICs, respectively, compared with adjacent normal-appearing tubal epithelium. Interestingly, only one STIC showed increased mucin-4 immunoreactivity. Carcinomas, when compared with STICs, overexpressed p16, Rsf-1, cyclin E and FASN in a higher proportion of cases. In conclusion, STICs express several markers including Rsf-1, cyclin E and FASN in high-grade serous carcinomas. In contrast, mucin-4 immunoreactivity either did not change or was reduced in most STICs. These results suggest that overexpression of Rsf-1, cyclin E and FASN occurs early in tumor progression.
Histones and their modifications in ovarian cancer – drivers of disease and therapeutic targets
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Deborah Joy Marsh
2014-06-01
Full Text Available Epithelial ovarian cancer has the highest mortality of the gynecological malignancies. High grade serous epithelial ovarian cancer (SEOC is the most common subtype, with the majority of women presenting with advanced disease where 5 year survival is around 25%. Platinum-based chemotherapy in combination with paclitaxel remains the most effective treatment despite platinum therapies being introduced almost 40 years ago. Advances in molecular medicine are underpinning new strategies for the treatment of cancer. Major advances have been made by international initiatives to sequence cancer genomes. For SEOC, with the exception of TP53 that is mutated in virtually 100% of these tumors, there is no other gene mutated at high frequency. There is extensive copy number variation, as well as changes in methylation patterns that will influence gene expression. To date, the role of histones and their post-translational modifications in ovarian cancer is a relatively understudied field. Post-translational histone modifications play major roles in gene expression as they direct the configuration of chromatin and so access by transcription factors. Histone modifications include methylation, acetylation and monoubiquitination, with involvement of enzymes including histone methyl transferases (HMTases, histone acetyltransferases/deacetylases and ubiquitin ligases/deubiquitinases respectively. Complexes such as the Polycomb Repressive Complex also play roles in the control of histone modifications and more recently roles for long non-coding (lnc RNA and microRNAs (miRNAs are emerging. Epigenomic-based therapies targeting histone modifications are being developed and offer new approaches for the treatment of ovarian cancer. Here we discuss histone modifications and their aberrant regulation in malignancy and specifically in ovarian cancer. We review current and upcoming histone-based therapies that have the potential to inform and improve treatment strategies for
Dougherty, Brian A; Lai, Zhongwu; Hodgson, Darren R; Orr, Maria C M; Hawryluk, Matthew; Sun, James; Yelensky, Roman; Spencer, Stuart K; Robertson, Jane D; Ho, Tony W; Fielding, Anitra; Ledermann, Jonathan A; Barrett, J Carl
2017-07-04
To gain a better understanding of the role of somatic mutations in olaparib response, next-generation sequencing (NGS) of BRCA1 and BRCA2 was performed as part of a planned retrospective analysis of tumors from a randomized, double-blind, Phase II trial (Study 19; D0810C00019; NCT00753545) in 265 patients with platinum-sensitive high-grade serous ovarian cancer. BRCA1/2 loss-of-function mutations were found in 55% (114/209) of tumors, were mutually exclusive, and demonstrated high concordance with Sanger-sequenced germline mutations in matched blood samples, confirming the accuracy (97%) of tumor BRCA1/2 NGS testing. Additionally, NGS identified somatic mutations absent from germline testing in 10% (20/209) of the patients. Somatic mutations had >80% biallelic inactivation frequency and were predominantly clonal, suggesting that BRCA1/2 loss occurs early in the development of these cancers. Clinical outcomes between placebo- and olaparib-treated patients with somatic BRCA1/2 mutations were similar to those with germline BRCA1/2 mutations, indicating that patients with somatic BRCA1/2 mutations benefit from treatment with olaparib.
Asaturova, A V; Ezhova, L S; Faizullina, N M; Adamyan, L V; Khabas, G N; Sannikova, M V
to investigate the frequency of the types of fallopian tubal secretory cell expansion (SCE) in diseases of the reproductive organs and to determine the immunophenotype and biological role of the cells in the early stages of the pathogenesis of high-grade ovarian serous carcinomas (HGOSC). The investigation enrolled 287 patients with extraovarian diseases and ovarian serous tumors varying in grade, whose fallopian tubes were morphologically and immunohistochemically examined using p53, Ki-67, PAX2, Bcl-2, beta-catenin, and ALDH1 markers. The material was statistically processed applying the Mann-Whitney test and χ2 test. The rate of secretory cell proliferation (SCP) (more than 10 consecutive secretory cells) and that of secretory cell overgrowth (SCO) (more than 30 consecutive secretory cells) increase with age in all investigated reproductive system diseases. The rate of SCP in the corpus fimbriatum of the patients with HGOSC was 5.9 times higher than that in those with extraovarian disease (pepithelium (2.8), in SCP (1.3), in SCO (1.2), in serous tubal intraepithelial carcinoma (STIC) (1.0), and in HGOSC (0.9); Bcl-2 was in the intact epithelium (2.2), in SCP (2.1), STIC (0.9), and in HGOSC (0.6), β-catenin was in the intact epithelium (0.5), in SCP (2.85), in SCO (2.95), in STIC (0.6), and in HGOSC (0.5); ALDH1 was in the intact epithelium (0.5), in SCP (2.91), in SCO (2.92), in STIC (1.2), and in HGOSC (0.6). There were statistically significant differences with a 95% confidence interval (pepithelium and pathology (fallopian tube lesions and HGOSC); 2) Bcl-2 between the intact epithelium and SCE (SCP and SCO) and between SCE and HGOSC; 3) beta-catenin between the intact epithelium and SCE (SCP and SCO) and between SCE and HGOSC; 4) ALDH1 between the intact epithelium and SCE, between and SCE and STIC, and between STIC and HGOSC. SCE was shown to be an independent intraepithelial lesion. The incidence of this abnormality increased with age and significantly
Yu, Dandan; Holm, Ruth; Goscinski, Mariusz Adam; Trope, Claes G; Nesland, Jahn M; Suo, Zhenhe
2016-01-01
Ovarian cancer is the most lethal gynecologic malignancy, in which cancer stem cells (CSC) have been reported to be the driving force of relapse and therapy-resistance. It is therefore important to explore CSC markers in ovarian cancer. This project aimed to explore the correlation between the expression of potential CSC maker Cacna2d1 and clinicopathological parameters in 238 epithelial ovarian cancer (EOC) samples. Immunohistochemically, positive Cacna2d1 expression was observed in 83.6% (199/238) of the EOC tumors, among which 107 tumors (44.9%) were highly positive and 92 (38.7%) tumors were weakly positive for the Cacna2d1 protein expression. Among the 158 serous carcinomas, the Cacna2d1 positivity was 148 (93.7%), in which 88 (55.7%) were highly positive, and 60 (38.0%) were weakly positive for the Cacna2d1 protein expression. Most strikingly, the Cacna2d1 was specifically expressed in the infiltration front areas of the EOC tumors. Statistical analyses showed that positive expression of Cacna2d1 was significantly associated with advanced FIGO stage (P<0.001), histological subtype (P=0.017) and tumor differentiation (P=0.015). Positive Cacna2d1 protein expression was significantly associated with poor overall survival (OS) and shorter progression free survival (PFS) in both total EOCs and serous carcinomas, although multivariate analyses did not reach statistical significance. In summary, our results suggest Cacna2d1 protein may play a crucial role in promoting aggressive EOC behavior and progression, and Cacna2d1 may serve as a novel predictive prognostic marker and a potential target for therapeutic intervention in EOCs. PMID:27725913
Towards prevention of ovarian cancer.
Ali, Aus Tariq
2018-01-01
Ovarian cancer is the leading cause of death of all gynaecological cancers. To date, there is no reliable, specific screening procedure for detecting ovarian cancer. The risk factors of ovarian cancer include modifiable and non-modifiable factors. The main goal of the ovarian cancer prevention program is to significantly reduce the risk of development of ovarian cancer and other cancers such as breast and/or peritoneal cancer. The application of non-surgical preventive approaches such as oral contraceptives, parity and breastfeeding has been shown to be highly protective against ovarian cancer development. Targeting inflammation has been also reported to be associated with a protective trend against ovarian cancer and can be achieved through either non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin or lifestyle modifications or both. Lifestyle modification that includes regular exercise, healthy diet supplemented with anti-oxidants and anti-inflammatory elements reduces the risk of the disease even further. Surgical protective approaches include; tubal ligation, hysterectomy and prophylactic bilateral salpingo-oophorectomy and the former is the most effective approach to protect against ovarian cancer. A better understanding of the risk factors of ovarian cancer and the current approaches to prevent it may increase the awareness and help to decrease the incidence of ovarian cancer, increase the five-year survival rate and decrease the mortality rate significantly in the general population especially among those at high risk for ovarian cancer. This review is an attempt to outline a potential program of ovarian cancer prevention and the potential challenges. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer.
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d'Adhemar, Charles J
2014-01-01
The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact\\/functioning TLR4\\/MyD88
The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer.
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Charles J d'Adhemar
Full Text Available The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4, and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic, whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05, indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2 cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4
Pina, Christian; Khattab, Ahmed; Katzman, Philip; Bruckner, Lauren; Andolina, Jeffrey; New, Maria; Yau, Mabel
2015-05-01
A 14-year-old female with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency underwent bilateral adrenalectomy at 6 years of age as a result of poor hormonal control. Because the patient was adrenalectomized, extra adrenal androgen production was suspected. Imaging studies including pelvic ultrasound and pelvic magnetic resonance imaging (MRI) were obtained to evaluate for adrenal rest tumors of the ovaries. Abdominal MRI was obtained to evaluate for residual adrenal tissue. A cystic lesion arising from her right ovary suspicious for ovarian neoplasm was noted on pelvic MRI. Right salpingo-oophorectomy was performed and histopathological examination revealed ovarian serous adenocarcinoma, low-grade, and well-differentiated. Tumor marker CA-125 was elevated and additional ovarian cancer staging workup confirmed stage IIIC due to one lymph node positive for carcinoma. The patient then developed a large left ovarian cyst, which led to a complete total abdominal hysterectomy and removal of the left ovary and fallopian tube. Pathology confirmed ovarian serous adenocarcinoma with microscopic focus of carcinoma in the left ovary. After numerous complications, the patient responded well to chemotherapy, CA-125 levels fell and no evidence of carcinoma was observed on subsequent imaging. To our knowledge, this is the first reported case of an ovarian serous adenocarcinoma in a patient with CAH. Although rare, we propose that the ovaries were the origin of androgen production and not residual adrenal tissue. The relationship between CAH and ovarian carcinomas has yet to be established, but further evaluation is needed given the poor survival rate of high-grade serous ovarian carcinoma.
DEFF Research Database (Denmark)
Ketabi, Zohreh; Bartuma, Katarina; Bernstein, Inge
2011-01-01
. The underlying MMR gene mutations in these families affected MSH2 in 49%, MSH6 in 33% and MLH1 in 17%. Immunohistochemical loss of the corresponding MMR protein was demonstrated in 33/36 (92%) tumors analyzed. CONCLUSION: The combined data from our cohorts demonstrate that ovarian cancer associated with Lynch...
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C.E. Henry
2017-06-01
Full Text Available OBJECTIVE: The ROR1 and ROR2 receptor tyrosine kinases have both been implicated in ovarian cancer progression and have been shown to drive migration and invasion. There is an increasing importance of the role of stroma in ovarian cancer metastasis; however, neither ROR1 nor ROR2 expression in tumor or stromal cells has been analyzed in the same clinical cohort. AIM: To determine ROR1 and ROR2 expression in ovarian cancer and surrounding microenvironment and examine associations with clinicopathological characteristics. METHODS: Immunohistochemistry for ROR1 and ROR2 was used to assess receptor expression in a cohort of epithelial ovarian cancer patients (n = 178. Results were analyzed in relation to clinical and histopathological characteristics and survival. Matched patient sample case studies of normal, primary, and metastatic lesions were used to examine ROR expression in relation to ovarian cancer progression. RESULTS: ROR1 and ROR2 are abnormally expressed in malignant ovarian epithelium and stroma. Higher ROR2 tumor expression was found in early-stage, low-grade endometrioid carcinomas. ROR2 stromal expression was highest in the serous subtype. In matched patient case studies, metastatic samples had higher expression of ROR2 in the stroma, and a recurrent sample had the highest expression of ROR2 in both tumor and stroma. CONCLUSION: ROR1 and ROR2 are expressed in tumor-associated stroma in all histological subtypes of ovarian cancer and hold potential as therapeutic targets which may disrupt tumor and stroma interactions.
Castellvi, Josep; Garcia, Angel; Rojo, Federico; Ruiz-Marcellan, Carmen; Gil, Antonio; Baselga, Jose; Ramon y Cajal, Santiago
2006-10-15
Growth factor receptors and cell signaling factors play a crucial role in human carcinomas and have been studied in ovarian tumors with varying results. Cell signaling involves multiple pathways and a myriad of factors that can be mutated or amplified. Cell signaling is driven through the mammalian target of rapamycin (mTOR) and extracellular regulated kinase (ERK) pathways and by some downstream molecules, such as 4E binding protein 1 (4EBP1), eukaryotic initiation factor 4E, and p70 ribosomal protein S6 kinase (p70S6K). The objectives of this study were to analyze the real role that these pathways play in ovarian cancer, to correlate them with clinicopathologic characteristics, and to identify the factors that transmit individual proliferation signals and are associated with pathologic grade and prognosis, regardless specific oncogenic alterations upstream. One hundred twenty-nine ovarian epithelial tumors were studied, including 20 serous cystadenomas, 7 mucinous cystadenomas, 11 serous borderline tumors, 16 mucinous borderline tumors, 29 serous carcinomas, 16 endometrioid carcinomas, 15 clear cell carcinomas, and 15 mucinous carcinomas. Tissue microarrays were constructed, and immunohistochemistry for the receptors epidermal growth factor receptor (EGFR) and c-erb-B2 was performed and with phosphorylated antibodies for protein kinase B (AKT), 4EBP1, p70S6K, S6, and ERK. Among 129 ovarian neoplasms, 17.8% were positive for c-erb-B2, 9.3% were positive for EGFR, 47.3% were positive for phosphorylated AKT (p-AKT), 58.9% were positive for p-ERK, 41.1% were positive for p-4EBP1, 26.4% were positive for p70S6K, and 15.5% were positive for p-S6. Although EGFR, p-AKT, and p-ERK expression did not differ between benign, borderline, or malignant tumors, c-erb-B2, p-4EBP1, p-p70S6K, and p-S6 were expressed significantly more often in malignant tumors. Only p-4EBP1 expression demonstrated prognostic significance (P = .005), and only surgical stage and p-4EBP1 expression
DEFF Research Database (Denmark)
Beral, V; Gaitskell, K; Hermon, C
2012-01-01
Smoking has been linked to mucinous ovarian cancer, but its effects on other ovarian cancer subtypes and on overall ovarian cancer risk are unclear, and the findings from most studies with relevant data are unpublished. To assess these associations, we review the published and unpublished evidence....
High-risk HPV is not associated with epithelial ovarian cancer in a Caucasian population
DEFF Research Database (Denmark)
Ingerslev, Kasper Hjorth; Hogdall, Estrid; Skovrider-Ruminski, Wojciech
2016-01-01
BACKGROUND: High-risk human papillomavirus (HPV) has been suspected to play a role in the carcinogenesis of epithelial ovarian cancer (EOC). However, results from previous studies are conflicting. In most of these studies, the number of tissue samples was small. The current study was therefore...... undertaken to examine the prevalence of high-risk HPV DNA in EOC in a large series of patients. METHOD: Formalin-fixed, paraffin-imbedded tumor tissue samples from 198 cases consecutively included in the Danish Pelvic Mass Study were analyzed. The material included 163 serous adenocarcinomas, 15 endometrioid...
Energy Technology Data Exchange (ETDEWEB)
Qiu, Jun-jun [Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai 200011 (China); Department of Obstetrics and Gynecology of Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032 (China); Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, 413 Zhaozhou Road, Shanghai 200011 (China); Wang, Yan [Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong' an Road, Shanghai 200032 (China); Department of Oncology, Shanghai Medical College, Fudan University, 130 Dong' an Road, Shanghai 200032 (China); Ding, Jing-xin; Jin, Hong-yan [Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai 200011 (China); Department of Obstetrics and Gynecology of Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032 (China); Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, 413 Zhaozhou Road, Shanghai 200011 (China); Yang, Gong, E-mail: yanggong@fudan.edu.cn [Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong' an Road, Shanghai 200032 (China); Department of Oncology, Shanghai Medical College, Fudan University, 130 Dong' an Road, Shanghai 200032 (China); Hua, Ke-qin, E-mail: huakeqin@126.com [Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai 200011 (China); Department of Obstetrics and Gynecology of Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032 (China); Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, 413 Zhaozhou Road, Shanghai 200011 (China)
2015-05-01
HOX transcript antisense RNA (HOTAIR) is a well-known long non-coding RNA (lncRNA) whose dysregulation correlates with poor prognosis and malignant progression in many forms of cancer. Here, we investigate the expression pattern, clinical significance, and biological function of HOTAIR in serous ovarian cancer (SOC). Clinically, we found that HOTAIR levels were overexpressed in SOC tissues compared with normal controls and that HOTAIR overexpression was correlated with an advanced FIGO stage and a high histological grade. Multivariate analysis revealed that HOTAIR is an independent prognostic factor for predicting overall survival in SOC patients. We demonstrated that HOTAIR silencing inhibited A2780 and OVCA429 SOC cell proliferation in vitro and that the anti-proliferative effects of HOTAIR silencing also occurred in vivo. Further investigation into the mechanisms responsible for the growth inhibitory effects by HOTAIR silencing revealed that its knockdown resulted in the induction of cell cycle arrest and apoptosis through certain cell cycle-related and apoptosis-related proteins. Together, these results highlight a critical role of HOTAIR in SOC cell proliferation and contribute to a better understanding of the importance of dysregulated lncRNAs in SOC progression. - Highlights: • HOTAIR overexpression correlates with an aggressive tumour phenotype and a poor prognosis in SOC. • HOTAIR promotes SOC cell proliferation both in vitro and in vivo. • The proliferative role of HOTAIR is associated with regulation of the cell cycle and apoptosis.
Hanna, Louise; Adams, Malcolm
2006-04-01
Ovarian cancer is the leading cause of death from gynaecological malignancy. The incidence is high in the Western world. The incidence of ovarian cancer is reduced by pregnancy, lactation, the oral contraceptive pill and tubal ligation. Lifestyle factors are important in the aetiology of ovarian cancer and current evidence suggests the risk can be reduced by eating a diet rich in fruit and vegetables, taking regular exercise, avoiding smoking, avoiding being overweight and avoiding long-term use of hormonal replacement therapy (HRT). Familial ovarian cancer is responsible for about 10% of ovarian cancer cases. Strategies available to high-risk women include screening (covered elsewhere) and prophylactic salpingo-oophorectomy. The precise role of chemoprevention for high-risk women in the form of the oral contraceptive pill is unclear.
Tubal origin of ovarian cancer - the double-edged sword of haemoglobin.
Lin, Shiou-Fu; Gerry, Emily; Shih, Ie-Ming
2017-05-01
Ovarian high-grade serous carcinoma (HGSC) is the most malignant neoplasm of the gynaecological tract. While the origins of many human malignant neoplasms are clear, the origin of HGSC remains poorly understood. This lack of knowledge limits our understanding of its pathogenesis and compromises efforts devoted to developing better early detection tools and effective preventative interventions. The paradigm of the tubal origin of HGSC has been advanced since the initial report of dysplastic lesions (now known as serous tubal intraepithelial carcinomas or STICs) that morphologically resemble HGSC in the Fallopian tube. These were observed in a group of patients with a genetic predisposition to ovarian cancer who were undergoing risk-reducing salpingo-oophorectomy. Since then, a series of clinico-pathological and molecular studies have characterized STICs and their concurrent HGSCs, and the results support the new paradigm of a tubal origin of many 'ovarian' HGSCs. Reactive oxygen species-containing ovulatory follicular fluid has been thought to be the major culprit behind DNA damage in tubal epithelial cells, leading to either cell death or, if the cells survive, mutagenesis. A recent report from this journal demonstrates that ferryl haemoglobin (Hb) in peritoneal fluid could prevent cell death from DNA-damaged fimbrial epithelial cells, facilitating ovulation-induced carcinogenesis of tubal epithelium. This timely study provides new insight into the tumour initiation event in HGSC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Patient-derived xenograft models to improve targeted therapy in epithelial ovarian cancer treatment
Directory of Open Access Journals (Sweden)
Clare eScott
2013-12-01
Full Text Available Despite increasing evidence that precision therapy targeted to the molecular drivers of a cancer has the potential to improve clinical outcomes, high-grade epithelial ovarian cancer patients are currently treated without consideration of molecular phenotype, and predictive biomarkers that could better inform treatment remain unknown. Delivery of precision therapy requires improved integration of laboratory-based models and cutting-edge clinical research, with pre-clinical models predicting patient subsets that will benefit from a particular targeted therapeutic. Patient-derived xenografts (PDX are renewable tumor models engrafted in mice, generated from fresh human tumors without prior in vitro exposure. PDX models allow an invaluable assessment of tumor evolution and adaptive response to therapy.PDX models have been applied to preclinical drug testing and biomarker identification in a number of cancers including ovarian, pancreatic, breast and prostate cancers. These models have been shown to be biologically stable and accurately reflect the patient tumor with regards to histopathology, gene expression, genetic mutations and therapeutic response. However, pre-clinical analyses of molecularly annotated PDX models derived from high-grade serous ovarian cancer (HG-SOC remain limited. In vivo response to conventional and/or targeted therapeutics has only been described for very small numbers of individual HG-SOC PDX in conjunction with sparse molecular annotation and patient outcome data. Recently, two consecutive panels of epithelial ovarian cancer PDX correlate in vivo platinum response with molecular aberrations and source patient clinical outcomes. These studies underpin the value of PDX models to better direct chemotherapy and predict response to targeted therapy. Tumor heterogeneity, before and following treatment, as well as the importance of multiple molecular aberrations per individual tumor underscore some of the important issues
International Nuclear Information System (INIS)
Ryu, Sang Young
1999-12-01
This study is to investigate whether FDG-PET scan can substitute for second look operation in patients with ovarian cancer showing complete response with chemotherapy. From Jan. 1999 to Oct. 1999, 10 patients with advanced ovarian cancer who showed clinical complete response with 6 cycles of combination chemotherapy were registered in KCCH. These patients showed no residual tumors in conventional radiologic imaging studies (CT or MRI), normal tumor marker, no evidence of disease by physical examination. PET scans and second look operation were performed in 10 patients with advanced ovarian cancer (3 patients with stage IIc, 2 patients with stage IIIb, 5 patients with IIIc), who showed complete response with cytoreductive surgery and 6 cycles of post-operative adjuvant cisplatin-based combination chemotherapy. Median age of patients was 45 years, and serous cystadenocarcinoma was most common histologic type. None showed active lesion in pelvis and abdomen with FDG-PET scan (SUV; > 3.5 kg/ml), and I patient showed active lesion in lung field. On second look operations, 5 patients (50%) showed positive result on multiple blind biopsy. The patient with active lesion on FDG-PET scan in lung field confirmed to have metastatic lesions by chest CT scan. In conclusion, FDG-PET scan is not useful for detection of small ovarian cancer lesions in pelvis and abdomen, and cannot substitute for second look operation to determine pathologic complete response
Energy Technology Data Exchange (ETDEWEB)
Ryu, Sang Young
1999-12-01
This study is to investigate whether FDG-PET scan can substitute for second look operation in patients with ovarian cancer showing complete response with chemotherapy. From Jan. 1999 to Oct. 1999, 10 patients with advanced ovarian cancer who showed clinical complete response with 6 cycles of combination chemotherapy were registered in KCCH. These patients showed no residual tumors in conventional radiologic imaging studies (CT or MRI), normal tumor marker, no evidence of disease by physical examination. PET scans and second look operation were performed in 10 patients with advanced ovarian cancer (3 patients with stage IIc, 2 patients with stage IIIb, 5 patients with IIIc), who showed complete response with cytoreductive surgery and 6 cycles of post-operative adjuvant cisplatin-based combination chemotherapy. Median age of patients was 45 years, and serous cystadenocarcinoma was most common histologic type. None showed active lesion in pelvis and abdomen with FDG-PET scan (SUV; > 3.5 kg/ml), and I patient showed active lesion in lung field. On second look operations, 5 patients (50%) showed positive result on multiple blind biopsy. The patient with active lesion on FDG-PET scan in lung field confirmed to have metastatic lesions by chest CT scan. In conclusion, FDG-PET scan is not useful for detection of small ovarian cancer lesions in pelvis and abdomen, and cannot substitute for second look operation to determine pathologic complete response.
DEFF Research Database (Denmark)
Pearce, C L; Near, A M; Van Den Berg, D J
2009-01-01
The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had...... been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P... and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted....
Trillsch, F; Mahner, S; Vettorazzi, E; Woelber, L; Reuss, A; Baumann, K; Keyver-Paik, M-D; Canzler, U; Wollschlaeger, K; Forner, D; Pfisterer, J; Schroeder, W; Muenstedt, K; Richter, B; Fotopoulou, C; Schmalfeldt, B; Burges, A; Ewald-Riegler, N; de Gregorio, N; Hilpert, F; Fehm, T; Meier, W; Hillemanns, P; Hanker, L; Hasenburg, A; Strauss, H-G; Hellriegel, M; Wimberger, P; Kommoss, S; Kommoss, F; Hauptmann, S; du Bois, A
2015-02-17
Incomplete surgical staging is a negative prognostic factor for patients with borderline ovarian tumours (BOT). However, little is known about the prognostic impact of each individual staging procedure. Clinical parameters of 950 patients with BOT (confirmed by central reference pathology) treated between 1998 and 2008 at 24 German AGO centres were analysed. In 559 patients with serous BOT and adequate ovarian surgery, further recommended staging procedures (omentectomy, peritoneal biopsies, cytology) were evaluated applying Cox regression models with respect to progression-free survival (PFS). For patients with one missing staging procedure, the hazard ratio (HR) for recurrence was 1.25 (95%-CI 0.66-2.39; P=0.497). This risk increased with each additional procedure skipped reaching statistical significance in case of two (HR 1.95; 95%-CI 1.06-3.58; P=0.031) and three missing steps (HR 2.37; 95%-CI 1.22-4.64; P=0.011). The most crucial procedure was omentectomy which retained a statistically significant impact on PFS in multiple analysis (HR 1.91; 95%-CI 1.15-3.19; P=0.013) adjusting for previously established prognostic factors as FIGO stage, tumour residuals, and fertility preservation. Individual surgical staging procedures contribute to the prognosis for patients with serous BOT. In this analysis, recurrence risk increased with each skipped surgical step. This should be considered when re-staging procedures following incomplete primary surgery are discussed.
Identification of six new susceptibility loci for invasive epithelial ovarian cancer.
Kuchenbaecker, Karoline B; Ramus, Susan J; Tyrer, Jonathan; Lee, Andrew; Shen, Howard C; Beesley, Jonathan; Lawrenson, Kate; McGuffog, Lesley; Healey, Sue; Lee, Janet M; Spindler, Tassja J; Lin, Yvonne G; Pejovic, Tanja; Bean, Yukie; Li, Qiyuan; Coetzee, Simon; Hazelett, Dennis; Miron, Alexander; Southey, Melissa; Terry, Mary Beth; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Neuhausen, Susan L; Ding, Yuan Chun; Hansen, Thomas V O; Jønson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; Barrowdale, Daniel; Dennis, Joe; Benitez, Javier; Osorio, Ana; Garcia, Maria Jose; Komenaka, Ian; Weitzel, Jeffrey N; Ganschow, Pamela; Peterlongo, Paolo; Bernard, Loris; Viel, Alessandra; Bonanni, Bernardo; Peissel, Bernard; Manoukian, Siranoush; Radice, Paolo; Papi, Laura; Ottini, Laura; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Frost, Debra; Perkins, Jo; Platte, Radka; Ellis, Steve; Godwin, Andrew K; Schmutzler, Rita Katharina; Meindl, Alfons; Engel, Christoph; Sutter, Christian; Sinilnikova, Olga M; Damiola, Francesca; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Claes, Kathleen; De Leeneer, Kim; Kirk, Judy; Rodriguez, Gustavo C; Piedmonte, Marion; O'Malley, David M; de la Hoya, Miguel; Caldes, Trinidad; Aittomäki, Kristiina; Nevanlinna, Heli; Collée, J Margriet; Rookus, Matti A; Oosterwijk, Jan C; Tihomirova, Laima; Tung, Nadine; Hamann, Ute; Isaccs, Claudine; Tischkowitz, Marc; Imyanitov, Evgeny N; Caligo, Maria A; Campbell, Ian G; Hogervorst, Frans B L; Olah, Edith; Diez, Orland; Blanco, Ignacio; Brunet, Joan; Lazaro, Conxi; Pujana, Miquel Angel; Jakubowska, Anna; Gronwald, Jacek; Lubinski, Jan; Sukiennicki, Grzegorz; Barkardottir, Rosa B; Plante, Marie; Simard, Jacques; Soucy, Penny; Montagna, Marco; Tognazzo, Silvia; Teixeira, Manuel R; Pankratz, Vernon S; Wang, Xianshu; Lindor, Noralane; Szabo, Csilla I; Kauff, Noah; Vijai, Joseph; Aghajanian, Carol A; Pfeiler, Georg; Berger, Andreas; Singer, Christian F; Tea, Muy-Kheng; Phelan, Catherine M; Greene, Mark H; Mai, Phuong L; Rennert, Gad; Mulligan, Anna Marie; Tchatchou, Sandrine; Andrulis, Irene L; Glendon, Gord; Toland, Amanda Ewart; Jensen, Uffe Birk; Kruse, Torben A; Thomassen, Mads; Bojesen, Anders; Zidan, Jamal; Friedman, Eitan; Laitman, Yael; Soller, Maria; Liljegren, Annelie; Arver, Brita; Einbeigi, Zakaria; Stenmark-Askmalm, Marie; Olopade, Olufunmilayo I; Nussbaum, Robert L; Rebbeck, Timothy R; Nathanson, Katherine L; Domchek, Susan M; Lu, Karen H; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Hein, Alexander; Ekici, Arif B; Beckmann, Matthias W; Fasching, Peter A; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Lambrechts, Sandrina; Dicks, Ed; Doherty, Jennifer A; Wicklund, Kristine G; Rossing, Mary Anne; Rudolph, Anja; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Moysich, Kirsten B; Odunsi, Kunle; Sucheston, Lara; Lele, Shashi; Wilkens, Lynne R; Goodman, Marc T; Thompson, Pamela J; Shvetsov, Yurii B; Runnebaum, Ingo B; Dürst, Matthias; Hillemanns, Peter; Dörk, Thilo; Antonenkova, Natalia; Bogdanova, Natalia; Leminen, Arto; Pelttari, Liisa M; Butzow, Ralf; Modugno, Francesmary; Kelley, Joseph L; Edwards, Robert P; Ness, Roberta B; du Bois, Andreas; Heitz, Florian; Schwaab, Ira; Harter, Philipp; Matsuo, Keitaro; Hosono, Satoyo; Orsulic, Sandra; Jensen, Allan; Kjaer, Susanne Kruger; Hogdall, Estrid; Hasmad, Hanis Nazihah; Azmi, Mat Adenan Noor; Teo, Soo-Hwang; Woo, Yin-Ling; Fridley, Brooke L; Goode, Ellen L; Cunningham, Julie M; Vierkant, Robert A; Bruinsma, Fiona; Giles, Graham G; Liang, Dong; Hildebrandt, Michelle A T; Wu, Xifeng; Levine, Douglas A; Bisogna, Maria; Berchuck, Andrew; Iversen, Edwin S; Schildkraut, Joellen M; Concannon, Patrick; Weber, Rachel Palmieri; Cramer, Daniel W; Terry, Kathryn L; Poole, Elizabeth M; Tworoger, Shelley S; Bandera, Elisa V; Orlow, Irene; Olson, Sara H; Krakstad, Camilla; Salvesen, Helga B; Tangen, Ingvild L; Bjorge, Line; van Altena, Anne M; Aben, Katja K H; Kiemeney, Lambertus A; Massuger, Leon F A G; Kellar, Melissa; Brooks-Wilson, Angela; Kelemen, Linda E; Cook, Linda S; Le, Nhu D; Cybulski, Cezary; Yang, Hannah; Lissowska, Jolanta; Brinton, Louise A; Wentzensen, Nicolas; Hogdall, Claus; Lundvall, Lene; Nedergaard, Lotte; Baker, Helen; Song, Honglin; Eccles, Diana; McNeish, Ian; Paul, James; Carty, Karen; Siddiqui, Nadeem; Glasspool, Rosalind; Whittemore, Alice S; Rothstein, Joseph H; McGuire, Valerie; Sieh, Weiva; Ji, Bu-Tian; Zheng, Wei; Shu, Xiao-Ou; Gao, Yu-Tang; Rosen, Barry; Risch, Harvey A; McLaughlin, John R; Narod, Steven A; Monteiro, Alvaro N; Chen, Ann; Lin, Hui-Yi; Permuth-Wey, Jenny; Sellers, Thomas A; Tsai, Ya-Yu; Chen, Zhihua; Ziogas, Argyrios; Anton-Culver, Hoda; Gentry-Maharaj, Aleksandra; Menon, Usha; Harrington, Patricia; Lee, Alice W; Wu, Anna H; Pearce, Celeste L; Coetzee, Gerry; Pike, Malcolm C; Dansonka-Mieszkowska, Agnieszka; Timorek, Agnieszka; Rzepecka, Iwona K; Kupryjanczyk, Jolanta; Freedman, Matt; Noushmehr, Houtan; Easton, Douglas F; Offit, Kenneth; Couch, Fergus J; Gayther, Simon; Pharoah, Paul P; Antoniou, Antonis C; Chenevix-Trench, Georgia
2015-02-01
Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
Delcourt, Vivian; Franck, Julien; Leblanc, Eric; Narducci, Fabrice; Robin, Yves-Marie; Gimeno, Jean-Pascal; Quanico, Jusal; Wisztorski, Maxence; Kobeissy, Firas; Jacques, Jean-François; Roucou, Xavier; Salzet, Michel; Fournier, Isabelle
2017-07-01
Recently, it was demonstrated that proteins can be translated from alternative open reading frames (altORFs), increasing the size of the actual proteome. Top-down mass spectrometry-based proteomics allows the identification of intact proteins containing post-translational modifications (PTMs) as well as truncated forms translated from reference ORFs or altORFs. Top-down tissue microproteomics was applied on benign, tumor and necrotic-fibrotic regions of serous ovarian cancer biopsies, identifying proteins exhibiting region-specific cellular localization and PTMs. The regions of interest (ROIs) were determined by MALDI mass spectrometry imaging and spatial segmentation. Analysis with a customized protein sequence database containing reference and alternative proteins (altprots) identified 15 altprots, including alternative G protein nucleolar 1 (AltGNL1) found in the tumor, and translated from an altORF nested within the GNL1 canonical coding sequence. Co-expression of GNL1 and altGNL1 was validated by transfection in HEK293 and HeLa cells with an expression plasmid containing a GNL1-FLAG (V5) construct. Western blot and immunofluorescence experiments confirmed constitutive co-expression of altGNL1-V5 with GNL1-FLAG. Taken together, our approach provides means to evaluate protein changes in the case of serous ovarian cancer, allowing the detection of potential markers that have never been considered. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.
MRI appearances of borderline ovarian tumours
Energy Technology Data Exchange (ETDEWEB)
Bent, C.L. [Department of Diagnostic Imaging, St Bartholomew' s Hospital, West Smithfield, London (United Kingdom)], E-mail: clare.bent@bartsandthelondon.nhs.uk; Sahdev, A.; Rockall, A.G. [Department of Diagnostic Imaging, St Bartholomew' s Hospital, West Smithfield, London (United Kingdom); Singh, N. [Department of Pathology, St Bartholomew' s Hospital, West Smithfield, London (United Kingdom); Sohaib, S.A. [Department of Radiology, Royal Marsden Hospital, London (United Kingdom); Reznek, R.H. [Cancer Imaging, St Bartholomew' s Hospital, West Smithfield, London (United Kingdom)
2009-04-15
This review was performed to describe the range of magnetic resonance imaging (MRI) appearances of borderline ovarian tumours. The MRI findings in 26 patients with 31 borderline ovarian tumours (mean age: 40.1 years, range: 14-85 years) were retrospectively reviewed. For each tumour, site, size, MRI characteristics, and enhancement following gadolinium administration were recorded. There were 20 serous and 11 mucinous borderline ovarian subtypes. Nine of 26 patients demonstrated bilateral disease on MRI; synchronous contralateral ovarian disease included three benign, five serous borderline, and one serous invasive tumour. A history of a metachronous mucinous borderline tumour was identified in one patient. MRI appearances were classified into four morphological categories: group 1 (6/31, 19%), unilocular cysts; group 2 (6/31, 19%), minimally septate cysts with papillary projections; group 3 (14/31, 45%), markedly septate lesions with plaque-like excrescences; and group 4 (5/31, 16%), predominantly solid with exophytic papillary projections, all of serous subtype. There was a significant difference in mean volume between serous (841.5 cm{sup 3}) and mucinous (6358.2 cm{sup 3}) subtypes (p = 0.009). All tumours demonstrated at least one MRI feature suggestive of malignancy. The present review demonstrates the variable MRI appearances of borderline ovarian tumours along with imaging features suggestive of tumour subtype. In patients in whom the clinical features are suggestive of a borderline ovarian tumour (young age and normal or minimally elevated CA125), the ability to predict a borderline disease using morphological features observed on MRI would be extremely helpful in surgical planning, with the potential to offer fertility or ovary-preserving surgery. Future studies are required to further this aim.
Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.
Chornokur, Ganna; Lin, Hui-Yi; Tyrer, Jonathan P; Lawrenson, Kate; Dennis, Joe; Amankwah, Ernest K; Qu, Xiaotao; Tsai, Ya-Yu; Jim, Heather S L; Chen, Zhihua; Chen, Ann Y; Permuth-Wey, Jennifer; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V; Bean, Yukie T; Beckmann, Matthias W; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bunker, Clareann H; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Dicks, Ed; Doherty, Jennifer A; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F; Eccles, Diana M; Edwards, Robert P; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goodman, Marc T; Gronwald, Jacek; Harrington, Patricia; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Claus K; Hogdall, Estrid; Hosono, Satoyo; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kelemen, Linda E; Kellar, Mellissa; Kiemeney, Lambertus A; Krakstad, Camilla; Kjaer, Susanne K; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; McNeish, Iain; Menon, Usha; Milne, Roger L; Modugno, Francesmary; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Pike, Malcolm C; Poole, Elizabeth M; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schernhammer, Eva; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Spiewankiewicz, Beata; Sucheston, Lara; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Thomsen, Lotte; Tangen, Ingvild L; Tworoger, Shelley S; van Altena, Anne M; Vierkant, Robert A; Vergote, Ignace; Walsh, Christine S; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Wu, Anna H; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Hasmad, Hanis N; Berchuck, Andrew; Iversen, Edwin S; Schildkraut, Joellen M; Ramus, Susan J; Goode, Ellen L; Monteiro, Alvaro N A; Gayther, Simon A; Narod, Steven A; Pharoah, Paul D P; Sellers, Thomas A; Phelan, Catherine M
2015-01-01
Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). These results, generated on a large cohort of women, revealed associations between inherited cellular transport
Ovarian Cancer and Comorbidity
DEFF Research Database (Denmark)
Noer, Mette Calundann; Sperling, Cecilie Dyg; Ottesen, Bent
2017-01-01
OBJECTIVES: Comorbidity influences survival in ovarian cancer, but the causal relations between prognosis and comorbidity are not well characterized. The aim of this study was to investigate the associations between comorbidity, system delay, the choice of primary treatment, and survival in Danish...... ovarian cancer patients. METHODS: This population-based study was conducted on data from 5317 ovarian cancer patients registered in the Danish Gynecological Cancer Database. Comorbidity was classified according to the Charlson Comorbidity Index and the Ovarian Cancer Comorbidity Index. Pearson χ test...... and multivariate logistic regression analyses were used to investigate the association between comorbidity and primary outcome measures: primary treatment ("primary debulking surgery" vs "no primary surgery") and system delay (more vs less than required by the National Cancer Patient Pathways [NCPPs]). Cox...
High Expression of SQSTM1/p62 Protein Is Associated with Poor Prognosis in Epithelial Ovarian Cancer
International Nuclear Information System (INIS)
Iwadate, Reiko; Inoue, Jun; Tsuda, Hitoshi; Takano, Masashi; Furuya, Kenichi; Hirasawa, Akira; Aoki, Daisuke; Inazawa, Johji
2014-01-01
High expression of SQSTM1/p62 (p62) protein, which functions as a hub for various cellular signaling pathways, has been detected in several human cancers. However, the clinicopathological impact of high p62 expression is largely unknown in epithelial ovarian cancer (EOC). Here, the expression level of p62 in primary EOCs (n=266) was assessed by immunohistochemistry, and its clinical significance was analyzed. Univariate and multivariate analyses were used to determine the impact of p62 expression on overall survival. p62 was expressed in the cytoplasm (Cyto) and/or nucleus (Nuc) in primary EOCs, and an expression subtype (Cyto High /Nuc Low ), showing high expression in the cytoplasm but low expression in the nucleus, was significantly correlated with serous carcinoma (P<0.001), advanced stage (P=0.005), presence of residual tumor (P<0.001), and low overall survival rate (P=0.013). Furthermore, in serous carcinomas (n=107), the p62 Cyto High /Nuc Low subtype was significantly correlated with low overall survival rate (P=0.019) as an independent factor (P=0.044). Thus, our findings suggest that high expression of cytoplasmic p62 may be a novel prognostic biomarker in EOC, particularly in serous carcinoma
Validation of Candidate Serum Ovarian Cancer Biomarkers for Early Detection
Directory of Open Access Journals (Sweden)
Feng Su
2007-01-01
Full Text Available Objective: We have previously analyzed protein profi les using Surface Enhanced Laser Desorption and Ionization Time-Of-Flight Mass Spectroscopy (SELDI-TOF-MS [Kozak et al. 2003, Proc. Natl. Acad. Sci. U.S.A. 100:12343–8] and identified 3 differentially expressed serum proteins for the diagnosis of ovarian cancer (OC [Kozak et al. 2005, Proteomics, 5:4589–96], namely, apolipoprotein A-I (apoA-I, transthyretin (TTR and transferin (TF. The objective of the present study is to determine the efficacy of the three OC biomarkers for the detection of early stage (ES OC, in direct comparison to CA125.Methods: The levels of CA125, apoA-I, TTR and TF were measured in 392 serum samples [82 women with normal ovaries (N, 24 women with benign ovarian tumors (B, 85 women with ovarian tumors of low malignant potential (LMP, 126 women with early stage ovarian cancer (ESOC, and 75 women with late stage ovarian cancer (LSOC], obtained through the GOG and Cooperative Human Tissue Network. Following statistical analysis, multivariate regression models were built to evaluate the utility of the three OC markers in early detection.Results: Multiple logistic regression models (MLRM utilizing all biomarker values (CA125, TTR, TF and apoA-I from all histological subtypes (serous, mucinous, and endometrioid adenocarcinoma distinguished normal samples from LMP with 91% sensitivity (specifi city 92%, and normal samples from ESOC with a sensitivity of 89% (specifi city 92%. MLRM, utilizing values of all four markers from only the mucinous histological subtype showed that collectively, CA125, TTR, TF and apoA-I, were able to distinguish normal samples from mucinous LMP with 90% sensitivity, and further distinguished normal samples from early stage mucinous ovarian cancer with a sensitivity of 95%. In contrast, in serum samples from patients with mucinous tumors, CA125 alone was able to distinguish normal samples from LMP and early stage ovarian cancer with a sensitivity of
[Association between obesity and ovarian cancer].
Valladares, Macarena; Corsini, Gino; Romero, Carmen
2014-05-01
Obesity is a risk factor for cancer. Epidemiological evidences associate ovarian cancer with obesity. Epithelial ovarian cancer (EOC) is the most common type of ovarian cancer and accounts for a high rate of mortality. The association between ovarian cancer and obesity could be explained by molecular factors secreted by adipose tissue such as leptin. In EOC, leptin increases cell proliferation and inhibits apoptosis. Additionally, adipose tissue synthesizes endogenous estrogens, which increase cell proliferation of epithelial ovarian cells. Also, obesity associated hyperinsulinism could increase ovarian estrogen secretion.
Genome-wide Association Study for Ovarian Cancer Susceptibility using Pooled DNA
Lu, Yi; Chen, Xiaoqing; Beesley, Jonathan; Johnatty, Sharon E.; deFazio, Anna; Lambrechts, Sandrina; Lambrechts, Diether; Despierre, Evelyn; Vergotes, Ignace; Chang-Claude, Jenny; Hein, Rebecca; Nickels, Stefan; Wang-Gohrke, Shan; Dörk, Thilo; Dürst, Matthias; Antonenkova, Natalia; Bogdanova, Natalia; Goodman, Marc T.; Lurie, Galina; Wilkens, Lynne R.; Carney, Michael E.; Butzow, Ralf; Nevanlinna, Heli; Heikkinen, Tuomas; Leminen, Arto; Kiemeney, Lambertus A.; Massuger, Leon F.A.G.; van Altena, Anne M.; Aben, Katja K.; Kjaer, Susanne Krüger; Høgdall, Estrid; Jensen, Allan; Brooks-Wilson, Angela; Le, Nhu; Cook, Linda; Earp, Madalene; Kelemen, Linda; Easton, Douglas; Pharoah, Paul; Song, Honglin; Tyrer, Jonathan; Ramus, Susan; Menon, Usha; Gentry-Maharaj, Alexandra; Gayther, Simon A.; Bandera, Elisa V.; Olson, Sara H.; Orlow, Irene; Rodriguez-Rodriguez, Lorna
2013-01-01
Recent genome-wide association studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate or low penetrance variants exist among the subset of SNPs not well tagged by the genotyping arrays used in the previous studies which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium. Given that most of the top 20 SNPs from pooling were validated in the same samples by individual genotyping, the lack of replication is likely to be due to the relatively small sample size in our stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by the less dense arrays. However our study lacked power to make clear statements on the existence of hitherto untagged small effect variants. PMID:22794196
Zhu, Junyong; Chen, Zuhua; Yong, Lei
2018-02-01
The majority of genes are alternatively spliced and growing evidence suggests that alternative splicing is modified in cancer and is associated with cancer progression. Systematic analysis of alternative splicing signature in ovarian cancer is lacking and greatly needed. We profiled genome-wide alternative splicing events in 408 ovarian serous cystadenocarcinoma (OV) patients in TCGA. Seven types of alternative splicing events were curated and prognostic analyses were performed with predictive models and splicing network built for OV patients. Among 48,049 mRNA splicing events in 10,582 genes, we detected 2,611 alternative splicing events in 2,036 genes which were significant associated with overall survival of OV patients. Exon skip events were the most powerful prognostic factors among the seven types. The area under the curve of the receiver-operator characteristic curve for prognostic predictor, which was built with top significant alternative splicing events, was 0.937 at 2,000 days of overall survival, indicating powerful efficiency in distinguishing patient outcome. Interestingly, splicing correlation network suggested obvious trends in the role of splicing factors in OV. In summary, we built powerful prognostic predictors for OV patients and uncovered interesting splicing networks which could be underlying mechanisms. Copyright © 2017 Elsevier Inc. All rights reserved.
Tate, Tyler; Baggett, Brenda; Rice, Photini; Watson, Jennifer; Orsinger, Gabe; Nymeyer, Ariel C.; Welge, Weston A.; Keenan, Molly; Saboda, Kathylynn; Roe, Denise J.; Hatch, Kenneth; Chambers, Setsuko; Black, John; Utzinger, Urs; Barton, Jennifer
2015-03-01
With early detection, five year survival rates for ovarian cancer are over 90%, yet no effective early screening method exists. Emerging consensus suggests that perhaps over 50% of the most lethal form of the disease, high grade serous ovarian cancer, originates in the Fallopian tube. Cancer changes molecular concentrations of various endogenous fluorophores. Using specific excitation wavelengths and emissions bands on a Multispectral Fluorescence Imaging (MFI) system, spatial and spectral data over a wide field of view can be collected from endogenous fluorophores. Wavelength specific reflectance images provide additional information to normalize for tissue geometry and blood absorption. Ratiometric combination of the images may create high contrast between neighboring normal and abnormal tissue. Twenty-six women undergoing oophorectomy or debulking surgery consented the use of surgical discard tissue samples for MFI imaging. Forty-nine pieces of ovarian tissue and thirty-two pieces of Fallopian tube tissue were collected and imaged with excitation wavelengths between 280 nm and 550 nm. After imaging, each tissue sample was fixed, sectioned and HE stained for pathological evaluation. Comparison of mean intensity values between normal, benign, and cancerous tissue demonstrate a general trend of increased fluorescence of benign tissue and decreased fluorescence of cancerous tissue when compared to normal tissue. The predictive capabilities of the mean intensity measurements are tested using multinomial logistic regression and quadratic discriminant analysis. Adaption of the system for in vivo Fallopian tube and ovary endoscopic imaging is possible and is briefly described.
... I find more information about ovarian and other gynecologic cancers? Centers for Disease Control and Prevention: 800-CDC-INFO or www. cdc. gov/ cancer/ gynecologic National Cancer Institute: 800-4-CANCER or www. ...
Serous tubal intraepithelial neoplasia: the concept and its application.
Meserve, Emily E K; Brouwer, Jan; Crum, Christopher P
2017-05-01
In recent years it has become clear that many extra-uterine (pelvic) high-grade serous carcinomas (serous carcinomas) are preceded by a precursor lesion in the distal fallopian tube. Precursors range from small self-limited 'p53 signatures' to expansile serous tubal intraepithelial neoplasms that include both serous tubal epithelial proliferations (or lesions) of uncertain significance and serous tubal intraepithelial carcinomas. These precursors can be considered from three perspectives. The first is biologic underpinnings, which are multifactorial, and include the intersection of DNA damage with Tp53 mutations and disturbances in transcriptional regulation that increase with age. The second perspective is the morphologic discovery and classification of intraepithelial neoplasms that are intercepted early in their natural history, either incidentally or in risk-reduction surgeries for germline mutations. For the practicing pathologist, as well as the investigators, a distinction between a primary intraepithelial neoplasm and an intramucosal carcinoma must be made to avoid misinterpreting (or underestimating) the significance of these proliferations. The third perspective is the application of this information to intervention, devising strategies that will actually lower the ovarian cancer death rate by opportunistic salpingectomy, widespread comprehensive genetic screening and early detection. Central to this issue are the questions of (1) whether some STICs are metastatic, (2) whether lower-grade epithelial proliferations can invade prior to evolving into intraepithelial carcinoma, or (3) metastasize and become malignant elsewhere ('precursor escape'). An important caveat is the persistent and unsettling reality that many high-grade serous carcinomas are not associated with an obvious point of initiation in the fallopian tube. The pathologist sits squarely in the midst of all of these issues, and has a pivotal role in managing expectations for stemming the death
Hormone therapy and ovarian cancer
DEFF Research Database (Denmark)
Mørch, Lina Steinrud; Løkkegaard, Ellen; Andreasen, Anne Helms
2009-01-01
CONTEXT: Studies have suggested an increased risk of ovarian cancer among women taking postmenopausal hormone therapy. Data are sparse on the differential effects of formulations, regimens, and routes of administration. OBJECTIVE: To assess risk of ovarian cancer in perimenopausal and postmenopau......CONTEXT: Studies have suggested an increased risk of ovarian cancer among women taking postmenopausal hormone therapy. Data are sparse on the differential effects of formulations, regimens, and routes of administration. OBJECTIVE: To assess risk of ovarian cancer in perimenopausal...... and postmenopausal women receiving different hormone therapies. DESIGN AND SETTING: Nationwide prospective cohort study including all Danish women aged 50 through 79 years from 1995 through 2005 through individual linkage to Danish national registers. Redeemed prescription data from the National Register...... bands included hormone exposures as time-dependent covariates. PARTICIPANTS: A total of 909,946 women without hormone-sensitive cancer or bilateral oophorectomy. MAIN OUTCOME MEASURE: Ovarian cancer. RESULTS: In an average of 8.0 years of follow-up (7.3 million women-years), 3068 incident ovarian...
Gungor, Tayfun; Altinkaya, S Ozlem; Akbay, Serap; Bilge, Umit; Mollamahmutoglu, Leyla
2010-03-01
Cystic tumors of ovary, whether benign, borderline, or malignant may be associated with mural nodule of various types, including sarcomas, sarcoma-like mural nodules (SLMN), and foci of anaplastic carcinoma. Cases of serous borderline ovarian tumor with mural nodules of mixed type are very rare. A 54-year-old woman referred with abdominal swelling. Imaging studies revealed a huge mass localized in pelvis and lower abdomen and grade 1-2 left renal hydronephrosis. Preoperative Ca-125 was 798 U/ml. In exploratory laparotomy there was a 16 cm mass adherent to lateral abdominal wall and intestines. Adhesiolysis and de-bulking surgery were performed including bilateral pelvic, para-aortic lymphadenectomy, appendectomy and omentectomy. Left ureter was found to be dilated because of the infiltration of distal part by the tumor, so distal ureteral resection and neoureterocystostomy were performed. Final pathology revealed borderline serous ovarian tumor with mural nodules which were consisted of SLMNs, multiple and sharply demarcated from the adjacent tumor, and sarcomatous nodules showing infiltrative appearance in metastatic regions. Mural nodules showed a positive reaction for vimentin and SMA but were negative for cytokeratin and also necrosis, hemorrhage, and 10-15 mitoses in 10 high power fields were noted. She had postoperative chemotherapy and follow-up is going on without metastases in her first year. The existence of sarcomatous nodules combined with the SLMN necessitates a careful histologic analysis for treatment and the determination of prognosis. However, too few cases of mixed type mural nodules have been published to warrant a conclusion regarding their prognosis.
DEFF Research Database (Denmark)
Johnatty, Sharon E; Beesley, Jonathan; Chen, Xiaoqing
2010-01-01
We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes...
Inhibin as a tumor marker of ovarian cancer in postmenopausal women
Directory of Open Access Journals (Sweden)
Modarres Gilani M
2010-05-01
Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Inhibin is a dimeric glycoprotein that has a depressive effect on the anterior hypophys secretion. The level of this tumor marker is undetectable in menopause women. In patients with gynecological cancer, especially granulosa and epidermal-type (mucinous, ovarian cancers considerable increase in the serum level of inhibin has been reported. The increased level of inhibin has been reported in patients with recurrent ovarian cancer."n"nMethods: We measured total serum inhibin and CA125 tumor marker level in 38 postmenopausal women with pathologically confirmed ovarian cancer before and after surgery out of 51 suspected women. Our control group were postmenopausal women that attended to our clinic for routine gynecologic check up. Both tumor markers were measured in these patients too."n"nResults: Among 38 women with ovarian cancer, 13(34.2% had elevated serum levels of total inhibin. Among the 16 women with serous adenocarcinoma, 3 patients (18.8% had elevated serum levels of inhibin. All the three women with granulosa cell tumor had elevated serum levels of inhibin (100% and 3 of 4(75% women with mucinous ovarian cancer had the same result. three out of 38 women in control group had elevated serum levels of
Lawrenson, Kate; Kar, Siddhartha; McCue, Karen; Kuchenbaeker, Karoline; Michailidou, Kyriaki; Tyrer, Jonathan; Beesley, Jonathan; Ramus, Susan J.; Li, Qiyuan; Delgado, Melissa K.; Lee, Janet M.; Aittomaki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker
2016-01-01
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10...
Gao, Faye F; Bhargava, Rohit; Yang, Huaitao; Li, Zaibo; Zhao, Chengquan
2013-08-01
In the past several decades, the concept of serous ovarian carcinoma has been revised repeatedly. However, the exact pathogenesis remains controversial. The most popular current concept is origin from the epithelium of the fimbriated ends of the fallopian tubes. The objective of our study was to evaluate the characteristic clinical and morphologic features of serous tubal intraepithelial carcinoma (STIC) and associated invasive carcinomas. One hundred sixteen consecutive cases of STIC seen from 2007 to 2011 were included in this study. High-grade serous carcinoma (HGSC) with or without a mixed component was identified in 107 cases (92.2%), non-HGSC in 5 cases, and STICs without invasive carcinoma in 4 cases. Using conventional criteria, HGSCs were classified as fallopian tube in origin in 65 cases (60.7%), as ovarian in 30 (28.0%), as peritoneal in 9 (8.4%), and as endometrial in 3 (2.8%). Among the 107 cases with HGSCs, most STICs (86; 80%) were present unilaterally, whereas invasive tumors more commonly involved the ovaries bilaterally (79%; 84 cases). These findings support the hypothesis that STIC acts as a precursor lesion for most fallopian tube, ovarian, and peritoneal HGSCs, but not for endometrial HGSC. Copyright © 2013 Elsevier Inc. All rights reserved.
Gene expression profiles as prognostic markers in women with ovarian cancer
DEFF Research Database (Denmark)
Jochumsen, Kirsten M; Tan, Qihua; Høgdall, Estrid V
2009-01-01
toward investigations for more individualized therapies and the use of gene expression profiles in the clinical practice. RNA from tumor tissue from 43 Danish patients with serous epithelial ovarian carcinoma (11 International Federation of Gynecology and Obstetrics [FIGO] stage I/II, 32 FIGO stage III...
Ovarian and tubal cancer in Denmark
DEFF Research Database (Denmark)
Gottschau, Mathilde; Mellemkjaer, Lene; Hannibal, Charlotte G
2016-01-01
INTRODUCTION: The Nordic countries are areas with a high-incidence of ovarian cancer; however, differences between the countries exist. MATERIAL AND METHODS: We used the Danish Cancer Registry to identify 11 264 cases of ovarian cancer and 363 cases of tubal cancer during 1993-2013. We calculated...... age-standardized (world standard population) incidence rates for overall and subtype-specific ovarian cancer, and for tubal cancer. We compared age-standardized incidence rates, and 1- and 5-year age-standardized relative survival rates, respectively, for ovarian and tubal cancer combined in four...... Nordic countries using the NORDCAN database. RESULTS: The incidence rate of ovarian cancer overall in Denmark decreased statistically significantly by approximately 2.3% per year among women aged
Directory of Open Access Journals (Sweden)
Jonathan Beesley
Full Text Available Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC. We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP within the TERT promoter. We demonstrate that the minor alleles at rs2736109, and at an additional TERT promoter SNP, rs2736108, are associated with decreased breast cancer risk, and that the combination of both SNPs substantially reduces TERT promoter activity.
DEFF Research Database (Denmark)
Johnatty, Sharon E; Beesley, Jonathan; Chen, Xiaoqing
2010-01-01
We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes in...
Germline Mutations of Inhibins in Early-Onset Ovarian Epithelial Tumors
Tournier, Isabelle; Marlin, Régine; Walton, Kelly; Charbonnier, Françoise; Coutant, Sophie; Théry, Jean-Christophe; Charbonnier, Camille; Spurrell, Cailyn; Vezain, Myriam; Ippolito, Lorena; Bougeard, Gaëlle; Roman, Horace; Tinat, Julie; Sabourin, Jean-Christophe; Stoppa-Lyonnet, Dominique; Caron, Olivier; Bressac-de Paillerets, Brigitte; Vaur, Dominique; King, Mary-Claire; Harrison, Craig; Frebourg, Thierry
2014-01-01
To identify novel genetic bases of early-onset epithelial ovarian tumors, we used the trio exome sequencing strategy in a patient without familial history of cancer who presented metastatic serous ovarian adenocarcinomas at 21 years of age. We identified a single de novo mutation (c.1157A>G/p.Asn386Ser) within the INHBA gene encoding the βA-subunit of inhibins/activins, which play a key role in ovarian development. In vitro, this mutation alters the ratio of secreted activins and inhibins. In a second patient with early-onset serous borderline papillary cystadenoma, we identified an unreported germline mutation (c.179G>T/p.Arg60Leu) of the INHA gene encoding the α-subunit, the partner of the βA-subunit. This mutation also alters the secreted activin/inhibin ratio, by disrupting both inhibin A and inhibin B biosynthesis. In a cohort of 62 cases, we detected an additional unreported germline mutation of the INHBA gene (c.839G>A/p.Gly280Glu). Our results strongly suggest that inhibin mutations contribute to the genetic determinism of epithelial ovarian tumors. PMID:24302632
Fertility drugs and ovarian cancer.
Ali, Aus Tariq
2017-06-20
The aetiology of ovarian cancer is multifactorial with both endogenous and exogenous risk factors playing an important role. The exact pathogenesis of ovarian cancer is still not well understood, despite the number of hypotheses published. Due to an increase in the number of women using fertility drugs, much attention has been focused on the long-term health effects of such drugs. Although fertility drugs facilitate the ovulation process, it is however associated with a significant increase in hormone concentrations, placing exposed women at increased risk of gynaecological cancer. Many clinical and epidemiological studies have examined the association between fertility drugs and ovarian cancer risk. Results from these studies have been contradictory, as some studies have reported an increased risk of ovarian cancer while others reported no increased risk. Nevertheless, recent studies have shown that women who used fertility drugs and did not conceive had a higher risk of developing ovarian cancer, compared to women who used fertility drugs and conceived and delivered successfully. This review discusses the effect of fertility drugs on the risk of developing ovarian cancer, providing details on four possible scenarios associated with fertility treatment. In addition, the limitations of previous studies and their impact on our understanding of the association between fertility drugs and ovarian cancer also have been highlighted. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Psammoma bodies in two types of human ovarian tumours: a mineralogical study
Fanlu, Meng; Changqiu, Wang; Yan, Li; Anhuai, Lu; Fang, Mei; Jianying, Liu; Jingyun, Du; Yan, Zhang
2015-06-01
Psammoma body (PB) is a common form of calcification in pathological diagnosis and closely relevant to tumours. This paper focuses on the mineralogical characteristics of PBs in ovarian serous cancer and teratoma by using polarization microscope (POM), environmental scanning electron microscope (ESEM), micro-Fourier transform infrared spectroscopy (micro-FT-IR), transmission electron microscope (TEM), micro-area synchrotron radiation X-ray powder diffraction (μ-SRXRD) and fluorescence (μ-SRXRF). Both the PBs in tissues and separated from eight typical cases were investigated. POM and ESEM observation revealed the inside-out growth pattern of PBs. μ-SRXRD and micro-FT-IR results demonstrated the dominant mineral phase of PBs in ovarian serous cancer and teratoma was AB-type carbonate hydroxyapatite (Ca10[(PO4)6-x-y(CO3)x(HPO4 2-)y][(OH)2-u(CO3)u] with 0 ≤ x,y,u ≤ 2). As observed by ESEM and TEM, the layer-rich PBs in teratoma were up to 70 μm and mainly consisted of 5 nm-wide, 5-12 nm-long columnar crystals; the PBs in ovarian serous cancer with a maximum diameter of 35 μm were composed of slightly longer columnar crystals and granulates with 20-100 nm in diameter. The selected area electron diffraction patterns showed dispersed polycrystalline diffraction rings with arching behavior of (002) diffraction, indicating the aggregated nanocrystals grew in the preferred orientation of (002) face. The EDX and μ-SRXRF results together indicated the existence of Na, Mg, Zn and Sr in PBs. These detailed mineralogical characteristics may help uncover the nature of the pathological PBs in ovary.
Bălu, Sevilla; Pirtea, L; Gaje, Puşa; Cîmpean, Anca Maria; Raica, M
2012-01-01
Ovarian cancer-related angiogenesis is a complex process orchestrated by many positive and negative regulators. Many growth factors are involved in the development of the tumor-associated vasculature, and from these, endocrine gland-derived vascular endothelial growth factor (EG-VEGF) seems to play a crucial role. EG-VEGF is the first organ-specific angiogenic factor and its effects are restricted to the endothelial cells of the endocrine glands. Although EG-VEGF was detected in both normal and neoplastic ovaries, its clinical significance remains controversial. In the present study, we analyzed 30 patients with epithelial ovarian cancer, and the immunohistochemical expression of EG-VEGF was compared with the conventional clinico-pathological parameters of prognosis. Neoplastic cells of the ovarian carcinoma expressed EG-VEGF in 73.33% of the cases, as a cytoplasmic granular product of reaction. We found a strong correlation between the expression of EG-VEGF at protein level and tumor stage, grade, and microscopic type. The expression of EG-VEGF was found in patients with stage III and IV, but not in stage II. The majority of serous adenocarcinoma, half of the cases with clear cell carcinoma and two cases with endometrioid carcinoma showed definite expression in tumor cells. No positive reaction was found in the cases with mucinous carcinoma. Our results showed that EG-VEGF expression is an indicator not only of the advanced stage, but also of ovarian cancer progression. Based on these data, we concluded that EG-VEGF expression in tumor cells of the epithelial ovarian cancer is a good marker of unfavorable prognosis and could be an attractive therapeutic target in patients with advanced-stage tumors, refractory conventional chemotherapy.
ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer
DEFF Research Database (Denmark)
Hedditch, Ellen L; Gao, Bo; Russell, Amanda J
2014-01-01
-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided. RESULTS: Associations with outcome were observed...... with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009...... ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian...
Oberaigner, Willi; Minicozzi, Pamela; Bielska-Lasota, Magdalena; Allemani, Claudia; de Angelis, Roberta; Mangone, Lucia; Sant, Milena
2012-04-01
Survival for ovarian cancer is the poorest of all gynaecological cancer sites. Our aim was to present the most up-to-date survival estimate for ovarian cancer by age and morphology and to answer the question whether survival for ovarian cancer improved in Europe during the 1990s. This analysis was performed with data from the EUROCARE database. We considered all adult women diagnosed with ovarian cancer between 1995 and 2002 and life status followed up until the end of 2003. A total of 97 691 cases were contributed by 72 European cancer registries in 24 countries. We estimated the most up-to-date relative survival for a mean of 23 661 patients followed up in 2000-2003 using the period hybrid approach and described the relative survival trends from the beginning of 1990s. Overall, the European age-standardised one-year, five-year and five-year conditional on surviving one-year relative survival were 67.2% (95% CI 66.6-67.8), 36.1% (95% CI 35.4-36.8) and 53.7% (95% CI 52.8-54.7), respectively. Five-year relative survival was 58.6% (95% CI 57.4-59.8), 37.1% (95% CI 36.1-38.1) and 20.5% (95% CI 19.1-21.9) in women aged 15-54, 55-74 and 75-99 years, respectively. The age-standardised five-year relative survival was 38.1% (95% CI 36.9-39.3) for serous tumours and 51.9% (95% CI 49.0-54.9) for mucinous cancers and the crude five-year relative survival was 85.6% (95% CI 81.2-90.0) for germ cell cancers. Overall, the age-standardised five-year relative survival increased from 32.4% (95% CI 31.7-33.2) in 1991-1993 to 36.3% (95% CI 35.5-37.0) in 2000-2003. There is a need to better understand the reasons for the wide variation in survival of ovarian cancer in Europe. Actions aiming to harmonise the protocols for therapy should contribute to narrowing the wide gap in survival and research on screening and early detection of ovarian cancer should be enforced.
Atypisk symptomdebut af cancer i tuba ovarii
DEFF Research Database (Denmark)
Hviid, Malene Meisner; Teklay, Biniam; Jensen, Pernille Tine
2013-01-01
with metastases to both ovaries and one inguinal lymph node. Recent studies suggest that serous borderline tumour of the ovaries originate from the fallopian tubes. The present case confirms this hypothesis. PET-CT is an important tool in diagnosing ovarian and fallopian tube cancers.......Fallopian tube cancer is rare and accounts for 0.3-1% of all gynaecological cancers. We describe a case of undiagnosed fallopian tube cancer presenting as a swollen inguinal lymph node and later diagnosed with PET-CT. Final histology revealed a serous adenocarcinoma of the fallopian tube...
Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC Risk.
Directory of Open Access Journals (Sweden)
Ganna Chornokur
Full Text Available Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC, we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC. Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS. SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020; this SNP was also associated with the borderline/low malignant potential (LMP tumors (P = 0.021. Other genes significantly associated with EOC histological subtypes (p<0.05 included the UGT1A (endometrioid, SLC25A45 (mucinous, SLC39A11 (low malignant potential, and SERPINA7 (clear cell carcinoma. In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4.These results, generated on a large cohort of women, revealed associations between inherited cellular
Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk
Chornokur, Ganna; Lin, Hui-Yi; Tyrer, Jonathan P.; Lawrenson, Kate; Dennis, Joe; Amankwah, Ernest K.; Qu, Xiaotao; Tsai, Ya-Yu; Jim, Heather S. L.; Chen, Zhihua; Chen, Ann Y.; Permuth-Wey, Jennifer; Aben, Katja KH.; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bunker, Clareann H.; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F.; Eccles, Diana M.; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goodman, Marc T.; Gronwald, Jacek; Harrington, Patricia; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A. T.; Hillemanns, Peter; Hogdall, Claus K.; Hogdall, Estrid; Hosono, Satoyo; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kelemen, Linda E.; Kellar, Mellissa; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F. A. G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain; Menon, Usha; Milne, Roger L.; Modugno, Francesmary; Moysich, Kirsten B.; Ness, Roberta B.; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Pike, Malcolm C.; Poole, Elizabeth M.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schernhammer, Eva; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Spiewankiewicz, Beata; Sucheston, Lara; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Thomsen, Lotte; Tangen, Ingvild L.; Tworoger, Shelley S.; van Altena, Anne M.; Vierkant, Robert A.; Vergote, Ignace; Walsh, Christine S.; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wu, Anna H.; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Hasmad, Hanis N.; Berchuck, Andrew; Iversen, Edwin S.; Schildkraut, Joellen M.; Ramus, Susan J.; Goode, Ellen L.; Monteiro, Alvaro N. A.; Gayther, Simon A.; Narod, Steven A.; Pharoah, Paul D. P.; Sellers, Thomas A.; Phelan, Catherine M.
2015-01-01
Background Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. Methods In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. Results The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). Conclusion These results, generated on a large cohort of women, revealed associations
Targeting Stromal-Cancer Cell Crosstalk Networks in Ovarian Cancer Treatment
Directory of Open Access Journals (Sweden)
Tsz-Lun Yeung
2016-01-01
Full Text Available Ovarian cancer is a histologically, clinically, and molecularly diverse disease with a five-year survival rate of less than 30%. It has been estimated that approximately 21,980 new cases of epithelial ovarian cancer will be diagnosed and 14,270 deaths will occur in the United States in 2015, making it the most lethal gynecologic malignancy. Ovarian tumor tissue is composed of cancer cells and a collection of different stromal cells. There is increasing evidence that demonstrates that stromal involvement is important in ovarian cancer pathogenesis. Therefore, stroma-specific signaling pathways, stroma-derived factors, and genetic changes in the tumor stroma present unique opportunities for improving the diagnosis and treatment of ovarian cancer. Cancer-associated fibroblasts (CAFs are one of the major components of the tumor stroma that have demonstrated supportive roles in tumor progression. In this review, we highlight various types of signaling crosstalk between ovarian cancer cells and stromal cells, particularly with CAFs. In addition to evaluating the importance of signaling crosstalk in ovarian cancer progression, we discuss approaches that can be used to target tumor-promoting signaling crosstalk and how these approaches can be translated into potential ovarian cancer treatment.
All-Cause Mortality After Fertility-Sparing Surgery for Stage I Epithelial Ovarian Cancer.
Melamed, Alexander; Rizzo, Anthony E; Nitecki, Roni; Gockley, Allison A; Bregar, Amy J; Schorge, John O; Del Carmen, Marcela G; Rauh-Hain, J Alejandro
2017-07-01
To compare all-cause mortality between women who underwent fertility-sparing surgery with those who underwent conventional surgery for stage I ovarian cancer. In a cohort study using the National Cancer Database, we identified women younger than 40 years diagnosed with stage IA and unilateral IC epithelial ovarian cancer between 2004 and 2012. Fertility-sparing surgery was defined as conservation of one ovary and the uterus. The primary outcome was time from diagnosis to death. We used propensity score methods to assemble a cohort of women who underwent fertility-sparing or conventional surgery but were otherwise similar on observed covariates and conducted survival analyses using the Kaplan-Meier method and Cox proportional hazard models. We identified 1,726 women with stage IA and unilateral IC epithelial ovarian cancer of whom 825 (47.8%) underwent fertility-sparing surgery. Fertility-sparing surgery was associated with younger age, residence in the northeastern and western United States, and serous or mucinous histology (Pfertility-sparing surgery and 37 deaths among propensity-matched women who underwent conventional surgery after a median follow-up of 63 months. Fertility-sparing surgery was not associated with hazard of death (hazard ratio 0.80, 95% confidence interval [CI] 0.49-1.29, P=.36). The probability of survival 10 years after diagnosis was 88.5% (95% CI 82.4-92.6) in the fertility-sparing group and 88.9% (95% CI 84.9-92.0) in the conventional surgery group. In patients with high-risk features such as clear cell histology, grade 3, or stage IC, 10-year survival was 80.5% (95% CI 68.5-88.3) among women who underwent fertility-sparing surgery and 83.4% (95% 76.0-88.7) among those who had conventional surgery (hazard ratio 0.86, 95% CI 0.49-1.53, P=.61). Compared with conventional surgery, fertility-sparing surgery was not associated with increased risk of death in young women with stage I epithelial ovarian cancer.
DEFF Research Database (Denmark)
Minlikeeva, Albina N; Freudenheim, Jo L; Eng, Kevin H
2017-01-01
carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival...... with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced).Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic......Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients.Methods: Among patients diagnosed with invasive ovarian...
Erratum to: Psammoma bodies in two types of human ovarian tumours: a mineralogical study
Meng, Fanlu; Wang, Changqiu; Li, Yan; Lu, Anhuai; Mei, Fang; Liu, Jianying; Du, Jingyun; Zhang, Yan
2015-06-01
Psammoma body (PB) is a common form of calcification in pathological diagnosis and closely relevant to tumours. This paper focuses on the mineralogical characteristics of PBs in ovarian serous cancer and teratoma by using polarization microscope (POM), environmental scanning electron microscope (ESEM), micro-Fourier transform infrared spectroscopy (micro-FT-IR), transmission electron microscope (TEM), micro-area synchrotron radiation X-ray powder diffraction (μ-SRXRD) and fluorescence (μ-SRXRF). Both the PBs in tissues and separated from eight typical cases were investigated. POM and ESEM observation revealed the inside-out growth pattern of PBs. μ-SRXRD and micro-FT-IR results demonstrated the dominant mineral phase of PBs in ovarian serous cancer and teratoma was AB-type carbonate hydroxyapatite (Ca10[(PO4)6-x-y(CO3)x(HPO4)y][(OH)2-u(CO3)u] with 0 ≤ x,y,u ≤ 2). As observed by ESEM and TEM, the layer-rich PBs in teratoma were up to 70 μm and mainly consisted of 5 nm-wide, 5-12 nm-long columnar crystals; the PBs in ovarian serous cancer with a maximum diameter of 35 μm were composed of slightly longer columnar crystals and granulates with 20-100 nm in diameter. The selected area electron diffraction patterns showed dispersed polycrystalline diffraction rings with arching behavior of (002) diffraction, indicating the aggregated nanocrystals grew in the preferred orientation of (002) face. The EDX and μ-SRXRF results together indicated the existence of Na, Mg, Zn and Sr in PBs. These detailed mineralogical characteristics may help uncover the nature of the pathological PBs in ovary.
Ovarian Cancer Stroma: Pathophysiology and the Roles in Cancer Development
International Nuclear Information System (INIS)
Furuya, Mitsuko
2012-01-01
Ovarian cancer represents one of the cancers with the worst prognostic in adult women. More than half of the patients who present with clinical signs such as abdominal bloating and a feeling of fullness already show advanced stages. The majority of ovarian cancers grow as cystic masses, and cancer cells easily spread into the pelvic cavity once the cysts rupture or leak. When the ovarian cancer cells disseminate into the peritoneal cavity, metastatic nests may grow in the cul-de-sac, and in more advanced stages, the peritoneal surfaces of the upper abdomen become the next largest soil for cancer progression. Ascites is also produced frequently in ovarian cancers, which facilitates distant metastasis. Clinicopathologic, epidemiologic and molecular studies on ovarian cancers have improved our understanding and therapeutic approaches, but still further efforts are required to reduce the risks in the patients who are predisposed to this lethal disease and the mortality of the patients in advanced stages. Among various molecules involved in ovarian carcinogenesis, special genes such as TP53, BRCA1 and BRCA2 have been well investigated. These genes are widely accepted as the predisposing factors that trigger malignant transformation of the epithelial cells of the ovary. In addition, adnexal inflammatory conditions such as chronic salpingitis and ovarian endometriosis have been great research interests in the context of carcinogenic background of ovarian cancers. In this review, I discuss the roles of stromal cells and inflammatory factors in the carcinogenesis and progression of ovarian cancers
Ovarian Cancer Stroma: Pathophysiology and the Roles in Cancer Development
Energy Technology Data Exchange (ETDEWEB)
Furuya, Mitsuko [Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004 (Japan)
2012-07-18
Ovarian cancer represents one of the cancers with the worst prognostic in adult women. More than half of the patients who present with clinical signs such as abdominal bloating and a feeling of fullness already show advanced stages. The majority of ovarian cancers grow as cystic masses, and cancer cells easily spread into the pelvic cavity once the cysts rupture or leak. When the ovarian cancer cells disseminate into the peritoneal cavity, metastatic nests may grow in the cul-de-sac, and in more advanced stages, the peritoneal surfaces of the upper abdomen become the next largest soil for cancer progression. Ascites is also produced frequently in ovarian cancers, which facilitates distant metastasis. Clinicopathologic, epidemiologic and molecular studies on ovarian cancers have improved our understanding and therapeutic approaches, but still further efforts are required to reduce the risks in the patients who are predisposed to this lethal disease and the mortality of the patients in advanced stages. Among various molecules involved in ovarian carcinogenesis, special genes such as TP53, BRCA1 and BRCA2 have been well investigated. These genes are widely accepted as the predisposing factors that trigger malignant transformation of the epithelial cells of the ovary. In addition, adnexal inflammatory conditions such as chronic salpingitis and ovarian endometriosis have been great research interests in the context of carcinogenic background of ovarian cancers. In this review, I discuss the roles of stromal cells and inflammatory factors in the carcinogenesis and progression of ovarian cancers.
Ovarian cancer mortality and industrial pollution
International Nuclear Information System (INIS)
García-Pérez, Javier; Lope, Virginia; López-Abente, Gonzalo; González-Sánchez, Mario
2015-01-01
We investigated whether there might be excess ovarian cancer mortality among women residing near Spanish industries, according to different categories of industrial groups and toxic substances. An ecologic study was designed to examine ovarian cancer mortality at a municipal level (period 1997–2006). Population exposure to pollution was estimated by means of distance from town to facility. Using Poisson regression models, we assessed the relative risk of dying from ovarian cancer in zones around installations, and analyzed the effect of industrial groups and pollutant substances. Excess ovarian cancer mortality was detected in the vicinity of all sectors combined, and, principally, near refineries, fertilizers plants, glass production, paper production, food/beverage sector, waste treatment plants, pharmaceutical industry and ceramic. Insofar as substances were concerned, statistically significant associations were observed for installations releasing metals and polycyclic aromatic chemicals. These results support that residing near industries could be a risk factor for ovarian cancer mortality. - Highlights: • We studied excess mortality due to ovarian cancer near Spanish industries. • Integrated nested Laplace approximations were used as a Bayesian inference tool. • We found excess ovarian cancer mortality near all industrial groups as a whole. • Risk also was found in towns near industries releasing carcinogens and metals. • Risk was associated with plants releasing polycyclic aromatic chemicals and POPs. - Our results support that residing in the vicinity of pollutant industries could be a risk factor for ovarian cancer mortality
DEFF Research Database (Denmark)
Seibaek, Lene; Blaakaer, Jan; Petersen, Lone Kjeld
2013-01-01
PURPOSE: The study objective was to survey general health and coping in women undergoing ovarian cancer surgery, and subsequently to develop and test a supportive care intervention. METHODS/MATERIALS: Women who underwent surgery on the suspicion of ovarian cancer participated in a follow...... standard levels. Concerning mental health, levels were below standard during the entire period, but did improve with time, also in women in whom the potential cancer diagnosis was refuted. The preoperative differences between these groups leveled out postoperatively in terms of physical health. At the end...
DEFF Research Database (Denmark)
Dahl Steffensen, Karina; Waldstrøm, Marianne; Jeppesen, Ulla
2008-01-01
, and malignant ovarian tumors. Patients and Methods: Serum from 233 patients (75 serous ovarian/tubal/peritoneal cancers, 24 borderline tumors, 110 benign ovarian tumors, and 24 with normal ovaries) were analyzed for EGFR, HER2, and VEGF using commercially available enzyme-linked immunosorbent assays (ELISA......). Results: The median EGFR serum level in patients with ovarian cancer was 51 ng/mL, and this was significantly lower than the median serum levels in borderline tumors (P =.0054) and benign ovarian tumors (P ovaries (P =.00028). The HER2 median serum level...... as in patients with normal ovaries (P =.00024). Conclusion: Significantly lower serum EGFR levels and higher VEGF levels were noted in patients with ovarian cancer compared with the levels in benign tumors and normal ovaries. Vascular endothelial growth factor and EGFR could have clinical importance as serum...
Ovarian Cancer Stroma: Pathophysiology and the Roles in Cancer Development
Directory of Open Access Journals (Sweden)
Mitsuko Furuya
2012-07-01
Full Text Available Ovarian cancer represents one of the cancers with the worst prognostic in adult women. More than half of the patients who present with clinical signs such as abdominal bloating and a feeling of fullness already show advanced stages. The majority of ovarian cancers grow as cystic masses, and cancer cells easily spread into the pelvic cavity once the cysts rupture or leak. When the ovarian cancer cells disseminate into the peritoneal cavity, metastatic nests may grow in the cul-de-sac, and in more advanced stages, the peritoneal surfaces of the upper abdomen become the next largest soil for cancer progression. Ascites is also produced frequently in ovarian cancers, which facilitates distant metastasis. Clinicopathologic, epidemiologic and molecular studies on ovarian cancers have improved our understanding and therapeutic approaches, but still further efforts are required to reduce the risks in the patients who are predisposed to this lethal disease and the mortality of the patients in advanced stages. Among various molecules involved in ovarian carcinogenesis, special genes such as TP53, BRCA1 and BRCA2 have been well investigated. These genes are widely accepted as the predisposing factors that trigger malignant transformation of the epithelial cells of the ovary. In addition, adnexal inflammatory conditions such as chronic salpingitis and ovarian endometriosis have been great research interests in the context of carcinogenic background of ovarian cancers. In this review, I discuss the roles of stromal cells and inflammatory factors in the carcinogenesis and progression of ovarian cancers.
Targeted Therapies in Epithelial Ovarian Cancer
Directory of Open Access Journals (Sweden)
Jurjees Hasan
2010-02-01
Full Text Available Molecularly targeted therapy is relatively new to ovarian cancer despite the unquestionable success with these agents in other solid tumours such as breast and colorectal cancer. Advanced ovarian cancer is chemosensitive and patients can survive several years on treatment. However chemotherapy diminishes in efficacy over time whilst toxicities persist. Newer biological agents that target explicit molecular pathways and lack specific chemotherapy toxicities such as myelosuppression offer the advantage of long-term therapy with a manageable toxicity profile enabling patients to enjoy a good quality of life. In this review we appraise the emerging data on novel targeted therapies in ovarian cancer. We discuss the role of these compounds in the front-line treatment of ovarian cancer and in relapsed disease; and describe how the development of predictive clinical, molecular and imaging biomarkers will define the role of biological agents in the treatment of ovarian cancer.
Targeted Therapies in Epithelial Ovarian Cancer
Energy Technology Data Exchange (ETDEWEB)
Dean, Emma; El-Helw, Loaie; Hasan, Jurjees, E-mail: jurjees.hasan@christie.nhs.uk [Christie Hospital NHS Foundation Trust / Wilmslow Road, Manchester, M20 4BX (United Kingdom)
2010-02-23
Molecularly targeted therapy is relatively new to ovarian cancer despite the unquestionable success with these agents in other solid tumours such as breast and colorectal cancer. Advanced ovarian cancer is chemosensitive and patients can survive several years on treatment. However chemotherapy diminishes in efficacy over time whilst toxicities persist. Newer biological agents that target explicit molecular pathways and lack specific chemotherapy toxicities such as myelosuppression offer the advantage of long-term therapy with a manageable toxicity profile enabling patients to enjoy a good quality of life. In this review we appraise the emerging data on novel targeted therapies in ovarian cancer. We discuss the role of these compounds in the front-line treatment of ovarian cancer and in relapsed disease; and describe how the development of predictive clinical, molecular and imaging biomarkers will define the role of biological agents in the treatment of ovarian cancer.
Paternal lineage early onset hereditary ovarian cancers: A Familial Ovarian Cancer Registry study.
Directory of Open Access Journals (Sweden)
Kevin H Eng
2018-02-01
Full Text Available Given prior evidence that an affected woman conveys a higher risk of ovarian cancer to her sister than to her mother, we hypothesized that there exists an X-linked variant evidenced by transmission to a woman from her paternal grandmother via her father. We ascertained 3,499 grandmother/granddaughter pairs from the Familial Ovarian Cancer Registry at the Roswell Park Cancer Institute observing 892 informative pairs with 157 affected granddaughters. We performed germline X-chromosome exome sequencing on 186 women with ovarian cancer from the registry. The rate of cancers was 28.4% in paternal grandmother/granddaughter pairs and 13.9% in maternal pairs consistent with an X-linked dominant model (Chi-square test X2 = 0.02, p = 0.89 and inconsistent with an autosomal dominant model (X2 = 20.4, p<0.001. Paternal grandmother cases had an earlier age-of-onset versus maternal cases (hazard ratio HR = 1.59, 95%CI: 1.12-2.25 independent of BRCA1/2 status. Reinforcing the X-linked hypothesis, we observed an association between prostate cancer in men and ovarian cancer in his mother and daughters (odds ratio, OR = 2.34, p = 0.034. Unaffected mothers with affected daughters produced significantly more daughters than sons (ratio = 1.96, p<0.005. We performed exome sequencing in reported BRCA negative cases from the registry. Considering age-of-onset, one missense variant (rs176026 in MAGEC3 reached chromosome-wide significance (Hazard ratio HR = 2.85, 95%CI: 1.75-4.65 advancing the age of onset by 6.7 years. In addition to the well-known contribution of BRCA, we demonstrate that a genetic locus on the X-chromosome contributes to ovarian cancer risk. An X-linked pattern of inheritance has implications for genetic risk stratification. Women with an affected paternal grandmother and sisters of affected women are at increased risk for ovarian cancer. Further work is required to validate this variant and to characterize carrier families.
Kobierzycki, Christopher; Pula, Bartosz; Skiba, Mateusz; Jablonska, Karolina; Latkowski, Krzysztof; Zabel, Maciej; Nowak-Markwitz, Ewa; Spaczynski, Marek; Kedzia, Witold; Podhorska-Okolow, Marzena; Dziegiel, Piotr
2013-12-01
Despite great progress in the understanding of ovarian cancer biology, clinicopathological data (i.e. grade, stage, histological type and residual disease after surgery) seem to be the most important prognostic factors. The present study aimed to investigate the relationship between expression of minichromosome maintenance proteins (MCM-3, MCM-7), metallothioneins (MT-I/II, MT-III), and Ki-67 in 103 ovarian cancer cases, mostly of the serous histological type. Statistical analysis revealed strong positive correlations in the expression of MCM-3 vs. Ki-67 (r=0.492), MCM-7 vs. Ki-67 (r=0.651), and MCM-3 vs. MCM-7 (r=0.515) (all pMCM-3 and Ki-67 with increasing grade of histological malignancy (p=0.0011, p=0.029, respectively). Regarding clinical progression, cytoplasmic MT-I/II expression was significantly higher in more advanced disease stages (III+IV vs. I+II; p=0.0247). Due to the correlations shown here, the determination of MCM proteins as proliferation markers of ovarian cancer, should be strongly considered.
Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer
Block, Matthew S.; Charbonneau, Bridget; Vierkant, Robert A.; Fogarty, Zachary; Bamlet, William R.; Pharoah, Paul D.P.; Chenevix-Trench, Georgia; Rossing, Mary Anne; Cramer, Daniel; Pearce, Celeste Leigh; Schildkraut, Joellen; Menon, Usha; Kjaer, Susanne K.; Levine, Douglas A.; Gronwald, Jacek; Culver, Hoda Anton; Whittemore, Alice S.; Karlan, Beth Y.; Lambrechts, Diether; Wentzensen, Nicolas; Kupryjanczyk, Jolanta; Chang-Claude, Jenny; Bandera, Elisa V.; Hogdall, Estrid; Heitz, Florian; Kaye, Stanley B.; Fasching, Peter A.; Campbell, Ian; Goodman, Marc T.; Pejovic, Tanja; Bean, Yukie T.; Hays, Laura E.; Lurie, Galina; Eccles, Diana; Hein, Alexander; Beckmann, Matthias W.; Ekici, Arif B.; Paul, James; Brown, Robert; Flanagan, James M.; Harter, Philipp; du Bois, Andreas; Schwaab, Ira; Hogdall, Claus K.; Lundvall, Lene; Olson, Sara H.; Orlow, Irene; Paddock, Lisa E.; Rudolph, Anja; Eilber, Ursula; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K.; Ziolkowska-Seta, Izabela; Brinton, Louise A.; Yang, Hannah; Garcia-Closas, Montserrat; Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace; Walsh, Christine S.; Lester, Jenny; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H.; Ziogas, Argyrios; Lubiński, Jan; Cybulski, Cezary; Menkiszak, Janusz; Jensen, Allan; Gayther, Simon A.; Ramus, Susan J.; Gentry-Maharaj, Aleksandra; Berchuck, Andrew; Wu, Anna H.; Pike, Malcolm C.; Van Den Berg, David; Terry, Kathryn L.; Vitonis, Allison F.; Ramirez, Starr M.; Rider, David N.; Knutson, Keith L.; Sellers, Thomas A.; Phelan, Catherine M.; Doherty, Jennifer A.; Johnatty, Sharon E.; deFazio, Anna; Song, Honglin; Tyrer, Jonathan; Kalli, Kimberly R.; Fridley, Brooke L.; Cunningham, Julie M.; Goode, Ellen L.
2014-01-01
Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance—p < 2.5×10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with CARD11 (caspase recruitment domain family, member 11) rs41324349 in patients with mucinous EOC (HR 1.82, 95% CI 1.41–2.35, p=4.13×10−6) and TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B) rs7501462 in patients with endometrioid EOC (HR 0.68, 95% CI 0.56–0.82, p=2.33×10−5). Other associations of note included TRAF2 (TNF receptor-associated factor 2) rs17250239 in patients with high-grade serous EOC (HR 0.84, 95% CI 0.77–0.92, p=6.49×10−5) and PLCG1 (phospholipase C, gamma 1) rs11696662 in patients with clear cell EOC (HR 0.43, 95% CI 0.26–0.73, p=4.56×10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. PMID:24740199
Directory of Open Access Journals (Sweden)
Lisa K. Mullany
2015-10-01
Full Text Available Evolutionary Action analyses of The Cancer Gene Atlas data sets show that many specific p53 missense and gain-of-function mutations are selectively overrepresented and functional in high-grade serous ovarian cancer (HGSC. As homozygous alleles, p53 mutants are differentially associated with specific loss of heterozygosity (R273; chromosome 17; copy number variation (R175H; chromosome 9; and up-stream, cancer-related regulatory pathways. The expression of immune-related cytokines was selectively related to p53 status, showing for the first time that specific p53 mutants impact, and are related to, the immune subtype of ovarian cancer. Although the majority (31% of HGSCs exhibit loss of heterozygosity, a significant number (24% maintain a wild-type (WT allele and represent another HGSC subtype that is not well defined. Using human and mouse cell lines, we show that specific p53 mutants differentially alter endogenous WT p53 activity; target gene expression; and responses to nutlin-3a, a small molecular that activates WT p53 leading to apoptosis, providing “proof of principle” that ovarian cancer cells expressing WT and mutant alleles represent a distinct ovarian cancer subtype. We also show that siRNA knock down of endogenous p53 in cells expressing homozygous mutant alleles causes apoptosis, whereas cells expressing WT p53 (or are heterozygous for WT and mutant p53 alleles are highly resistant. Therefore, despite different gene regulatory pathways associated with specific p53 mutants, silencing mutant p53 might be a suitable, powerful, global strategy for blocking ovarian cancer growth in those tumors that rely on mutant p53 functions for survival. Knowing p53 mutational status in HGSC should permit new strategies tailored to control this disease.
Canaz, Emel; Kilinc, Metin; Sayar, Hamide; Kiran, Gurkan; Ozyurek, Eser
2017-09-01
Wide variation exists in ovarian cancer incidence rates suggesting the importance of environmental factors. Due to increasing environmental pollution, trace elements and heavy metals have drawn attention in studies defining the etiology of cancer, but scant data is available for ovarian cancer. Our aim was to compare the tissue concentrations of lead, selenium and nickel in epithelial ovarian cancer, borderline tumor and healthy ovarian tissues. The levels of lead, selenium and nickel were estimated using atomic absorption spectrophotometry in formalin-fixed paraffin-embedded tissue samples. Tests were carried out in 20 malignant epithelial ovarian cancer, 15 epithelial borderline tumor and 20 non-neoplastic healthy ovaries. Two samples were collected for borderline tumors, one from papillary projection and one from the smooth surface of cyst wall. Pb and Ni concentrations were found to be higher both in malignant and borderline tissues than those in healthy ovaries. Concentrations of Pb and Ni in malignant tissues, borderline papillary projections and capsular tissue samples were not different. Comparison of Se concentrations of malignant, borderline and healthy ovarian tissues did not reveal statistical difference. Studied metal levels were not found to be different in either papillary projection or in cyst wall of the borderline tumors. This study revealed the accumulation of lead and nickel in ovarian tissue is associated with borderline and malignant proliferation of the surface epithelium. Accumulation of these metals in epithelial ovarian cancer and borderline ovarian tumor has not been demonstrated before. Copyright © 2017 Elsevier GmbH. All rights reserved.
Multiple metastases from ovarian cancer
African Journals Online (AJOL)
Ovarian cancer affects women in the age group >60 years much ... ovarian cancer presenting with liver and thoracic vertebral metastases 4 months after ... manifested by parenchymal liver or lung ... categorised as stage Ic as per International.
Directory of Open Access Journals (Sweden)
Dipanwita Nag
2016-01-01
Full Text Available Primary carcinoma of the fallopian tube is rare and accounts for about 0.14-1.8% of all gynecological malignancies. Correct diagnosis is rarely made preoperatively as clinically tubal carcinoma closely resembles ovarian carcinoma. Here, we report two cases of bilateral primary fallopian tube carcinomas. Case 1: A 54-year-old female presented with postmenopausal bleeding, abdominal pain, and pervaginal watery discharge for 10 days. Ultrasonography (USG of pelvis showed endometrial thickening and multiple tiny echogenic foci in omentum suggestive of omental cake. With a provisional diagnosis of endometrial carcinoma, total abdominal hysterectomy with bilateral salpingo-oophorectomy and omentectomy was done. On gross examination, small and rudimentary right ovary was adherent to the fimbrial end of the tube. Left-sided tubo-ovarian mass was present, cut section of which showed yellowish solid area in tubal wall and encroaching on ovarian surface. On histological examination, sections from the fimbrial end of both fallopian tubes showed features of papillary serous adenocarcinoma. Case 2: 70-year-old lady, 15 years postmenopausal presented with gradual onset pain and swelling of abdomen, urinary incontinence since 4 days. USG showed bulky uterus, 5 cm × 2 cm fibroid, bilateral tubes, and ovaries were not visualized. Serum cancer antigen-125 was raised (159.7 U/ml. Total hysterectomy and bilateral salpingo-oophorectomy with infracolic omentectomy was done. On gross examination, ovaries were firmly attached to tubes and no apparent solid area was noted. On microscopy, papillary serous adenocarcinoma arising from tubal wall was seen infiltrating focally into ovarian stroma; tubal epithelium showed dysplastic change. Sections from omentum showed numerous psammoma bodies.
Risk for borderline ovarian tumours after exposure to fertility drugs
DEFF Research Database (Denmark)
Bjørnholt, Sarah Marie; Kjaer, Susanne Krüger; Nielsen, Thor Schütt Svane
2015-01-01
numbers. To obtain information on use of fertility drugs, hospital files and medical records of infertility-associated visits to all Danish fertility clinics were collected and supplemented with information from the Danish IVF register. We used case-cohort techniques to calculate rate ratios (RRs......STUDY QUESTION: Do fertility drugs increase the risk for borderline ovarian tumours, overall and according to histological subtype? SUMMARY ANSWER: The use of any fertility drug did not increase the overall risk for borderline ovarian tumours, but an increased risk for serous borderline ovarian...... tumours was observed after the use of progesterone. WHAT IS KNOWN ALREADY: Many epidemiological studies have addressed the connection between fertility drugs use and risk for ovarian cancer; most have found no strong association. Fewer studies have assessed the association between use of fertility drugs...
Ovarian cancer immunotherapy: opportunities, progresses and challenges
Directory of Open Access Journals (Sweden)
Stevens Richard
2010-02-01
Full Text Available Abstract Due to the low survival rates from invasive ovarian cancer, new effective treatment modalities are urgently needed. Compelling evidence indicates that the immune response against ovarian cancer may play an important role in controlling this disease. We herein summarize multiple immune-based strategies that have been proposed and tested for potential therapeutic benefit against advanced stage ovarian cancer. We will examine the evidence for the premise that an effective therapeutic vaccine against ovarian cancer is useful not only for inducing remission of the disease but also for preventing disease relapse. We will also highlight the questions and challenges in the development of ovarian cancer vaccines, and critically discuss the limitations of some of the existing immunotherapeutic strategies. Finally, we will summarize our own experience on the use of patient-specific tumor-derived heat shock protein-peptide complex for the treatment of advanced ovarian cancer.
Directory of Open Access Journals (Sweden)
Karin Hellner
2016-08-01
Full Text Available Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC. The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE cells. We identified frequent mutations involving a 40 kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p < 2−16, which was not found in patients without cancer (n = 108. Importantly, we show that SOX2 overexpression in FTE is nearly ubiquitous in patients with HGSOCs (n = 100, and common in BRCA1-BRCA2 mutation carriers (n = 71 who underwent prophylactic salpingo-oophorectomy. We propose that the finding of SOX2 overexpression in FTE could be exploited to develop biomarkers for detecting disease at a premalignant stage, which would reduce mortality from this devastating disease.
Hormone therapy and different ovarian cancers
DEFF Research Database (Denmark)
Mørch, Lina Steinrud; Løkkegaard, Ellen; Andreasen, Anne Helms
2012-01-01
Postmenopausal hormone therapy use increases the risk of ovarian cancer. In the present study, the authors examined the risks of different histologic types of ovarian cancer associated with hormone therapy. Using Danish national registers, the authors identified 909,946 women who were followed from...... 1995-2005. The women were 50-79 years of age and had no prior hormone-sensitive cancers or bilateral oophorectomy. Hormone therapy prescription data were obtained from the National Register of Medicinal Product Statistics. The National Cancer and Pathology Register provided data on ovarian cancers......, including information about tumor histology. The authors performed Poisson regression analyses that included hormone exposures and confounders as time-dependent covariates. In an average of 8.0 years of follow up, 2,681 cases of epithelial ovarian cancer were detected. Compared with never users, women...
2004-08-01
Co[ýVr/ lgbt t A eic , n Sc t 1t’.jar lni ttItrtii, I’alogy Review Ovarian Tumorigenesis A Proposed Model Based on Morphological and Molecular...surface epithelium. We tested muliplex detection of antibodies to candidate ovarian TAAs and statistical modeling for discrimination of sera of ovarian...cancer patients and controls. The best model generated an AUC of 0.86 (0.78-0.90) for discrimination of sera of EOC patients and healthy patients using
Genetic profiles distinguish different types of hereditary ovarian cancer
DEFF Research Database (Denmark)
Domanska, Katarina; Malander, Susanne; Staaf, Johan
2010-01-01
(HBOC) syndrome and the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Genome-wide array comparative genomic hybridization was applied to 12 HBOC associated tumors with BRCA1 mutations and 8 HNPCC associated tumors with mismatch repair gene mutations with 24 sporadic ovarian cancers......Heredity represents the strongest risk factor for ovarian cancer with disease predisposing mutations identified in 15% of the tumors. With the aim to identify genetic classifiers for hereditary ovarian cancer, we profiled hereditary ovarian cancers linked to the hereditary breast and ovarian cancer...... that HBOC and HNPCC associated ovarian cancer develop along distinct genetic pathways and genetic profiles can thus be applied to distinguish between different types of hereditary ovarian cancer....
Ovarian cancer mortality and industrial pollution.
García-Pérez, Javier; Lope, Virginia; López-Abente, Gonzalo; González-Sánchez, Mario; Fernández-Navarro, Pablo
2015-10-01
We investigated whether there might be excess ovarian cancer mortality among women residing near Spanish industries, according to different categories of industrial groups and toxic substances. An ecologic study was designed to examine ovarian cancer mortality at a municipal level (period 1997-2006). Population exposure to pollution was estimated by means of distance from town to facility. Using Poisson regression models, we assessed the relative risk of dying from ovarian cancer in zones around installations, and analyzed the effect of industrial groups and pollutant substances. Excess ovarian cancer mortality was detected in the vicinity of all sectors combined, and, principally, near refineries, fertilizers plants, glass production, paper production, food/beverage sector, waste treatment plants, pharmaceutical industry and ceramic. Insofar as substances were concerned, statistically significant associations were observed for installations releasing metals and polycyclic aromatic chemicals. These results support that residing near industries could be a risk factor for ovarian cancer mortality. Copyright © 2015 Elsevier Ltd. All rights reserved.
Ramus, Susan J.; Antoniou, Antonis C; Kuchenbaecker, Karoline B.; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Złowocka, Elżbieta; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Tejada, Maria-Isabel; Hamann, Ute; Rookus, Matti; van Leeuwen, Flora E.; Aalfs, Cora M.; Meijers-Heijboer, Hanne E.J.; van Asperen, Christi J.; van Roozendaal, K.E.P.; Hoogerbrugge, Nicoline; Collée, J. Margriet; Kriege, Mieke; van der Luijt, Rob B.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Walker, Lisa; Porteous, Mary E.; Kennedy, M. John; Pathak, Harsh; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; Caux-Moncoutier, Virginie; de Pauw, Antoine; Gauthier-Villars, Marion; Mazoyer, Sylvie; Léoné, Mélanie; Calender, Alain; Lasset, Christine; Bonadona, Valérie; Hardouin, Agnès; Berthet, Pascaline; Bignon, Yves-Jean; Uhrhammer, Nancy; Faivre, Laurence; Loustalot, Catherine; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy K.; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Tea, Muy-Kheng; Pfeiler, Georg; Fink-Retter, Anneliese; Hansen, Thomas v. O.; Ejlertsen, Bent; Johannsson, Oskar Th.; Offit, Kenneth; Kirchhoff, Tomas; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion; Phillips, Kelly-Anne; Van Le, Linda; Hoffman, James S; Toland, Amanda Ewart; Montagna, Marco; Tognazzo, Silvia; Imyanitov, Evgeny; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Tornero, Eva; Navarro, Matilde; Moysich, Kirsten B.; Karlan, Beth Y.; Gross, Jenny; Olah, Edith; Vaszko, Tibor; Teo, Soo-Hwang; Ganz, Patricia A.; Beattie, Mary S.; Dorfling, Cecelia M; van Rensburg, Elizabeth J; Diez, Orland; Kwong, Ava; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schäfer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Plante, Marie; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan Chun; Wang, Xianshu; Lindor, Noralane; Fredericksen, Zachary; Pankratz, V. Shane; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Pharoah, Paul D.P.; Gayther, Simon A.; Simard, Jacques; Easton, Douglas F.; Couch, Fergus J.; Chenevix-Trench, Georgia
2012-01-01
Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67–0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21–1.83) P-trend = 1.8 × 10−4, rs717852 HR = 1.25 (95% CI: 1.10–1.42) P-trend = 6.6 × 10−4, rs9303542 HR = 1.16 (95% CI: 1.02–1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81–0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10–1.42) P-trend = 6.1 × 10−4. The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer. PMID:22253144
Niskakoski, Anni; Pasanen, Annukka; Lassus, Heini; Renkonen-Sinisalo, Laura; Kaur, Sippy; Mecklin, Jukka-Pekka; Bützow, Ralf; Peltomäki, Päivi
2018-03-27
Molecular alterations preceding endometrial and ovarian cancer and the sequence of events are unknown. Consecutive specimens from lifelong surveillance for Lynch syndrome provides a natural setting to address such questions. To molecularly define the multistep gynecological tumorigenesis, DNA mismatch repair gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia were identified from a nation-wide registry and endometrial biopsy specimens taken from these individuals during 20 years of screening were collected. A total of 213 endometrial and ovarian specimens from Lynch syndrome individuals and 197 histology-matched (non-serous) samples from sporadic cases were available for this investigation. The specimens were profiled for markers linked to endometrial and ovarian tumorigenesis, including ARID1A protein expression, mismatch repair status, and tumor suppressor gene promoter methylation. In Lynch syndrome-associated endometrial and ovarian carcinomas, ARID1A protein was lost in 61-100% and mismatch repair was deficient in 97-100%, compared to 0-17% and 14-44% in sporadic cases (P = 0.000). ARID1A loss appeared in complex hyperplasia and deficient mismatch repair and tumor suppressor gene promoter methylation in histologically normal endometrium. Despite quantitative differences between Lynch syndrome and sporadic cases, ARID1A expression, mismatch repair, and tumor suppressor gene promoter methylation divided endometrial samples from both patient groups into three categories of increasing abnormality, comprising normal endometrium and simple hyperplasia (I), complex hyperplasia with or without atypia (II), and endometrial cancer (III). Complex hyperplasias without vs. with atypia were molecularly indistinguishable. In conclusion, surveillance specimens from Lynch syndrome identify mismatch repair deficiency, tumor suppressor gene promoter methylation, and ARID1A loss as early changes in tumor development. Our findings are
Campagnola, Paul J.; Tilbury, Karissa B.; Campbell, Kirby R.; Eliceiri, Kevin W.; Patankar, Manish
2017-02-01
Ovarian cancer remains the most deadly gynecological cancer with a poor aggregate survival rate. To improve upon this situation, we utilized collagen-specific Second Harmonic Generation (SHG) imaging microscopy and optical scattering measurements to probe structural differences in the extracellular matrix of normal stroma, benign tumors, endometrioid tumors, and low and high-grade serous (LGS and HGS) tumors. The SHG signatures of the emission directionality and conversion efficiency as well as the optical scattering are related to the organization of collagen on the sub-micron size. The wavelength dependence of these readouts adds additional characterization of the size and distribution of collagen fibrils/fibers relative to the interrogating wavelengths. We found strong wavelength dependent dependencies of these metrics that were different between the different tumors that are related to respective structural attributes in the collagen organization. These sub-resolution determinations are consistent with the dualistic classification of type I and II serous tumors. However, type I endometrioid tumors have strongly differing ECM architecture than the serous malignancies. Moreover, our analyses are further consistent with LGS and benign tumors having similar etiology. We identified optimal wavelengths for the SHG metrics as well as optical scattering measurements. The SHG metrics and optical scattering measurements were then used to form a linear discriminant model to classify the tissues, and we obtained high accuracy ( 90%) between the tissue types. This delineation is superior to current clinical performance and has potential applicability in supplementing histological analysis, understanding the etiology, as well as development of an in vivo screening tool.
Risk of ovarian cancer in women with first-degree relatives with cancer
DEFF Research Database (Denmark)
Soegaard, Marie; Frederiksen, Kirsten; Jensen, Allan
2009-01-01
OBJECTIVE: To assess the risk of ovarian cancer in women with first-degree relatives with cancer at one of the four most frequent hereditary sites based on validated cancer diagnoses and to examine the association according to age at diagnosis of ovarian cancer and histology. DESIGN: Case......-control study. SETTING AND POPULATION: First-degree relatives of 554 women with invasive epithelial ovarian cancer and 1,564 controls were included. METHODS: Analyses were performed using multiple logistic regression models. RESULTS: Ovarian cancer in a first-degree relative was significantly associated...... with increased risk of ovarian cancer (OR, 2.4; 95% CI, 1.4-4.1 (mother or sister)). Ovarian cancer in a first-degree relative appeared to be a stronger risk factor for early-onset (cancer than late-onset (OR, 5.3; 95% CI, 2.0-14.1 vs. OR, 1.8; 95% CI, 1.0-3.4). The positive association...
Pelvic Inflammatory Disease and the Risk of Ovarian Cancer and Borderline Ovarian Tumors
DEFF Research Database (Denmark)
Rasmussen, Christina B; Kjaer, Susanne K; Albieri, Vanna
2017-01-01
Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to...
Seidman, Jeffrey D; Krishnan, Jayashree; Yemelyanova, Anna; Vang, Russell
2016-09-01
Serous tubal intraepithelial carcinoma (STIC), the putative precursor of the majority of extrauterine high-grade serous carcinomas, has been reported in both high-risk women (those with a germline BRCA mutation, a personal history of breast carcinoma, and/or family history of breast or ovarian carcinoma) and average risk women from the general population. We reviewed grossly normal adnexal specimens from 388 consecutive, unselected women undergoing surgery, including those with germline BRCA mutation (37 patients), personal history of breast cancer or family history of breast/ovarian cancer (74 patients), endometrial cancer (175 patients), and a variety of other conditions (102 patients). Among 111 high-risk cases and 277 non-high-risk cases, 3 STICs were identified (0.8%), all in non-high-risk women (high risk vs. non-high risk: P=not significant). STIC was found in 2 women with nonserous endometrial carcinoma and 1 with complex atypical endometrial hyperplasia. Salpingoliths (mucosal calcifications), found in 9% of high-risk cases, and fimbrial adenofibromas in 9.9% of high-risk cases, were significantly more common in high-risk as compared with non-high-risk women (1.8% and 2.5%, respectively; PSTIC and endometrial hyperplasia and carcinoma, and clarify the frequency of non-neoplastic tubal findings in grossly normal fallopian tubes.
Anthropometric characteristics and ovarian cancer risk and survival.
Minlikeeva, Albina N; Moysich, Kirsten B; Mayor, Paul C; Etter, John L; Cannioto, Rikki A; Ness, Roberta B; Starbuck, Kristen; Edwards, Robert P; Segal, Brahm H; Lele, Sashikant; Odunsi, Kunle; Diergaarde, Brenda; Modugno, Francesmary
2018-02-01
Multiple studies have examined the role of anthropometric characteristics in ovarian cancer risk and survival; however, their results have been conflicting. We investigated the associations between weight change, height and height change and risk and outcome of ovarian cancer using data from a large population-based case-control study. Data from 699 ovarian cancer cases and 1,802 controls who participated in the HOPE study were included. We used unconditional logistic regression adjusted for age, race, number of pregnancies, use of oral contraceptives, and family history of breast or ovarian cancer to examine the associations between self-reported height and weight and height change with ovarian cancer risk. Cox proportional hazards regression models adjusted for age and stage were used to examine the association between the exposure variables and overall and progression-free survival among ovarian cancer cases. We observed an increased risk of ovarian cancer mortality and progression for gaining more than 20 pounds between ages 18-30, HR 1.36; 95% CI 1.05-1.76, and HR 1.31; 95% CI 1.04-1.66, respectively. Losing weight and gaining it back multiple times was inversely associated with both ovarian cancer risk, OR 0.78; 95% CI 0.63-0.97 for 1-4 times and OR 0.73; 95% CI 0.54-0.99 for 5-9 times, and mortality, HR 0.63; 95% CI 0.40-0.99 for 10-14 times. Finally, being taller during adolescence and adulthood was associated with increased risk of mortality. Taller stature and weight gain over lifetime were not related to ovarian cancer risk. Our results suggest that height and weight and their change over time may influence ovarian cancer risk and survival. These findings suggest that biological mechanisms underlying these associations may be hormone driven and may play an important role in relation to ovarian carcinogenesis and tumor progression.
Plasma and ovarian tissue sphingolipids profiling in patients with advanced ovarian cancer.
Knapp, Paweł; Bodnar, Lubomir; Błachnio-Zabielska, Agnieszka; Świderska, Magdalena; Chabowski, Adrian
2017-10-01
The role of lipids in carcinogenesis through induction of abnormal cell lines in the human body is currently undisputable. Based on the literature, bioactive sphingolipids play an essential role in the development and progression of cancer and are involved in the metastatic process. The aim of this study was to determine the concentration of selected sphingolipids in patients with advanced ovarian cancer (AOC, FIGO III/IV, high grade ovarian cancer). Seventy-four patients with ovarian cancer were enrolled. Plasma concentrations of C16-Cer, C18:1-Cer and C18-Cer were assessed by LC/MS/MS. The content of tissue sphingolipids was measured using a UHPLC/MS/MS. Plasma concentration of 3 ceramides: C16-Cer, C18:1-Cer and C18-Cer was significantly elevated in women with advanced ovarian cancer compared to control group (P=0.031; 0.022; 0.020; respectively). There were increases in concentration of 5 ceramides: C16-Cer, C18:1-Cer, C18-Cer, C24:1-Cer, C24-Cer (P=0.025; 0.049; 0.032; 0.005; 0.013, respectively) and S1P (P=0.004) in ovarian tissue of women with advanced ovarian cancer compared to healthy individuals. Importantly, significantly higher risk of ovarian cancer when the plasma concentration of C16-Cer>311.88ng/100μl (AUC: 0.76, P=0.0261); C18:1-Cer>4.75ng/100μl (AUC: 0.77, P=0.0160) and C18-Cer>100.76ng/100μl (AUC:0.77, P=0.0136) was noticed. Bioactive sphingolipids play an essential role in the development and progression of cancer and they also take part in the process of metastasizing. This study suggests that some sphingolipids can be used as potential biomarkers of advanced ovarian cancer and that they can play an important role in the pathogenesis of this disease. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
Comparison of glycoprotein expression between ovarian and colon adenocarcinomas
DEFF Research Database (Denmark)
Multhaupt, H A; Arenas-Elliott, C P; Warhol, M J
1999-01-01
, carcinoembryonic antigen, and cytokeratins 7 and 20 to detect tumor-associated glycoproteins and keratin proteins in ovarian and colonic carcinomas. RESULTS: CA125, carcinoembryonic antigen, and cytokeratins 7 and 20 can distinguish between colonic and serous or endometrioid adenocarcinomas of the ovary in both...... primary and metastatic lesions. Mucinous ovarian adenocarcinomas differed in that they express carcinoembryonic antigen and cytokeratins 7 and 20 and weakly express CA125. The other glycoprotein antigens were equally expressed by ovarian and colonic adenocarcinomas and therefore were of no use...... in distinguishing between these 2 entities. CONCLUSION: A panel of monoclonal antibodies against cytokeratins 7 and 20 antigens, CA125, and carcinoembryonic antigen is useful in differentiating serous and endometrioid adenocarcinomas of the ovary from colonic adenocarcinomas. Mucinous ovarian adenocarcinomas cannot...
The comparison between presenting symptoms of ovarian cancer ...
African Journals Online (AJOL)
The sensation of abdominal mass was more common in women with ovarian cancer than other abdominalpelvic cancers (P=0.00l). Constipation was documented in the patients with colon cancer more than women with ovarian cancer (P=0.012), whereas urinary symptoms were more common in patients with ovarian ...
Evaluating the ovarian cancer gonadotropin hypothesis
DEFF Research Database (Denmark)
Lee, Alice W; Tyrer, Jonathan P; Doherty, Jennifer A
2015-01-01
OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment...... of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. METHODS: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway...... genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. RESULTS: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some...
Asaturova, A V; Ezhova, L S; Faizullina, N M; Sannikova, M V; Khabas, G N
2016-01-01
to study the incidence of fallopian tube lesions (secretory cell proliferations (SCP), p53 signature, serous tubal intraepithelial lesions (STIL), and serous tubal intraepithelial carcinomas (STIC) in ovarian epithelial tumors and to propose their pathogenetic association with a certain histotype of the ovarian tumor. The investigation enrolled 136 patients with ovarian epithelial tumors, whose fallopian tubes were morphologically and immunohistochemically (IHC) examined using p53, Ki-67, and PAX2. Statistical analysis was carried out applying the Mann-Whitney test and χ(2) test. Lesions meeting the STIC criteria were found in 14.7% of cases (only in ovarian serous carcinoma (OSC)), those suspecting STICs were in 25.7%, and those without signs of STICs were in 59.6%. IFC examination diagnosed STIC in 10% of cases (only in OSC), STIL in 13.3%, p53 signature in 11.7% (only in serous tumors), and the normal/reactively changed tubal epithelium in 65%. The incidence of STILs correlated with the malignant potential of serous tumors significantly (pSTIC and high-grade OSC and revealed significant differences in the incidence of other fallopian tubal intraepithelial lesions in serous cystadenomas, borderline tumors, and OSC, in different ovarian carcinomas. The findings may suggest that the earliest stage in the pathogenesis of OSC is the development of SCP, followed by the formation of p53 signatures that may further give rise to STIL, and finally STC (due to the acquisition of additional mutations).
Technical challenges and limitations of current mouse models of ovarian cancer
Directory of Open Access Journals (Sweden)
Garson Kenneth
2012-11-01
Full Text Available Abstract The development of genetically engineered models (GEM of epithelial ovarian cancer (EOC has been very successful, with well validated models representing high grade and low grade serous adenocarcinomas and endometrioid carcinoma (EC. Most of these models were developed using technologies intended to target the ovarian surface epithelium (OSE, the cell type long believed to be the origin of EOC. More recent evidence has highlighted what is likely a more prevalent role of the secretory cell of the fallopian tube in the ontogeny of EOC, however none of the GEM of EOC have demonstrated successful targeting of this important cell type. The precise technologies exploited to develop the existing GEM of EOC are varied and carry with them advantages and disadvantages. The use of tissue specific promoters to model disease has been very successful, but the lack of any truly specific OSE or oviductal secretory cell promoters makes the outcomes of these models quite unpredictable. Effecting genetic change by the administration of adenoviral vectors expressing Cre recombinase may alleviate the perceived need for tissue specific promoters, however the efficiencies of infection of different cell types is subject to numerous biological parameters that may lead to preferential targeting of certain cell populations. One important future avenue of GEM of EOC is the evaluation of the role of genetic modifiers. We have found that genetic background can lead to contrasting phenotypes in one model of ovarian cancer, and data from other laboratories have also hinted that the exact genetic background of the model may influence the resulting phenotype. The different genetic backgrounds may modify the biology of the tumors in a manner that will be relevant to human disease, but they may also be modifying parameters which impact the response of the host to the technologies employed to develop the model.
Lawrenson, Kate; Kar, Siddhartha; McCue, Karen; Kuchenbaeker, Karoline; Michailidou, Kyriaki; Tyrer, Jonathan; Beesley, Jonathan; Ramus, Susan J.; Li, Qiyuan; Delgado, Melissa K.; Lee, Janet M.; Aittomäki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K.; Arver, Brita; Bandera, Elisa V.; Barile, Monica; Barkardottir, Rosa B.; Barrowdale, Daniel; Beckmann, Matthias W.; Benitez, Javier; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Blomqvist, Carl; Blot, William; Bogdanova, Natalia; Bojesen, Anders; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Bruinsma, Fiona; Brunet, Joan; Buhari, Shaik Ahmad; Burwinkel, Barbara; Butzow, Ralf; Buys, Saundra S.; Cai, Qiuyin; Caldes, Trinidad; Campbell, Ian; Canniotto, Rikki; Chang-Claude, Jenny; Chiquette, Jocelyne; Choi, Ji-Yeob; Claes, Kathleen B. M.; Collonge-Rame, Marie- Agnès; Damette, Alexandre; Barouk-Simonet, Emmanuelle; Bonnet, Françoise; Bubien, Virginie; Sevenet, Nicolas; Longy, Michel; Berthet, Pascaline; Vaur, Dominique; Castera, Laurent; Ferrer, Sandra Fert; Bignon, Yves-Jean; Uhrhammer, Nancy; Coron, Fanny; Faivre, Laurence; Baurand, Amandine; Jacquot, Caroline; Bertolone, Geoffrey; Lizard, Sarab; Leroux, Dominique; Dreyfus, Hélène; Rebischung, Christine; Peysselon, Magalie; Peyrat, Jean-Philippe; Fournier, Joëlle; Révillion, Françoise; Adenis, Claude; Vénat-Bouvet, Laurence; Léone, Mélanie; Boutry-Kryza, Nadia; Calender, Alain; Giraud, Sophie; Verny-Pierre, Carole; Lasset, Christine; Bonadona, Valérie; Barjhoux, Laure; Sobol, Hagay; Bourdon, Violaine; Noguchi, Tetsuro; Remenieras, Audrey; Coupier, Isabelle; Pujol, Pascal; Sokolowska, Johanna; Bronner, Myriam; Delnatte, Capucine; Bézieau, Stéphane; Mari, Véronique; Gauthier-Villars, Marion; Buecher, Bruno; Rouleau, Etienne; Golmard, Lisa; Moncoutier, Virginie; Belotti, Muriel; de Pauw, Antoine; Elan, Camille; Fourme, Emmanuelle; Birot, Anne-Marie; Saule, Claire; Laurent, Maïté; Houdayer, Claude; Lesueur, Fabienne; Mebirouk, Noura; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Warcoin, Mathilde; Prieur, Fabienne; Lebrun, Marine; Kientz, Caroline; Muller, Danièle; Fricker, Jean-Pierre; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Mortemousque, Isabelle; Bressac-de-Paillerets, Brigitte; Caron, Olivier; Guillaud-Bataille, Marine; Cook, Linda S.; Cox, Angela; Cramer, Daniel W.; Cross, Simon S.; Cybulski, Cezary; Czene, Kamila; Daly, Mary B.; Damiola, Francesca; Dansonka-Mieszkowska, Agnieszka; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Diez, Orland; Doherty, Jennifer A.; Domchek, Susan M.; Dorfling, Cecilia M.; Dörk, Thilo; Dumont, Martine; Ehrencrona, Hans; Ejlertsen, Bent; Ellis, Steve; Gregory, Helen; Miedzybrodzka, Zosia; Morrison, Patrick J.; Donaldson, Alan; Rogers, Mark T.; Kennedy, M. John; Porteous, Mary E.; Brady, Angela; Barwell, Julian; Foo, Claire; Lalloo, Fiona; Side, Lucy E.; Eason, Jacqueline; Henderson, Alex; Walker, Lisa; Cook, Jackie; Snape, Katie; Murray, Alex; McCann, Emma; Engel, Christoph; Lee, Eunjung; Evans, D. Gareth; Fasching, Peter A.; Feliubadalo, Lidia; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foretova, Lenka; Fostira, Florentia; Foulkes, William D.; Fridley, Brooke L.; Friedman, Eitan; Frost, Debra; Gambino, Gaetana; Ganz, Patricia A.; Garber, Judy; García-Closas, Montserrat; Gentry-Maharaj, Aleksandra; Ghoussaini, Maya; Giles, Graham G.; Glasspool, Rosalind; Godwin, Andrew K.; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Goode, Ellen L.; Goodman, Marc T.; Greene, Mark H.; Gronwald, Jacek; Guénel, Pascal; Haiman, Christopher A.; Hall, Per; Hallberg, Emily; Hamann, Ute; Hansen, Thomas V. O.; Harrington, Patricia A.; Hartman, Mikael; Hassan, Norhashimah; Healey, Sue; Rookus, M. A.; van Leeuwen, F. E.; van der Kolk, L. E.; Schmidt, M. K.; Russell, N. S.; de Lange, J. L.; Wijnands, R.; Collée, J. M.; Hooning, M. J.; Seynaeve, C.; van Deurzen, C. H. M.; Obdeijn, I. M.; van Asperen, C. J.; Tollenaar, R. A. E. M.; van Cronenburg, T. C. T. E. F.; Kets, C. M.; Ausems, M. G. E. M.; van der Pol, C. C.; van Os, T. A. M.; Waisfisz, Q.; Meijers-Heijboer, H. E. J.; Gómez-Garcia, E. B.; Oosterwijk, J. C.; Mourits, M. J.; de Bock, G. H.; Vasen, H. F.; Siesling, S.; Verloop, J.; Overbeek, L. I. H.; Heitz, Florian; Herzog, Josef; Høgdall, Estrid; Høgdall, Claus K.; Hogervorst, Frans B. L.; Hollestelle, Antoinette; Hopper, John L.; Hulick, Peter J.; Huzarski, Tomasz; Imyanitov, Evgeny N.; Fox, Stephen; Kirk, Judy; Lindeman, Geoff; Price, Melanie; Bowtell, David; deFazio, Anna; Webb, Penny; Isaacs, Claudine; Ito, Hidemi; Jakubowska, Anna; Janavicius, Ramunas; Jensen, Allan; John, Esther M.; Johnson, Nichola; Kabisch, Maria; Kang, Daehee; Kapuscinski, Miroslav; Karlan, Beth Y.; Khan, Sofia; Kiemeney, Lambertus A.; Kjaer, Susanne Kruger; Knight, Julia A.; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kupryjanczyk, Jolanta; Kwong, Ava; de la Hoya, Miguel; Laitman, Yael; Lambrechts, Diether; Le, Nhu; De Leeneer, Kim; Lester, Jenny; Levine, Douglas A.; Li, Jingmei; Lindblom, Annika; Long, Jirong; Lophatananon, Artitaya; Loud, Jennifer T.; Lu, Karen; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Le Marchand, Loic; Margolin, Sara; Marme, Frederik; Massuger, Leon F. A. G.; Matsuo, Keitaro; Mazoyer, Sylvie; McGuffog, Lesley; McLean, Catriona; McNeish, Iain; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R.; Milne, Roger L.; Montagna, Marco; Moysich, Kirsten B.; Muir, Kenneth; Mulligan, Anna Marie; Nathanson, Katherine L.; Ness, Roberta B.; Neuhausen, Susan L.; Nevanlinna, Heli; Nord, Silje; Nussbaum, Robert L.; Odunsi, Kunle; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I.; Olson, Janet E.; Olswold, Curtis; O'Malley, David; Orlow, Irene; Orr, Nick; Osorio, Ana; Park, Sue Kyung; Pearce, Celeste L.; Pejovic, Tanja; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M.; Poole, Elizabeth M.; Pylkäs, Katri; Radice, Paolo; Rantala, Johanna; Rashid, Muhammad Usman; Rennert, Gad; Rhenius, Valerie; Rhiem, Kerstin; Risch, Harvey A.; Rodriguez, Gus; Rossing, Mary Anne; Rudolph, Anja; Salvesen, Helga B.; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schildkraut, Joellen M.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Sellers, Thomas A.; Seynaeve, Caroline; Shah, Mitul; Shen, Chen-Yang; Shu, Xiao-Ou; Sieh, Weiva; Singer, Christian F.; Sinilnikova, Olga M.; Slager, Susan; Song, Honglin; Soucy, Penny; Southey, Melissa C.; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Sutter, Christian; Swerdlow, Anthony; Tchatchou, Sandrine; Teixeira, Manuel R.; Teo, Soo H.; Terry, Kathryn L.; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; Toland, Amanda Ewart; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Tseng, Chiu-chen; Tung, Nadine; Tworoger, Shelley S.; Vachon, Celine; van den Ouweland, Ans M. W.; van Doorn, Helena C.; van Rensburg, Elizabeth J.; Van't Veer, Laura J.; Vanderstichele, Adriaan; Vergote, Ignace; Vijai, Joseph; Wang, Qin; Wang-Gohrke, Shan; Weitzel, Jeffrey N.; Wentzensen, Nicolas; Whittemore, Alice S.; Wildiers, Hans; Winqvist, Robert; Wu, Anna H.; Yannoukakos, Drakoulis; Yoon, Sook-Yee; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Khanna, Kum Kum; Simard, Jacques; Monteiro, Alvaro N.; French, Juliet D.; Couch, Fergus J.; Freedman, Matthew L.; Easton, Douglas F.; Dunning, Alison M.; Pharoah, Paul D.; Edwards, Stacey L.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Gayther, Simon A.
2016-01-01
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10−3) and ABHD8 (P<2 × 10−3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk. PMID:27601076
Directory of Open Access Journals (Sweden)
Yallapu Murali M
2010-04-01
Full Text Available Abstract Background Chemo/radio-resistance is a major obstacle in treating advanced ovarian cancer. The efficacy of current treatments may be improved by increasing the sensitivity of cancer cells to chemo/radiation therapies. Curcumin is a naturally occurring compound with anti-cancer activity in multiple cancers; however, its chemo/radio-sensitizing potential is not well studied in ovarian cancer. Herein, we demonstrate the effectiveness of a curcumin pre-treatment strategy for chemo/radio-sensitizing cisplatin resistant ovarian cancer cells. To improve the efficacy and specificity of curcumin induced chemo/radio sensitization, we developed a curcumin nanoparticle formulation conjugated with a monoclonal antibody specific for cancer cells. Methods Cisplatin resistant A2780CP ovarian cancer cells were pre-treated with curcumin followed by exposure to cisplatin or radiation and the effect on cell growth was determined by MTS and colony formation assays. The effect of curcumin pre-treatment on the expression of apoptosis related proteins and β-catenin was determined by Western blotting or Flow Cytometry. A luciferase reporter assay was used to determine the effect of curcumin on β-catenin transcription activity. The poly(lactic acid-co-glycolic acid (PLGA nanoparticle formulation of curcumin (Nano-CUR was developed by a modified nano-precipitation method and physico-chemical characterization was performed by transmission electron microscopy and dynamic light scattering methods. Results Curcumin pre-treatment considerably reduced the dose of cisplatin and radiation required to inhibit the growth of cisplatin resistant ovarian cancer cells. During the 6 hr pre-treatment, curcumin down regulated the expression of Bcl-XL and Mcl-1 pro-survival proteins. Curcumin pre-treatment followed by exposure to low doses of cisplatin increased apoptosis as indicated by annexin V staining and cleavage of caspase 9 and PARP. Additionally, curcumin pre
Distinct DNA Methylation Profiles in Ovarian Tumors: Opportunities for Novel Biomarkers
Directory of Open Access Journals (Sweden)
Lorena Losi
2018-05-01
Full Text Available Aberrant methylation of multiple promoter CpG islands could be related to the biology of ovarian tumors and its determination could help to improve treatment strategies. DNA methylation profiling was performed using the Methylation Ligation-dependent Macroarray (MLM, an array-based analysis. Promoter regions of 41 genes were analyzed in 102 ovarian tumors and 17 normal ovarian samples. An average of 29% of hypermethylated promoter genes was observed in normal ovarian tissues. This percentage increased slightly in serous, endometrioid, and mucinous carcinomas (32%, 34%, and 45%, respectively, but decreased in germ cell tumors (20%. Ovarian tumors had methylation profiles that were more heterogeneous than other epithelial cancers. Unsupervised hierarchical clustering identified four groups that are very close to the histological subtypes of ovarian tumors. Aberrant methylation of three genes (BRCA1, MGMT, and MLH1, playing important roles in the different DNA repair mechanisms, were dependent on the tumor subtype and represent powerful biomarkers for precision therapy. Furthermore, a promising relationship between hypermethylation of MGMT, OSMR, ESR1, and FOXL2 and overall survival was observed. Our study of DNA methylation profiling indicates that the different histotypes of ovarian cancer should be treated as separate diseases both clinically and in research for the development of targeted therapies.
Pochechueva, Tatiana; Chinarev, Alexander; Schoetzau, Andreas; Fedier, André; Bovin, Nicolai V; Hacker, Neville F; Jacob, Francis; Heinzelmann-Schwarz, Viola
2016-01-01
Altered levels of naturally occurring anti-glycan antibodies (AGA) circulating in human blood plasma are found in different pathologies including cancer. Here the levels of AGA directed against 22 negatively charged (sialylated and sulfated) glycans were assessed in high-grade serous ovarian cancer (HGSOC, n = 22) patients and benign controls (n = 31) using our previously developed suspension glycan array (SGA). Specifically, the ability of AGA to differentiate between controls and HGSOC, the most common and aggressive type of ovarian cancer with a poor outcome was determined. Results were compared to CA125, the commonly used ovarian cancer biomarker. AGA to seven glycans that significantly (P<0.05) differentiated between HGSOC and control were identified: AGA to top candidates SiaTn and 6-OSulfo-TF (both IgM) differentiated comparably to CA125. The area under the curve (AUC) of a panel of AGA to 5 glycans (SiaTn, 6-OSulfo-TF, 6-OSulfo-LN, SiaLea, and GM2) (0.878) was comparable to CA125 (0.864), but it markedly increased (0.985) when combined with CA125. AGA to SiaTn and 6-OSulfo-TF were also valuable predictors for HGSOC when CA125 values appeared inconclusive, i.e. were below a certain threshold. AGA-glycan binding was in some cases isotype-dependent and sensitive to glycosidic linkage switch (α2-6 vs. α2-3), to sialylation, and to sulfation of the glycans. In conclusion, plasma-derived AGA to sialylated and sulfated glycans including SiaTn and 6-OSulfo-TF detected by SGA present a valuable alternative to CA125 for differentiating controls from HGSOC patients and for predicting the likelihood of HGSOC, and may be potential HGSOC tumor markers.
Serous endometrial intraepithelial carcinoma: a case series and literature review
International Nuclear Information System (INIS)
Pathiraja, P; Dhar, S; Haldar, K
2013-01-01
Minimal uterine serous cancer (MUSC) or serous endometrial intraepithelial carcinoma (EIC) has been described by many different names since 1998. There have been very few cases reported in literature since EIC/MUSC was recognized as a separate entity. The World health Organization (WHO) Classification favors the term serous EIC. Although serous EIC is confined to the uterine endometrium at initial histology diagnosis, a significant number of patients could have distal metastasis at diagnosis, without symptoms. Serous EIC is considered as being the precursor of uterine serous cancer (USC), but pure serous EIC also has an aggressive behavior similar to USC. It is therefore prudent to have an accurate diagnosis and appropriate surgical staging. There are very few published articles in literature that discuss the pure form of serous EIC. The aim of this series is to share our experience and review evidence for optimum management of serous EIC. We report a series of five women treated in our institute in the last 3 years. We reviewed the relevant literature on serous EIC and various management strategies, to recommend best clinical practice. Pure serous EIC is a difficult histopathological diagnosis, which requires ancillary immunohistochemical staining. It can have an aggressive clinical behavior with early recurrence and poor survival. Optimum surgical staging, with appropriate adjuvant treatment, should be discussed when treating these patients
Pelvic inflammatory disease and risk of invasive ovarian cancer and ovarian borderline tumors
DEFF Research Database (Denmark)
Rasmussen, Christina B; Faber, Mette T; Jensen, Allan
2013-01-01
PURPOSE: The aim of the study was to examine the potential association between a history of pelvic inflammatory disease (PID) and risk of epithelial ovarian cancer or ovarian borderline tumors. METHODS: In a population-based case-control study in Denmark, we included 554 women with invasive ovarian...... cancer, 202 with ovarian borderline tumors, and 1,564 controls aged 35-79 years. The analyses were performed in multiple logistic regression models. RESULTS: We found a significantly increased risk of ovarian borderline tumors among women with a history of PID (OR = 1.50; 95% CI 1.......08-2.08) but no apparent association between PID and risk of invasive ovarian cancer (OR = 0.83; 95% CI 0.65-1.05). We found no effect of age at time of first PID or time since first PID on the risk for either condition. CONCLUSION: Our results suggest that a history of PID is associated with an increased risk of ovarian...
Primary peritoneal serous carcinoma: A rare case and palliative approach
Directory of Open Access Journals (Sweden)
Viral M Bhanvadia
2014-01-01
Full Text Available Primary peritoneal serous carcinoma (PPSC is a rare primary malignancy that diffusely involves the peritoneum, indistinguishable clinically and histopathologically from primary serous ovarian carcinoma. The origin of PPSC has not been well characterized. Here we present a case of PPSC diagnosed in ultrasonography-guided fine needle aspiration cytology (FNAC in a 76- old female presenting with ascites, abdominal pain, distension and constipation. PPSC is an unusual tumour but cytomorphology is distinctive enough to diagnose preoperatively. In the case report hereby described PPSC is an inoperable malignancy, hence chemotherapy and palliative care are the only offered treatment.
Ovarian Cancer: The Interplay of Lifestyle and Genes
Braem, M.G.M.
2014-01-01
Ovarian cancer is a highly lethal disease that is mostly diagnosed at an advanced stage. In Europe, only 36% of women with ovarian cancer can expect to survive 5 years. While our knowledge of ovarian cancer has changed substantially throughout the years, our understanding of its etiology still lacks
International Nuclear Information System (INIS)
Zhang Hong; Xu Huimin; Wu Jinchang
2000-03-01
The objective of research is to investigate radioimmunoimaging (RII) on ovarian tumor by labelling anti-ovarian cancer monoclonal antibody (OC125) with 99m Tc. the nude mice models were produced by injection ovarian serous cyst adenocarcinoma cell HO8910. Experimental group was injected with 99m Tc-OC125 as tracer and control groups were injected normal mice IgG labelled with 99m Tc and anti-HO8910 antibody labelled with 99m Tc. RII using 99m Tc-OC125 McAb was also performed on 4 nude mice model of glioma (control group). Imaging positive rate, negative rate and tumor/non-tumor ratio were calculated. Results show positive rate of imaging of tumor was 100%. The most distinct pictures were gained between 4 to 6 h after injection of tracer. T/NT ratios of experimental group were higher than that of control groups (P 99m Tc on the nude mice models was sensitive and specific. 16 ovarian neoplasm patients were received RII 6 h after intravenous injected OC125 McAb labelled with 99m Tc. Four patients of malignant tumor repeated RII after operation and chemotherapy. The result of RII was accorded perfectly with operation. RII also can find micro recurrence focus of post-operation. The sensitivity and specificity was more excellent than the radioimmunoassay of CA125. RII is useful for defining character of ovarian tumor, especially for detecting early recurrence focus of post-operation patients
Computed tomographic findings of ovarian tumors
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Kwon, Kwi Ryeon; Lee, Ki Man; Woo, Seong Ku; Suh, Soo Jhi [Keimyung University School of Medicine, Seoul (Korea, Republic of); Kang, Duk Sik [Kyungpook National University College of Medicine, Taegu (Korea, Republic of)
1986-08-15
The diagnosis of ovarian tumor has been mainly dependent on manual pelvic examination and ultrasonography. But in case of malignant ovarian tumor, CT has more advantages over ultrasonography in assessing anatomic details, relationships to bowel loops, precise extents of tumors and follow-up examinations after surgery. Authors analyzed CT features of 46 cases of pathologically proven ovarian tumors for recent 4 years at Keimyung University Dongsan Hospital. The results were as follows: 1. The most common tumor was serous cyst adenocarcinoma (9 cases: 20%), followed by metastases (8 cases: 17%), mucinous cyst adenocarcinoma (7 cases: 15%), mucinous cyst adenocarcinoma (5 cases: 11%), teratoma (5 cases: 11%), lymphoma (3 cases: 7%) and dysgerminoma (2 cases: 4%). 2. The ovarian tumors were variable in size from 2.5 cm to 33 cm in diameter. Most of the solid tumors were smaller than 10 cm in diameter and most of the cystic tumors were larger than 10 cm in diameter. Usually mucinous tumors were much larger than serous tumors. Mucinous cyst adenomas were the largest tumors. 3. Unilateral tumors (left 19, right 13 cases) were more common than bilateral tumors (12 cases). Bilateral tumors were seen in serous and mucinous cyst adenocarcinoma, metastases and lymphoma. 4. CT features of mucinous cyst adenomas were smooth margins and thin wall of the tumor masses and multifaceted cysts with internal septa in all 7 cases. 5. In contrast, CT demonstration of bilaterally, irregular margin, thick wall, enhancing solid lesion, septal irregularity, adhesion to adjacent structures, peritoneal/omental implantation, ascites and hydronephrosis were signs suggesting malignancy. CT features of the serous cyst adenocarcinoma were mostly solid to mixed nature (83%), irregular margin (75%), enhancing solid lesion (67%), papillary growth (75%), internal septa (58%), multilocularity (58%) and calcification (25%) in descending order of frequency. 6. On CT, mucinous cystadenocarcinoma were
Predictive and therapeutic markers in ovarian cancer
Gray, Joe W.; Guan, Yinghui; Kuo, Wen-Lin; Fridlyand, Jane; Mills, Gordon B.
2013-03-26
Cancer markers may be developed to detect diseases characterized by increased expression of apoptosis-suppressing genes, such as aggressive cancers. Genes in the human chromosomal regions, 8q24, 11q13, 20q11-q13, were found to be amplified indicating in vivo drug resistance in diseases such as ovarian cancer. Diagnosis and assessment of amplification levels certain genes shown to be amplified, including PVT1, can be useful in prediction of poor outcome of patient's response and drug resistance in ovarian cancer patients with low survival rates. Certain genes were found to be high priority therapeutic targets by the identification of recurrent aberrations involving genome sequence, copy number and/or gene expression are associated with reduced survival duration in certain diseases and cancers, specifically ovarian cancer. Therapeutics to inhibit amplification and inhibitors of one of these genes, PVT1, target drug resistance in ovarian cancer patients with low survival rates is described.
75 FR 54451 - National Ovarian Cancer Awareness Month, 2010
2010-09-07
... National Ovarian Cancer Awareness Month, 2010 By the President of the United States of America A... claim more lives than any other gynecologic cancer. During National Ovarian Cancer Awareness Month, we... and other cancers. Across the Federal Government, we are working to promote awareness of ovarian...
Statin use and mortality among ovarian cancer patients
DEFF Research Database (Denmark)
Verdoodt, Freija; Hansen, Merete Kjaer; Kjaer, Susanne K.
2017-01-01
-cause or ovarian cancer-specific mortality. Among 4,419 patients with epithelial ovarian cancer, post-diagnostic statin use was not statistically significantly associated with all-cause (HR: 0.90, 95% CI: 0.78–1.04) or ovarian cancer-specific mortality (HR: 0.90, 95% CI: 0.76–1.08). There was little evidence...
Proteomics Analysis for Finding Serum Markers of Ovarian Cancer
Directory of Open Access Journals (Sweden)
Yushan Cheng
2014-01-01
Full Text Available A combination of peptide ligand library beads (PLLB and 1D gel liquid chromatography-mass spectrometry/mass spectrometry (1DGel-LC-MS/MS was employed to analyze serum samples from patients with ovarian cancer and from healthy controls. Proteomic analysis identified 1200 serum proteins, among which 57 proteins were upregulated and 10 were downregulated in the sera from cancer patients. Retinol binding protein 4 (RBP4 is highly upregulated in the ovarian cancer serum samples. ELISA was employed to measure plasma concentrations of RBP4 in 80 samples from ovarian cancer patients, healthy individuals, myoma patients, and patients with benign ovarian tumor, respectively. The plasma concentrations of RBP4 ranging from 76.91 to 120.08 ng/mL with the mean value 89.13±1.67 ng/mL in ovarian cancer patients are significantly higher than those in healthy individuals (10.85±2.38 ng/mL. Results were further confirmed with immunohistochemistry, demonstrating that RBP4 expression levels in normal ovarian tissue were lower than those in ovarian cancer tissues. Our results suggested that RBP4 is a potential biomarker for diagnostic of screening ovarian cancer.
Stage at diagnosis and ovarian cancer survival
DEFF Research Database (Denmark)
Maringe, Camille; Walters, Sarah; Butler, John
2012-01-01
We investigate what role stage at diagnosis bears in international differences in ovarian cancer survival.......We investigate what role stage at diagnosis bears in international differences in ovarian cancer survival....
Directory of Open Access Journals (Sweden)
Yun-Jung Choi
2016-12-01
Full Text Available The cancer stem cell (CSC hypothesis postulates that cancer cells are composed of hierarchically-organized subpopulations of cells with distinct phenotypes and tumorigenic capacities. As a result, CSCs have been suggested as a source of disease recurrence. Recently, silver nanoparticles (AgNPs have been used as antimicrobial, disinfectant, and antitumor agents. However, there is no study reporting the effects of AgNPs on ovarian cancer stem cells (OvCSCs. In this study, we investigated the cytotoxic effects of AgNPs and their mechanism of causing cell death in A2780 (human ovarian cancer cells and OvCSCs derived from A2780. In order to examine these effects, OvCSCs were isolated and characterized using positive CSC markers including aldehyde dehydrogenase (ALDH and CD133 by fluorescence-activated cell sorting (FACS. The anticancer properties of the AgNPs were evaluated by assessing cell viability, leakage of lactate dehydrogenase (LDH, reactive oxygen species (ROS, and mitochondrial membrane potential (mt-MP. The inhibitory effect of AgNPs on the growth of ovarian cancer cells and OvCSCs was evaluated using a clonogenic assay. Following 1–2 weeks of incubation with the AgNPs, the numbers of A2780 (bulk cells and ALDH+/CD133+ colonies were significantly reduced. The expression of apoptotic and anti-apoptotic genes was measured by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR. Our observations showed that treatment with AgNPs resulted in severe cytotoxicity in both ovarian cancer cells and OvCSCs. In particular, AgNPs showed significant cytotoxic potential in ALDH+/CD133+ subpopulations of cells compared with other subpopulation of cells and also human ovarian cancer cells (bulk cells. These findings suggest that AgNPs can be utilized in the development of novel nanotherapeutic molecules for the treatment of ovarian cancers by specific targeting of the ALDH+/CD133+ subpopulation of cells.
Appendectomy with cytoreductive surgery for ovarian and type 2 endometrial carcinoma.
Wong, L F A; Wahab, N A; Gleeson, N
2014-01-01
There is considerable variation within and between cancer centers in the practice of appendectomy as part of cytoreductive surgery for ovarian carcinoma and in the surgical staging of endometrial carcinoma. The purpose of this study was to determine the prevalence and the type of appendiceal pathology, the morbidity associated with appendectomy in gynaecologic cancer surgery. This is a retrospective review of all cytoreductive surgery for ovarian carcinoma and surgical staging for endometrial carcinoma with appendectomy over a four year period. Two hundred and fifty-one patients (38 patients for endometrial carcinoma surgery and 213 patients for ovarian cytoreduction) had an appendectomy performed. Metastases to the appendix was present in 46 (23.2%) of primary ovarian carcinoma and one (2.6%) primary endometrial carcinosarcoma. The appendix was more likely to be involved in advanced stage ovarian cancer with positive peritoneal washings, omental deposits, grade 3 differentiation, and papillary serous histology. Sixteen (6.4%) co-incidental primary appendiceal tumours were detected. No postoperative morbidity specific to appendectomy was identified. One case of ovarian carcinoma was upstaged from IC to IIIA by the appendiceal metastases. There was no upstaging of disease in the endometrial carcinoma group. Appendectomy is an integral part of ovarian cytoreductive surgery but the authors found it did not upstage the disease in a clinically significant manner. The incidence of co-incidental appendiceal primary tumours was high in this series and may add value to the procedure in preventing further surgeries. The absence of procedure related morbidity is reassuring. The authors recommend appendectomy for all ovarian staging surgery and its consideration in type 2 endometrial cancer.
Characterization of the Chicken Ovarian Cancer Model
National Research Council Canada - National Science Library
Rodriguez, Gustavo
2002-01-01
.... Unlike other ovarian cancer models, which require experimental induction of ovarian tumors, chickens develop ovarian adenocarcinoma spontaneously, with an incidence ranging from 13 to 40 percent...
Characterization of the Chicken Ovarian Cancer Model
National Research Council Canada - National Science Library
Rodriguez, Gustavo C
2004-01-01
.... Unlike other ovarian cancer models, which require experimental induction of ovarian tumors, chickens develop ovarian adenocarcinoma spontaneously, with an incidence ranging from 13 to 40 percent...
Characterization of the Chicken Ovarian Cancer Model
National Research Council Canada - National Science Library
Rodriguez, Gustavo C
2005-01-01
.... Unlike other ovarian cancer models, which require experimental induction of ovarian tumors, chickens develop ovarian adenocarcinoma spontaneously, with an incidence ranging from 13 to 40 percent...
Characterization of the Chicken Ovarian Cancer Model
National Research Council Canada - National Science Library
Rodriguez, Gustavo
2003-01-01
.... Unlike other ovarian cancer models, which require experimental induction of ovarian tumors, chickens develop ovarian adenocarcinoma spontaneously, with an incidence ranging from 13 to 40 percent...
Characterization of the Chicken Ovarian Cancer Model
National Research Council Canada - National Science Library
Rodriquez, Gustavo
2001-01-01
.... Unlike other ovarian cancer models, which require experimental induction of ovarian tumors, chickens develop ovarian adenocarcinoma spontaneously, with an incidence ranging from 13 to 40 percent...
Infrequent Expression of the Cancer-Testis Antigen, PASD1, in Ovarian Cancer
Directory of Open Access Journals (Sweden)
Ghazala Khan
2015-01-01
Full Text Available Ovarian cancer is very treatable in the early stages of disease; however, it is usually detected in the later stages, at which time, treatment is no longer as effective. If discovered early (Stage I, there is a 90% chance of five-year survival. Therefore, it is imperative that early-stage biomarkers are identified to enhance the early detection of ovarian cancer. Cancer-testis antigens (CTAs, such as Per ARNT SIM (PAS domain containing 1 (PASD1, are unique in that their expression is restricted to immunologically restricted sites, such as the testis and placenta, which do not express MHC class I, and cancer, making them ideally positioned to act as targets for immunotherapy as well as potential biomarkers for cancer detection where expressed. We examined the expression of PASD1a and b in a number of cell lines, as well as eight healthy ovary samples, eight normal adjacent ovarian tissues, and 191 ovarian cancer tissues, which were predominantly stage I ( n = 164 and stage II ( n = 14 disease. We found that despite the positive staining of skin cancer, only one stage Ic ovarian cancer patient tissue expressed PASD1a and b at detectable levels. This may reflect the predominantly stage I ovarian cancer samples examined. To examine the restriction of PASD1 expression, we examined endometrial tissue arrays and found no expression in 30 malignant tumor tissues, 23 cases of hyperplasia, or 16 normal endometrial tissues. Our study suggests that the search for a single cancer-testes antigen/biomarker that can detect early ovarian cancer must continue.
Molecular biomarker set for early detection of ovarian cancer
Bajic, Vladimir B.; Kaur, Mandeep
2015-01-01
Embodiments of the present invention concern methods and compositions related to detection of ovarian cancer, including detection of the stage of ovarian cancer, in some cases. In particular, the invention encompasses use of expression of TFAP2A and in some embodiments CA125 and/or E2F5 to identify ovarian cancer, including detecting mRNA and/or protein levels of the respective gene products. Kits for detection of ovarian cancer are also described.
Molecular biomarker set for early detection of ovarian cancer
Bajic, Vladimir B.
2015-06-16
Embodiments of the present invention concern methods and compositions related to detection of ovarian cancer, including detection of the stage of ovarian cancer, in some cases. In particular, the invention encompasses use of expression of TFAP2A and in some embodiments CA125 and/or E2F5 to identify ovarian cancer, including detecting mRNA and/or protein levels of the respective gene products. Kits for detection of ovarian cancer are also described.
DEFF Research Database (Denmark)
Ramus, Susan J; Antoniou, Antonis C; Kuchenbaecker, Karoline B
2012-01-01
Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers ...
Ramus, Susan J.; Antoniou, Antonis C.; Kuchenbaecker, Karoline B.; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Złowocka, Elżbieta; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Tejada, Maria-Isabel; Hamann, Ute; Rookus, Matti; van Leeuwen, Flora E.; Aalfs, Cora M.; Meijers-Heijboer, Hanne E. J.; van Asperen, Christi J.; van Roozendaal, K. E. P.; Hoogerbrugge, Nicoline; Collée, J. Margriet; Kriege, Mieke; van der Luijt, Rob B.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Walker, Lisa; Porteous, Mary E.; Kennedy, M. John; Pathak, Harsh; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; Caux-Moncoutier, Virginie; de Pauw, Antoine; Gauthier-Villars, Marion; Mazoyer, Sylvie; Léoné, Mélanie; Calender, Alain; Lasset, Christine; Bonadona, Valérie; Hardouin, Agnès; Berthet, Pascaline; Bignon, Yves-Jean; Uhrhammer, Nancy; Faivre, Laurence; Loustalot, Catherine; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy K.; John, Esther M.; Southey, Melissa; Goldgar, David; Singer, Christian F.; tea, Muy-Kheng; Pfeiler, Georg; Fink-Retter, Anneliese; Hansen, Thomas v O.; Ejlertsen, Bent; Johannsson, Oskar Th; Offit, Kenneth; Kirchhoff, Tomas; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion; Phillips, Kelly-Anne; van Le, Linda; Hoffman, James S.; Ewart Toland, Amanda; Montagna, Marco; Tognazzo, Silvia; Imyanitov, Evgeny; Issacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Iganacio; Tornero, Eva; Navarro, Matilde; Moysich, Kirsten B.; Karlan, Beth Y.; Gross, Jenny; Olah, Edith; Vaszko, Tibor; teo, Soo-Hwang; Ganz, Patricia A.; Beattie, Mary S.; Dorfling, Cecelia M.; van Rensburg, Elizabeth J.; Diez, Orland; Kwong, Ava; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schäfer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Plante, Marie; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan Chun; Wang, Xianshu; Lindor, Noralane; Fredericksen, Zachary; Pankratz, V. Shane; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Pharoah, Paul D. P.; Gayther, Simon A.; Simard, Jacques; Easton, Douglas F.; Couch, Fergus J.; Chenevix-Trench, Georgia; Miedzybrodzka, Zosia; Gregory, Helen; Morrison, Patrick; Jeffers, Lisa; Ong, Kai-Ren; Hoffman, Jonathan; Donaldson, Alan; James, Margaret; Downing, Sarah; Taylor, Amy; Murray, Alexandra; Rogers, Mark T.; McCann, Emma; Barton, David; Porteous, Mary; Drummond, Sarah; Kivuva, Emma; Searle, Anne; Goodman, Selina; Hill, Kathryn; Murday, Victoria; Bradshaw, Nicola; Snadden, Lesley; Longmuir, Mark; Watt, Catherine; Gibson, Sarah; Haque, Eshika; Tobias, Ed; Duncan, Alexis; Izatt, Louise; Langman, Caroline; Whaite, Anna; Dorkins, Huw; Barwell, Julian; Serra-Feliu, Gemma; Ellis, Ian; Houghton, Catherine; Taylor, Jane; Side, Lucy; Male, Alison; Berlin, Cheryl; Eason, Jacqueline; Collier, Rebecca; Claber, Oonagh; Jobson, Irene; McLeod, Diane; Halliday, Dorothy; Durell, Sarah; Stayner, Barbara; Shanley, Susan; Rahman, Nazneen; Houlston, Richard; Bancroft, Elizabeth; D'Mello, Lucia; Page, Elizabeth; Ardern-Jones, Audrey; Kohut, Kelly; Wiggins, Jennifer; Castro, Elena; Mitra, Anita; Robertson, Lisa; Quarrell, Oliver; Bardsley, Cathryn; Goff, Sheila; Brice, Glen; Winchester, Lizzie; Eddy, Charlotte; Tripathi, Vishakha; Attard, Virginia; Lucassen, Anneke; Crawford, Gillian; McBride, Donna; Smalley, Sarah; Sinilnikova, Olga; Barjhoux, Laure; Verny-Pierre, Carole; Giraud, Sophie; Léone, Mélanie; Buecher, Bruno; Houdayer, Claude; Moncoutier, Virginie; Belotti, Muriel; Tirapo, Carole; Bressac-de-Paillerets, Brigitte; Remenieras, Audrey; Byrede, Véronique; Caron, Olivier; Lenoir, Gilbert; Urhammer, Nancy; Sobol, Hagay; Bourdon, Violaine; Noguchi, Tetsuro; Eisinger, François; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Coupier, Isabelle; Pujol, Pascal; Peyrat, Jean-Philippe; Fournier, Joëlle; Révilliion, Françoise; Vennin, Philippe; Adenis, Claude; Rouleau, Etienne; Lidereau, Rosette; Demange, Liliane; Nogues, Catherine; Muller, Danièle; Fricker, Jean-Pierre; Barouk-Simonet, Emmanuelle; Bonnet, Françoise; Bubien, Virginie; Sevenet, Nicolas; Longy, Michel; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Leroux, Dominique; Dreyfus, Hélène; Rebischung, Christine; Peysselon, Megalie; Coron, Fanny; Prieur, Fabienne; Lebrun, Marine; Kientz, Caroline; Frénay, Marc; Vénat-Bouvet, Laurence; Delnatte, Capucine; Mortemousque, Isabelle; Lynch, Henry T.; Snyder, Carrie L.; Hogervorst, F. B. L.; Verhoef, S.; Verheus, M.; van't Veer, L. J.; van Leeuwen, F. E.; Collée, M.; van den Ouweland, A. M. W.; Jager, A.; Hooning, M. J.; Tilanus-Linthorst, M. M. A.; Seynaeve, C.; van Asperen, C. J.; Wijnen, J. T.; Vreeswijk, M. P.; Tollenaar, R. A.; Devilee, P.; Ligtenberg, M. J.; Hoogerbrugge, N.; Ausems, M. G.; van der Luijt, R. B.; van Os, T. A.; Gille, J. J. P.; Waisfisz, Q.; Gomez-Garcia, E. B.; van Roozendaal, C. E.; Blok, Marinus J.; Caanen, B.; Oosterwijk, J. C.; van der Hout, A. H.; Mourits, M. J.; Vasen, H. F.; Thorne, Heather; Niedermayr, Eveline; Gill, Mona; Collins, Lucine; Gokgoz, Nalan; Selander, Teresa; Weerasooriya, Nayana; Karlsson, Per; Nordlilng, Margareta; Bergman, Annika; Einbeigi, Zakaria; Liedgren, Sigrun; Borg, Åke; Loman, Niklas; Soller, Maria; Jernström, Helena; Harbst, Katja; Henriksson, Karin; Arver, Brita; von Wachenfeldt, Anna; Barbany-Bustinza, Gisela; Rantala, Johanna; Grönberg, Henrik; Stattin, Eva-Lena; Emanuelsson, Monica; Ehrencrona, Hans; Rosenquist, Richard; Dahl, Niklas
2012-01-01
Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of
Peluso, John J
2011-08-01
Various ovarian cell types including granulosa cells and ovarian surface epithelial cells express the progesterone (P4) binding protein, progesterone receptor membrane component-1 (PGRMC1). PGRMC1 is also expressed in ovarian tumors. PGRMC1 plays an essential role in promoting the survival of both normal and cancerous ovarian cell in vitro. Given the clinical significance of factors that regulate the viability of ovarian cancer, this review will focus on the role of PGRMC1 in ovarian cancer, while drawing insights into the mechanism of PGRMC1's action from cell lines derived from healthy ovaries as well as ovarian tumors. Studies using PGRMC1siRNA demonstrated that P4's ability to inhibit ovarian cells from undergoing apoptosis in vitro is dependent on PGRMC1. To confirm the importance of PGRMC1, the ability of PGRMC1-deplete ovarian cancer cell lines to form tumors in intact nude mice was assessed. Compared to PGRMC1-expressing ovarian cancer cells, PGRMC1-deplete ovarian cancer cells formed tumors in fewer mice (80% compared to 100% for controls). Moreover, the number of tumors derived from PGRMC1-deplete ovarian cancer cells was 50% of that observed in controls. Finally, the tumors that formed from PGRMC1-deplete ovarian cancer cells were about a fourth the size of tumors derived from ovarian cancer cells with normal levels of PGRMC1. One reason for PGRMC1-deplete tumors being smaller is that they had a poorly developed microvasculature system. How PGRMC1 regulates cell viability and in turn tumor growth is not known but part of the mechanism likely involves the regulation of genes that promote cell survival and inhibit apoptosis. Copyright © 2011 Elsevier Inc. All rights reserved.
Seebacher, Veronika; Polterauer, Stephan; Reinthaller, Alexander; Koelbl, Heinz; Achleitner, Regina; Berger, Astrid; Concin, Nicole
2018-04-19
AB0 blood groups and Rhesus factor expression have been associated with carcinogenesis, response to treatment and tumor progression in several malignancies. The aim of the present study was to test the hypothesis that AB0 blood groups and Rhesus factor expression are associated with clinical outcome in patients with epithelial ovarian cancer (EOC). AB0 blood groups and Rhesus factor expression were evaluated in a retrospective multicenter study including 518 patients with EOC. Their association with patients' survival was assessed using univariate and multivariable analyses. Neither AB0 blood groups nor Rhesus factor expression were associated with clinico-pathological parameters, recurrence-free, cancer-specific, or overall survival. In a subgroup of patients with high-grade serous adenocarcinoma, however, blood groups B and AB were associated with a better 5-year cancer-specific survival rate compared to blood groups A and 0 (60.3 ± 8.6% vs. 43.8 ± 3.6%, p = 0.04). Yet, this was not significant in multivariable analysis. AB0 blood groups and Rhesus factor expression are both neither associated with features of biologically aggressive disease nor clinical outcome in patients with EOC. Further investigation of the role of the blood group B antigen on cancer-specific survival in the subgroup of high-grade serous should be considered.
Histone Deacetylase Inhibitor Therapy in Epithelial Ovarian Cancer
Directory of Open Access Journals (Sweden)
Noriyuki Takai
2010-01-01
Full Text Available Since epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and promotion of tumorigenesis in ovarian cancers, novel compounds endowed with a histone deacetylase (HDAC inhibitory activity are an attractive therapeutic approach. In this review, we discuss the biologic and therapeutic effects of HDAC inhibitors (HDACIs in treating ovarian cancer. HDACIs were able to mediate inhibition of cell growth, cell cycle arrest, apoptosis, and expression of genes related to the malignant phenotype in a variety of ovarian cancer cell lines. Furthermore, HDACIs were able to induce the accumulation of acetylated histones in the chromatin of the p21WAF1 gene in human ovarian carcinoma cells. In xenograft models, some of HDACIs have demonstrated antitumor activity with only few side effects. Some clinical trials demonstrate that HDACI drugs provide an important class of new mechanism-based therapeutics for ovarian cancer. In this review, we discuss the biologic and therapeutic effects of HDACIs in treating ovarian cancer, especially focusing on preclinical studies and clinical trials.
Lu, Karen H; Skates, Steven; Hernandez, Mary A; Bedi, Deepak; Bevers, Therese; Leeds, Leroy; Moore, Richard; Granai, Cornelius; Harris, Steven; Newland, William; Adeyinka, Olasunkanmi; Geffen, Jeremy; Deavers, Michael T; Sun, Charlotte C; Horick, Nora; Fritsche, Herbert; Bast, Robert C
2013-10-01
A 2-stage ovarian cancer screening strategy was evaluated that incorporates change of carbohydrate antigen 125 (CA125) levels over time and age to estimate risk of ovarian cancer. Women with high-risk scores were referred for transvaginal ultrasound (TVS). A single-arm, prospective study of postmenopausal women was conducted. Participants underwent an annual CA125 blood test. Based on the Risk of Ovarian Cancer Algorithm (ROCA) result, women were triaged to next annual CA125 test (low risk), repeat CA125 test in 3 months (intermediate risk), or TVS and referral to a gynecologic oncologist (high risk). A total of 4051 women participated over 11 years. The average annual rate of referral to a CA125 test in 3 months was 5.8%, and the average annual referral rate to TVS and review by a gynecologic oncologist was 0.9%. Ten women underwent surgery on the basis of TVS, with 4 invasive ovarian cancers (1 with stage IA disease, 2 with stage IC disease, and 1 with stage IIB disease), 2 ovarian tumors of low malignant potential (both stage IA), 1 endometrial cancer (stage I), and 3 benign ovarian tumors, providing a positive predictive value of 40% (95% confidence interval = 12.2%, 73.8%) for detecting invasive ovarian cancer. The specificity was 99.9% (95% confidence interval = 99.7%, 100%). All 4 women with invasive ovarian cancer were enrolled in the study for at least 3 years with low-risk annual CA125 test values prior to rising CA125 levels. ROCA followed by TVS demonstrated excellent specificity and positive predictive value in a population of US women at average risk for ovarian cancer. Copyright © 2013 American Cancer Society.
2017-05-03
Anxiety; Fatigue; Nausea and Vomiting; Neurotoxicity Syndrome; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage I Ovarian Cancer; Stage IA Fallopian Tube Cancer; Stage IB Fallopian Tube Cancer; Stage IC Fallopian Tube Cancer; Stage II Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIB Fallopian Tube Cancer; Stage IIC Fallopian Tube Cancer; Stage III Ovarian Cancer; Stage III Primary Peritoneal Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIC Fallopian Tube Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer
Leary, A. F.; Quinn, M.; Fujiwara, K.; Coleman, R. L.; Kohn, E.; Sugiyama, T.; Glasspool, R.; Ray-Coquard, I.; Colombo, N.; Bacon, M.; Zeimet, A.; Westermann, A.; Gomez-Garcia, E.; Provencher, D.; Welch, S.; Small, W.; Millan, D.; Okamoto, A.; Stuart, G.; Ochiai, K.
2017-01-01
This manuscript reports the consensus statements on designing clinical trials in rare ovarian tumours reached at the fifth Ovarian Cancer Consensus Conference (OCCC) held in Tokyo, November 2015. Three important questions were identified concerning rare ovarian tumours (rare epithelial ovarian
The latest animal models of ovarian cancer for novel drug discovery.
Magnotti, Elizabeth; Marasco, Wayne A
2018-03-01
Epithelial ovarian cancer is a heterogeneous disease classified into five subtypes, each with a different molecular profile. Most cases of ovarian cancer are diagnosed after metastasis of the primary tumor and are resistant to traditional platinum-based chemotherapeutics. Mouse models of ovarian cancer have been utilized to discern ovarian cancer tumorigenesis and the tumor's response to therapeutics. Areas covered: The authors provide a review of mouse models currently employed to understand ovarian cancer. This article focuses on advances in the development of orthotopic and patient-derived tumor xenograft (PDX) mouse models of ovarian cancer and discusses current humanized mouse models of ovarian cancer. Expert opinion: The authors suggest that humanized mouse models of ovarian cancer will provide new insight into the role of the human immune system in combating and augmenting ovarian cancer and aid in the development of novel therapeutics. Development of humanized mouse models will take advantage of the NSG and NSG-SGM3 strains of mice as well as new strains that are actively being derived.
Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Prevention
... black women, but have decreased in both groups. Women who have a family history of ovarian cancer and/or certain inherited gene ... ovarian, fallopian tube, and primary peritoneal cancer: Personal history of breast cancer A woman who has had breast cancer has an increased ...
A Molecularly Targeted Theranostic Probe for Ovarian Cancer
Chen, Wenxue; Bardhan, Rizia; Bartels, Marc; Perez-Torres, Carlos; Pautler, Robia G.; Halas, Naomi J.; Joshi, Amit
2014-01-01
Overexpression of the human epidermal growth factor receptor (HER) family has been implicated in ovarian cancer because of its participation in signaling pathway regulating cellular proliferation, differentiation, motility, and survival. Currently, effective diagnostic and therapeutic schemes are lacking for treating ovarian cancer and consequently ovarian cancer has a high mortality rate. While HER2 receptor expression does not usually affect the survival rates of ovarian cancer to the same extent as in breast cancer, it can be employed as a docking site for directed nanotherapies in cases with de novo or acquired chemotherapy resistance. In this study, we have exploited a novel gold nanoshell-based complex (nanocomplex) for targeting, dual modal imaging, and photothermal therapy of HER2 overexpressing and drug resistant ovarian cancer OVCAR3 cells in vitro. The nanocomplexes are engineered to simultaneously provide contrast as fluorescence optical imaging probe and a magnetic resonance imaging (MRI) agent. Both immunofluorescence staining and MRI successfully demonstrate that nanocomplex-anti-HER2 conjugates specifically bind to OVCAR3 cells as opposed to the control, MDA-MB-231 cells, which have low HER2 expression. In addition, nanocomplexes targeted to OVCAR3 cells, when irradiated with near infrared (NIR) laser result in selective destruction of cancer cells through photothermal ablation. We also demonstrate that NIR light therapy and the nanocomplexes by themselves are non-cytotoxic in vitro. To the best of our knowledge, this is the first demonstration of a successful integration of dual modal bioimaging with photothermal cancer therapy for treatment of ovarian cancer. Based on their efficacy in vitro, these nanocomplexes are highly promising for image guided photo-thermal therapy of ovarian cancer as well as other HER2 overexpressing cancers. PMID:20371708
78 FR 54741 - National Ovarian Cancer Awareness Month, 2013
2013-09-06
... National Ovarian Cancer Awareness Month, 2013 By the President of the United States of America A... of women will die of this disease. During National Ovarian Cancer Awareness Month, we lend our... of the United States, do hereby proclaim September 2013 as National Ovarian Cancer Awareness Month. I...
77 FR 55095 - National Ovarian Cancer Awareness Month, 2012
2012-09-06
... National Ovarian Cancer Awareness Month, 2012 By the President of the United States of America A... leave in our hearts will be deeply felt forever. During National Ovarian Cancer Awareness Month, we... campaign, we are working to raise awareness about the signs and symptoms of ovarian cancer. The Affordable...
Increased COX-2 expression in patients with ovarian cancer
African Journals Online (AJOL)
ajl yemi
2011-10-26
Oct 26, 2011 ... 10%) subtypes (Kristensen et al., 2003; Green et al.,. 1999). The disease ... history of ovarian and/or breast cancer, and nulliparity, whereas the oral ... and molecular mechanisms of ovarian cancer remain unclear. It is most ..... chemotherapy on the prognosis in advanced epithelial ovarian cancer. N. Engl.
Buis, C. C. M.; van Leeuwen, F. E.; Mooij, T. M.; Burger, C. W.; Lambalk, Cornelis B.; Kortman, Marian; Laven, Joop S. E.; Jansen, Cees A. M.; Helmerhorst, Frans M.; Cohlen, Ben J.; Willemsen, Wim N. P.; Smeenk, Jesper M. J.; Simons, Arnold H. M.; van der Veen, Fulco; Evers, Johannes L. H.; van Dop, Peter A.; Macklon, Nicholas S.
2013-01-01
Is ovarian or extra-ovarian endometriosis associated with an increased risk of ovarian cancer and borderline ovarian tumours (BOT)? We found a 3- to 8-fold increased risk of ovarian tumours associated with endometriosis: the magnitude of the risk increase depended on the definition of endometriosis.
Risk of borderline ovarian tumors among women with benign ovarian tumors
DEFF Research Database (Denmark)
Guleria, Sonia; Jensen, Allan; Kjær, Susanne K
2018-01-01
tumors among women with a benign ovarian tumor. METHODS: This nationwide cohort study included all Danish women diagnosed with a benign ovarian tumor (n=139,466) during 1978-2012. The cohort was linked to the Danish Pathology Data Bank and standardized incidence ratios (SIR) with 95% confidence intervals...... (CI) were calculated. RESULTS: Women with benign ovarian tumors had increased risks for subsequent borderline ovarian tumors (SIR 1.62, 95% CI 1.43-1.82), and this applied to both serous (SIR 1.69, 95% CI 1.39-2.03) and mucinous (SIR 1.75, 95% CI 1.45-2.10) histotypes of borderline ovarian tumors....... The risk for borderline ovarian tumors was primarily increased for women diagnosed with a benign ovarian tumor before 40years of age. The risk remained increased up to 9years after a benign ovarian tumor diagnosis. Finally, the associations did not change markedly when analyzed for the different histotypes...
Investigate the Role of Obesity in Ovarian Cancer Initiation and Progression
2017-07-01
cells and in transformed ovarian cells affected by obesity that lead to ovarian cancer initiation and progression. 15. SUBJECT TERMS Obesity, Ovarian...5 7. Participants & Other Collaborating Organizations...that lead to ovarian cancer initiation and progression. We also aim to identify secreted factors from adipose tissue that promote ovarian cancer
Ovarian cancer: Novel molecular aspects for clinical assessment.
Palmirotta, Raffaele; Silvestris, Erica; D'Oronzo, Stella; Cardascia, Angela; Silvestris, Franco
2017-09-01
Ovarian cancer is a very heterogeneous tumor which has been traditionally characterized according to the different histological subtypes and differentiation degree. In recent years, innovative molecular screening biotechnologies have allowed to identify further subtypes of this cancer based on gene expression profiles, mutational features, and epigenetic factors. These novel classification systems emphasizing the molecular signatures within the broad spectrum of ovarian cancer have not only allowed a more precise prognostic prediction, but also proper therapeutic strategies for specific subgroups of patients. The bulk of available scientific data and the high refinement of molecular classifications of ovarian cancers can today address the research towards innovative drugs with the adoption of targeted therapies tailored for single molecular profiles leading to a better prediction of therapeutic response. Here, we summarize the current state of knowledge on the molecular bases of ovarian cancer, from the description of its molecular subtypes derived from wide high-throughput analyses to the latest discoveries of the ovarian cancer stem cells. The latest personalized treatment options are also presented with recent advances in using PARP inhibitors, anti-angiogenic, anti-folate receptor and anti-cancer stem cells treatment approaches. Copyright © 2017 Elsevier B.V. All rights reserved.
Liu, Joyce F; Barry, William T; Birrer, Michael; Lee, Jung-Min; Buckanovich, Ronald J; Fleming, Gini F; Rimel, Bj; Buss, Mary K; Nattam, Sreenivasa; Hurteau, Jean; Luo, Weixiu; Quy, Philippa; Whalen, Christin; Obermayer, Lisa; Lee, Hang; Winer, Eric P; Kohn, Elise C; Ivy, S Percy; Matulonis, Ursula A
2014-10-01
Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7-not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7-16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23-0·76; p=0·005). Grade
Research Summaries: The 11th Biennial Rivkin Center Ovarian Cancer Research Symposium.
Armstrong, Deborah K
2017-11-01
In September 2016, the 11th biennial ovarian cancer research symposium was presented by the Rivkin Center for Ovarian Cancer and the American Association for Cancer Research. The 2016 symposium focused on 4 broad areas of research: Mechanisms of Initiation and Progression of Ovarian Cancer, Tumor Microenvironment and Models of Ovarian Cancer, Detection and Prevention of Ovarian Cancer, and Novel Therapeutics for Ovarian Cancer. The presentations and abstracts from each of these areas are reviewed in this supplement to the International Journal of Gynecologic Oncology.
2018-06-04
Fallopian Tube Carcinoma; Primary Peritoneal Carcinoma; Stage I Ovarian Cancer; Stage IA Ovarian Cancer; Stage IB Ovarian Cancer; Stage IC Ovarian Cancer; Stage II Ovarian Cancer; Stage IIA Ovarian Cancer; Stage IIB Ovarian Cancer; Stage IIC Ovarian Cancer; Stage III Ovarian Cancer; Stage IIIA Ovarian Cancer; Stage IIIB Ovarian Cancer; Stage IIIC Ovarian Cancer; Stage IV Ovarian Cancer
Comparative proteome analysis of human epithelial ovarian cancer
Directory of Open Access Journals (Sweden)
Gagné Jean-Philippe
2007-09-01
Full Text Available Abstract Background Epithelial ovarian cancer is a devastating disease associated with low survival prognosis mainly because of the lack of early detection markers and the asymptomatic nature of the cancer until late stage. Using two complementary proteomics approaches, a differential protein expression profile was carried out between low and highly transformed epithelial ovarian cancer cell lines which realistically mimic the phenotypic changes observed during evolution of a tumour metastasis. This investigation was aimed at a better understanding of the molecular mechanisms underlying differentiation, proliferation and neoplastic progression of ovarian cancer. Results The quantitative profiling of epithelial ovarian cancer model cell lines TOV-81D and TOV-112D generated using iTRAQ analysis and two-dimensional electrophoresis coupled to liquid chromatography tandem mass spectrometry revealed some proteins with altered expression levels. Several of these proteins have been the object of interest in cancer research but others were unrecognized as differentially expressed in a context of ovarian cancer. Among these, series of proteins involved in transcriptional activity, cellular metabolism, cell adhesion or motility and cytoskeleton organization were identified, suggesting their possible role in the emergence of oncogenic pathways leading to aggressive cellular behavior. Conclusion The differential protein expression profile generated by the two proteomics approaches combined to complementary characterizations studies will open the way to more exhaustive and systematic representation of the disease and will provide valuable information that may be helpful to uncover the molecular mechanisms related to epithelial ovarian cancer.
Ovarian cancer-related hypophosphatemic osteomalacia--a case report.
Lin, Hung-An; Shih, Shyang-Rong; Tseng, Yu-Ting; Chen, Chi-Hau; Chiu, Wei-Yih; Hsu, Chih-Yao; Tsai, Keh-Sung
2014-12-01
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused primarily by benign mesenchymal tumors. It has been associated with malignancies in rare cases. High serum levels of fibroblast growth factor (FGF) 23 reported in a group of patients with ovarian cancer had normal serum phosphate levels. There had been no ovarian cancer-related hypophosphatemic osteomalacia in a search of the literature. We investigated a 57-year-old woman with progressive low back pain. Clinical, biochemical, and radiological assessments were performed. The patient's serum phosphate and FGF23 levels were evaluated at baseline and after treatment for ovarian cancer. The patient presented with progressive low back pain and weight loss during the previous 6 months. Imaging studies revealed low bone mineral density and multiple suspicious spinal metastatic lesions. Laboratory examination showed hypophosphatemia, hyperphosphaturia, normocalcemia, an elevated serum alkaline phosphatase level, and an elevated serum FGF23 level. Because TIO was suspected, a tumor survey was performed, and ovarian carcinoma with multiple metastasis was detected. After surgery and chemotherapy treatments for ovarian cancer, the serum phosphate and FGF23 levels returned to normal, and the low back pain improved. To our knowledge, this is the first case of ovarian cancer-related hypophosphatemic osteomalacia reported in the literature. TIO should be considered in patients with ovarian cancer presenting with weakness, bone pain, and fractures. Investigation of TIO is appropriate when these patients present hypophosphatemia.
Ovarian Cancer-Related Hypophosphatemic Osteomalacia—A Case Report
Lin, Hung-An; Shih, Shyang-Rong; Tseng, Yu-Ting; Chen, Chi-Hau; Chiu, Wei-Yih; Hsu, Chih-Yao
2014-01-01
Context: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused primarily by benign mesenchymal tumors. It has been associated with malignancies in rare cases. High serum levels of fibroblast growth factor (FGF) 23 reported in a group of patients with ovarian cancer had normal serum phosphate levels. There had been no ovarian cancer-related hypophosphatemic osteomalacia in a search of the literature. Objective: We investigated a 57-year-old woman with progressive low back pain. Design and Intervention: Clinical, biochemical, and radiological assessments were performed. The patient's serum phosphate and FGF23 levels were evaluated at baseline and after treatment for ovarian cancer. Results: The patient presented with progressive low back pain and weight loss during the previous 6 months. Imaging studies revealed low bone mineral density and multiple suspicious spinal metastatic lesions. Laboratory examination showed hypophosphatemia, hyperphosphaturia, normocalcemia, an elevated serum alkaline phosphatase level, and an elevated serum FGF23 level. Because TIO was suspected, a tumor survey was performed, and ovarian carcinoma with multiple metastasis was detected. After surgery and chemotherapy treatments for ovarian cancer, the serum phosphate and FGF23 levels returned to normal, and the low back pain improved. Conclusions: To our knowledge, this is the first case of ovarian cancer-related hypophosphatemic osteomalacia reported in the literature. TIO should be considered in patients with ovarian cancer presenting with weakness, bone pain, and fractures. Investigation of TIO is appropriate when these patients present hypophosphatemia. PMID:25181387
DDX4 (DEAD box polypeptide 4) colocalizes with cancer stem cell marker CD133 in ovarian cancers
International Nuclear Information System (INIS)
Kim, Ki Hyung; Kang, Yun-Jeong; Jo, Jin-Ok; Ock, Mee Sun; Moon, Soo Hyun; Suh, Dong Soo; Yoon, Man Soo; Park, Eun-Sil; Jeong, Namkung; Eo, Wan-Kyu; Kim, Heung Yeol; Cha, Hee-Jae
2014-01-01
Highlights: • Germ cell marker DDX4 was significantly increased in ovarian cancer. • Ovarian cancer stem cell marker CD133 was significantly increased in ovarian cancer. • DDX4 and CD133 were mostly colocalized in various types of ovarian cancer tissues. • CD133 positive ovarian cancer cells also express DDX4 whereas CD133-negative cells did not possess DDX4. • Germ cell marker DDX4 has the potential of ovarian cancer stem cell marker. - Abstract: DDX4 (DEAD box polypeptide 4), characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), is an RNA helicase which is implicated in various cellular processes involving the alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. DDX4 is known to be a germ cell-specific protein and is used as a sorting marker of germline stem cells for the production of oocytes. A recent report about DDX4 in ovarian cancer showed that DDX4 is overexpressed in epithelial ovarian cancer and disrupts a DNA damage-induced G2 checkpoint. We investigated the relationship between DDX4 and ovarian cancer stem cells by analyzing the expression patterns of DDX4 and the cancer stem cell marker CD133 in ovarian cancers via tissue microarray. Both DDX4 and CD133 were significantly increased in ovarian cancer compared to benign tumors, and showed similar patterns of expression. In addition, DDX4 and CD133 were mostly colocalized in various types of ovarian cancer tissues. Furthermore, almost all CD133 positive ovarian cancer cells also express DDX4 whereas CD133-negative cells did not possess DDX4, suggesting a strong possibility that DDX4 plays an important role in cancer stem cells, and/or can be used as an ovarian cancer stem cell marker
Sakurai, Manabu; Matsumoto, Koji; Gosho, Masahiko; Sakata, Akiko; Hosokawa, Yoshihiko; Tenjimbayashi, Yuri; Katoh, Takashi; Shikama, Ayumi; Komiya, Haruna; Michikami, Hiroo; Tasaka, Nobutaka; Akiyama-Abe, Azusa; Nakao, Sari; Ochi, Hiroyuki; Onuki, Mamiko; Minaguchi, Takeo; Yoshikawa, Hiroyuki; Satoh, Toyomi
2017-01-01
Our 2007 study of 32 patients with ovarian cancer reported the possible involvement of tissue factor (TF) in the development of venous thromboembolism (VTE) before treatment, especially in clear cell carcinoma (CCC). This follow-up study further investigated this possibility in a larger cohort. We investigated the intensity of TF expression (ITFE) and other variables for associations with VTE using univariate and multivariate analyses in 128 patients with epithelial ovarian cancer initially treated between November 2004 and December 2010, none of whom had received neoadjuvant chemotherapy. Before starting treatment, all patients were ultrasonographically screened for VTE. The ITFE was graded based on immunostaining of surgical specimens. Histological types were serous carcinoma (n = 42), CCC (n = 12), endometrioid carcinoma (n = 15), mucinous carcinoma (n = 53), and undifferentiated carcinoma (n = 6). The prevalence of VTE was significantly higher in CCC (34%) than in non-CCC (17%, P = 0.03). As ITFE increased, the frequencies of CCC and VTE increased significantly (P epithelial ovarian cancer may involve TF expression in cancer tissues.
Menstrual pain and risk of epithelial ovarian cancer
DEFF Research Database (Denmark)
Babic, Ana; Harris, Holly R; Vitonis, Allison F
2018-01-01
to lack of power. We assessed menstrual pain using either direct questions about having experienced menstrual pain, or indirect questions about menstrual pain as indication for use of hormones or medications. We used multivariate logistic regression to calculate the odds ratio (OR) for the association......Menstrual pain, a common gynecological condition, has been associated with increased risk of ovarian cancer in some, but not all studies. Furthermore, potential variations in the association between menstrual pain and ovarian cancer by histologic subtype have not been adequately evaluated due...... between severe menstrual pain and ovarian cancer, adjusting for potential confounders and multinomial logistic regression to calculate ORs for specific histologic subtypes. We observed no association between ovarian cancer and menstrual pain assessed by indirect questions. Among studies using direct...
... vein thrombosis (DVT) , heart attack, and stroke. Current theories suggest that some types of ovarian cancer may ... Annual Meeting CME Overview CREOG Meetings Calendar Congressional Leadership Conference Advocacy Legislative Priorities GR & Outreach State Advocacy ...
DNA damage signaling and apoptosis in preinvasive tubal lesions of ovarian carcinoma.
Chene, Gautier; Ouellet, Veronique; Rahimi, Kurosh; Barres, Veronique; Caceres, Katia; Meunier, Liliane; Cyr, Louis; De Ladurantaye, Manon; Provencher, Diane; Mes Masson, Anne Marie
2015-06-01
High-grade serous ovarian cancer (HGSC) is the most life-threatening gynecological malignancy despite surgery and chemotherapy. A better understanding of the molecular basis of the preinvasive stages might be helpful in early detection and diagnosis. Genetic instability is 1 of the characteristics shared by most human cancers, and its level is variable through precancerous lesions to advanced cancer. Because DNA damage response (DDR) has been described as 1 of the first phases in genomic instability, we investigated the level of DDR activation and the apoptosis pathway in serous tubal intraepithelial carcinoma (STIC), the potential precursor of HGSC. A tissue microarray including 21 benign fallopian tubes, 21 STICs, 17 HGSCs from patients with STICs (associated ovarian cancer [AOC]) from the same individuals, and 30 HGSCs without STICs (non-AOC) was used in this study.Immunohistochemistry was performed to evaluate the level of DDR proteins (pATM, pChk2, γH2AX, 53BP1, and TRF2), apoptosis proteins (Bcl2, BAX, and BIM), and cyclin E. The expression of all DDR proteins increased from benign fallopian tubes to STICs. The level of expression of pATM, pChk2, γH2AX, and TRF2 was also increased in STICs in comparison with AOC. BAX, BIM, and cyclin E expressions were high in STICs, whereas Bcl2 expression was low. Immunohistochemical profiles of AOC and non-AOC were also different. These results suggest an activation of the DDR and apoptosis pathways in STICs, indicating that genomic instability may occur early in the precancerous lesions of HGSC.
Pathogenesis of ovarian cancer: current perspectives | Chesang ...
African Journals Online (AJOL)
Objective: To present a review of current knowledge of the pathogenesis of ovarian cancer and its clinical implications. Data Source: Extensive literature search was conducted to identify relevant studies. Study Selection: Studies in the English language about or related to pathogenesis of ovarian cancer were selected.
Is tissue CA125 expression in epithelial ovarian adenocarcinoma heterogenic?
DEFF Research Database (Denmark)
Sparholt, Morten H; Høgdall, Claus K; Nedergaard, Lotte
2013-01-01
To evaluate if heterogeneity of tissue cancer antigen 125 (CA125) expression is present in epithelial serous adenocarcinomas. Furthermore, to investigate whether there is a correlation between levels of CA125 tissue expression, serum level of CA125, stage, and grade. A total of 10 patients...... diagnosed with serous ovarian adenocarcinomas were included. Preoperative blood samples were collected to determine serum CA125 levels. Tumor tissue from primary surgery was collected and processed for immunohistochemical analyses. CA125 was expressed in varying degrees in tumor tissues from all patients....... Mean tissue CA125 expression for each patient ranged from 36% to 98%. Intrapatient variations in tissue expression ranged from 10% to 90% point. No significant correlations between levels of CA125 tissue expression, serum level of CA125, stage, and grade were found. We found that the tissue expression...
The Effect of Gynecologic Oncologist Availability on Ovarian Cancer Mortality
Stewart, Sherri L.; Cooney, Darryl; Hirsch, Shawn; Westervelt, Lauren; Richards, Thomas B.; Rim, Sun Hee; Thomas, Cheryll C.
2015-01-01
AIM To determine the association between the distribution of gynecologic oncologist (GO) and population-based ovarian cancer death rates. MATERIALS AND METHODS Data on ovarian cancer incidence and mortality in the United States (U.S.) was supplemented with U.S. census data, and analyzed in relation to practicing GOs. GO locations were geocoded to link association between county variables and GO availability. Logistic regression was used to measure areas of high and low ovarian cancer mortality, adjusting for contextual variables. RESULTS Practicing GOs were unevenly distributed in the United States, with the greatest numbers in metropolitan areas. Ovarian cancer incidence and death rates increased as distance to a practicing GO increased. A relatively small number (153) of counties within 24 miles of a GO had high ovarian cancer death rates compared to 577 counties located 50 or more miles away with high ovarian cancer death rates. Counties located 50 or more miles away from a GO practice had an almost 60% greater odds of high ovarian cancer mortality compared to those with closer practicing GOs (OR 1.59, 95% CI 1.18–2.15). CONCLUSION The distribution of GOs across the United States appears to be significantly associated with ovarian cancer mortality. Efforts that facilitate outreach of GOs to certain populations may increase geographic access. Future studies examining other factors associated with lack of GO access (e.g. insurance and other socioeconomic factors) at the individual level will assist with further defining barriers to quality ovarian cancer care in the United States. PMID:26478860
Horn, Lars-Christian; Angermann, Karolin; Hentschel, Bettina; Einenkel, Jens; Höhn, Anne Kathrin
2017-04-01
Borderline ovarian tumors (BOT) arise from cystadenomas and represent a transition step within the development of low-grade ovarian carcinomas (Type I tumors). That pathway mirrors the adenoma-to-carcinoma sequence known for colorectal cancer. It has been suggested that papillary tubal hyperplasia (PTH) and salpingoliths may be associated with the development of BOT. To evaluate the frequency of the presence of benign cystadenoma and its transition to BOT in a given patient as well as the presence of PTH and salpingoliths we re-valuated in 74 consecutive cases of BOT with different histologic types. The majority of cases represented serous-BOT (60.8%), followed by mucinous BOT (25.7%), other histologic types were rare. 86.5% showed an adenoma-BOT sequence, which was seen in all mucinous BOT but was missed in 15.6% of serous BOT. Two cases had salpingoliths without associated PTH. PTH was seen in four out of the 74 (5.4%) BOT and occurred only in cases with serous histology. The vast majority of BOT represent a transition from benign cystadenoma to BOT in cases with mucinous and serous histology. Salpingoliths are rarely seen in association with BOT and occurred exclusively in BOT with serous histology. PTH may represent a distinct lesion but is rarely seen in association with BOT, especially in those with non-serous histology. Further studies are needed to evaluate the frequency and pathogenetic association of PTH with BOT. Copyright © 2017 Elsevier GmbH. All rights reserved.
2017-09-12
Stage IA Fallopian Tube Cancer; Stage IA Ovarian Cancer; Stage IB Fallopian Tube Cancer; Stage IB Ovarian Cancer; Stage IC Fallopian Tube Cancer; Stage IC Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer
Mismatch repair and treatment resistance in ovarian cancer
International Nuclear Information System (INIS)
Helleman, Jozien; Staveren, Iris L van; Dinjens, Winand NM; Kuijk, Patricia F van; Ritstier, Kirsten; Ewing, Patricia C; Burg, Maria EL van der; Stoter, Gerrit; Berns, Els MJJ
2006-01-01
The treatment of ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR) inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy. We determined, microsatellite instability (MSI) as a marker for MMR inactivation (analysis of BAT25 and BAT26), MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA) and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR) in 75 ovarian carcinomas and eight ovarian cancer cell lines MSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation), SKOV3 (no MLH1 mRNA expression) and 2774 (no altered expression of MMR genes). Overall, there was no association between cisplatin response and MMR status in these eight cell lines. Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation, however, none of these showed MSI. Forty-six of these patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response). The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation. No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients. Although no association between response and MMR status was seen in the primary tumor the possible role of MMR inactivation in acquired resistance deserves further investigation
Mismatch repair and treatment resistance in ovarian cancer
Energy Technology Data Exchange (ETDEWEB)
Helleman, Jozien; Staveren, Iris L van [Department of Medical Oncology, Erasmus MC/Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Dinjens, Winand NM [Department of Pathology, Erasmus MC/Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Kuijk, Patricia F van; Ritstier, Kirsten [Department of Medical Oncology, Erasmus MC/Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Ewing, Patricia C [Department of Pathology, Erasmus MC/Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Burg, Maria EL van der; Stoter, Gerrit [Department of Medical Oncology, Erasmus MC/Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Berns, Els MJJ [Department of Medical Oncology, Erasmus MC/Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Erasmus MC, Department of Medical Oncology, Josephine Nefkens Institute, Room Be424, P.O. Box 1738, 3000 DR (Netherlands)
2006-07-31
The treatment of ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR) inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy. We determined, microsatellite instability (MSI) as a marker for MMR inactivation (analysis of BAT25 and BAT26), MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA) and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR) in 75 ovarian carcinomas and eight ovarian cancer cell lines MSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation), SKOV3 (no MLH1 mRNA expression) and 2774 (no altered expression of MMR genes). Overall, there was no association between cisplatin response and MMR status in these eight cell lines. Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation, however, none of these showed MSI. Forty-six of these patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response). The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation. No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients. Although no association between response and MMR status was seen in the primary tumor the possible role of MMR inactivation in acquired resistance deserves further investigation.
Mismatch repair and treatment resistance in ovarian cancer
Directory of Open Access Journals (Sweden)
van der Burg Maria EL
2006-07-01
Full Text Available Abstract Background The treatment of ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy. Methods We determined, microsatellite instability (MSI as a marker for MMR inactivation (analysis of BAT25 and BAT26, MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR in 75 ovarian carcinomas and eight ovarian cancer cell lines Results MSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation, SKOV3 (no MLH1 mRNA expression and 2774 (no altered expression of MMR genes. Overall, there was no association between cisplatin response and MMR status in these eight cell lines. Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation, however, none of these showed MSI. Forty-six of these patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response. The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation. Conclusion No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients. Although no association between response and MMR status was seen in the primary tumor the possible role of MMR inactivation in acquired resistance deserves further investigation.
Directory of Open Access Journals (Sweden)
Luiz Gustavo A Chuffa
Full Text Available Ovarian cancer is the fourth most common cause of cancer deaths among women, and chronic alcoholism may exert co-carcinogenic effects. Because melatonin (mel has oncostatic properties, we aimed to investigate and characterize the chemical induction of ovarian tumors in a model of ethanol-preferring rats and to verify the influence of mel treatment on the overall features of these tumors. After rats were selected to receive ethanol (EtOH, they were surgically injected with 100 µg of 7,12-dimethyl-benz[a]anthracene (DMBA plus sesame oil directly under the left ovarian bursa. At 260 days old, half of the animals received i.p. injections of 200 µg mel/100 g b.w. for 60 days. Four experimental groups were established: Group C, rats bearing ovarian carcinomas (OC; Group C+EtOH, rats voluntarily consuming 10% (v/v EtOH and bearing OC; Group C+M, rats bearing OC and receiving mel; and Group C+EtOH+M, rats with OC consuming EtOH and receiving mel. Estrous cycle and nutritional parameters were evaluated, and anatomopathological analyses of the ovarian tumors were conducted. The incidence of ovarian tumors was higher in EtOH drinking animals 120 days post-DMBA administration, and mel efficiently reduced the prevalence of some aggressive tumors. Although mel promoted high EtOH consumption, it was effective in synchronizing the estrous cycle and reducing ovarian tumor mass by 20%. While rats in the C group displayed cysts containing serous fluid, C+EtOH rats showed solid tumor masses. After mel treatment, the ovaries of these rats presented as soft and mobile tissues. EtOH consumption increased the incidence of serous papillary carcinomas and sarcomas but not clear cell carcinomas. In contrast, mel reduced the incidence of sarcomas, endometrioid carcinomas and cystic teratomas. Combination of DMBA with EtOH intake potentiated the incidence of OC with malignant histologic subtypes. We concluded that mel reduces ovarian masses and the incidence of
Ricciardi, Enzo; Tomao, Federica; Aletti, Giovanni; Bazzurini, Luca; Bocciolone, Luca; Boveri, Sara; Landoni, Fabio; Lapresa, Maria Teresa; Maruccio, Matteo; Parma, Gabriella; Peccatori, Fedro; Petrella, Maria Cristina; Zanagnolo, Vanna; Colombo, Nicoletta; Maggioni, Angelo
2017-09-01
Occult cancers' reported rates vary from 2-12% and serous tubal intraepithelial carcinomas (STICs) have been identified in 3-12% of the prophylactically removed tubes of women carrying a BRCA mutation. The aim of this study was to evaluate the incidence of tubal minor epithelial atypia (STIL), STIC, and occult invasive cancer and to evaluate the cancer-specific mortality in a prospective series of women at higher risk of ovarian and breast cancer undergoing risk-reducing salpingo-oophorectomy (RRSO) n a tertiary cancer center. A series of RRSO specimens (including endometrial biopsy) from women carrying a BRCA mutation, BRCA-unknown and BRCA-negative were collected between January 1998 and April 2016 at the Division of Gynecology at the European Institute of Oncology. Inclusion criteria were: asymptomatic women who had a negative gynecologic screening within 3 months prior to RRSO. Exclusion criteria were: women with ovarian/tubal cancer prior to RRSO. A total of 411 women underwent RRSO. Median age at RRSO was 47.0 years (range=32-70 years); 75.2% had a history of breast cancer. Fifteen women were diagnosed with an occult cancer (7 STIC, 4 invasive cancers, 2 breast cancers metastatic to the adnexa, 2 endometrial cancer) (3.6%). Sixteen showed a STIL (3.9%). When excluding cases with preoperative positive markers, the occult invasive cancer rate drops to 1.5%. Our study, covering an 18-year period, shows a substantial low risk of occult cancer among a high-risk population of women undergoing RRSO. Our data still support the indication for RRSO in higher-risk patients. An endometrial biopsy should also be routinely obtained as it raises the chances of detecting occult endometrial cancers that may be otherwise missed. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
Risks of Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Screening
... black women. Different factors increase or decrease the risk of getting ovarian, fallopian tube, and primary peritoneal ... decrease the number of deaths from ovarian cancer. Risks of Ovarian, Fallopian Tube, and Primary Peritoneal Cancer ...
Identification of BRCA1-deficient ovarian cancers
DEFF Research Database (Denmark)
Skytte, Anne-Bine; Waldstrøm, Marianne; Rasmussen, Anders Aamann
2011-01-01
of offering genetic counseling and due to beneficial effects of PARP inhibitor treatment in this group. Since DNA sequencing is expensive and time-consuming efforts have been devoted to develop more indirect methods for BRCA screening that can improve the selection of patients for sequence-based BRCA testing....... Design. BRCA1-immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH) and methylation analyses were performed on formalin-fixed, paraffin-embedded ovarian cancer tissue. Sample: 54 ovarian cancers; 15 BRCA1 cancers, 4 BRCA2 cancers, 10 cancers from patients with a family history...
TRPM7 is required for ovarian cancer cell growth, migration and invasion
Energy Technology Data Exchange (ETDEWEB)
Wang, Jing; Liao, Qian-jin [The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 (China); Zhang, Yi [Department of Obstetrics and Gynaecology, Xiangya Hospital, Central South University, Changsha 410078 (China); Zhou, Hui; Luo, Chen-hui; Tang, Jie; Wang, Ying; Tang, Yan; Zhao, Min; Zhao, Xue-heng [The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 (China); Zhang, Qiong-yu [Department of Basic Medical Science, Yongzhou Vocational Technical College, Yong Zhou 425100 (China); Xiao, Ling, E-mail: lingxiaocsu@126.com [Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha 410013 (China); Institute of Clinical Pharmacology, Central South University, Changsha 410018 (China)
2014-11-28
Highlights: • Silence of TRPM7 in ovarian cancer cells inhibits cell proliferation, migration and invasion. • Silence of TRPM7 decreases phosphorylation levels of Akt, Src and p38 in ovarian cancer cells. • Silence of TRPM7 increases expression of filamentous actin and number of focal adhesions in ovarian cancer cells. - Abstract: Our previous study demonstrated that the melastatin-related transient receptor potential channel 7 (TRPM7) was highly expressed in ovarian carcinomas and its overexpression was significantly associated with poor prognosis in ovarian cancer patients. However, the function of TRPM7 in ovarian cancer is mostly unknown. In this study, we examined the roles of TRPM7 in ovarian cancer cell proliferation, migration and invasion. We found that short hairpin RNA interference-mediated silence of TRPM7 significantly inhibited cell proliferation, colony formation, migration and invasion in multiple ovarian cancer cell lines. Mechanistic investigation revealed that silence of TRPM7 decreased phosphorylation levels of Akt, Src and p38 and increased filamentous actin and focal adhesion number in ovarian cancer cells. Thus, our results suggest that TRPM7 is required for proliferation, migration and invasion of ovarian cancer cells through regulating multiple signaling transduction pathways and the formation of focal adhesions.
DEFF Research Database (Denmark)
Pearce, C.L.; Wu, A.H.; Gayther, S.A.
2008-01-01
There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone...... receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR...... single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were...
Statin use and risk for ovarian cancer
DEFF Research Database (Denmark)
Baandrup, L; Dehlendorff, C; Friis, Søren
2015-01-01
BACKGROUND: Limited data suggest that statin use reduces the risk for ovarian cancer. METHODS: Using Danish nationwide registries, we identified 4103 cases of epithelial ovarian cancer during 2000-2011 and age-matched them to 58,706 risk-set sampled controls. Conditional logistic regression....... The inverse association between statin use and mucinous tumours merits further investigation....
Huang, Tianyi; Tworoger, Shelley S; Hecht, Jonathan L; Rice, Megan S; Sood, Anil K; Kubzansky, Laura D; Poole, Elizabeth M
2016-12-01
The β 2 -adrenergic signaling pathway mediates the effects of chronic stress on ovarian cancer progression in mouse models. The relevance of this pathway to human ovarian cancer remains unknown. We assessed tumor expression of β 2 -adrenergic receptor (ADRB2) using tissue microarrays in 237 ovarian cancer cases from the Nurses' Health Studies (NHS/NHSII). Competing risks Cox regression was used to evaluate whether associations of reproductive, hormonal, and psychosocial factors with ovarian cancer risk differed by ADRB2. We also examined the association between tumor ADRB2 expression and ovarian cancer survival. Forty-five (19%) cases were positive for ADRB2 staining. High levels of anxiety symptoms were positively associated with ADRB2-positive tumors (HR, 2.59; 95% confidence interval [CI], 1.15-5.84) but not with ADRB2-negative tumors (HR, 1.16; 95% CI, 0.81-1.66; P heterogeneity = 0.07). We observed similar results for depression. No associations were observed for job strain, caregiving stress, or widowhood for either positive or negative ADRB2 status. Lifetime ovulatory years were more strongly associated with ADRB2-positive tumors (HR per 5 years, 1.60; 95% CI, 1.15-2.21) compared with ADRB2-negative tumors (HR, 1.11; 95% CI, 0.96-1.27; P heterogeneity = 0.04). Significant heterogeneity by ADRB2 was also observed for parity (P heterogeneity = 0.01), oral contraceptive use (P heterogeneity = 0.03), and age at menopause (P heterogeneity = 0.04). Tumor expression of ADRB2 was not associated with ovarian cancer mortality (HR, 1.05; 95% CI, 0.69-1.59). Several stress- and ovulation-related factors were differentially associated with ovarian tumors responsive to β 2 -adrenergic signaling. Replication in larger studies is warranted to confirm the role of β 2 -adrenergic signaling in ovarian cancer etiology. Cancer Epidemiol Biomarkers Prev; 25(12); 1587-94. ©2016 AACR. ©2016 American Association for Cancer Research.
[Early detection of ovarian cancer: tomorrow? A review].
Chene, G; Penault-Llorca, F; Robin, N; Cayre, A; Provencher, D M; Dauplat, J
2013-02-01
Ovarian cancer is the most lethal of the gynaecological malignancies because this «silent killer» is almost always diagnosed at an advanced stage. Precursor lesions have at least been discovered. This review will describe in details specific features of tubal and ovarian preinvasive lesions and the old and novel techniques that could be used for early detection of ovarian cancer. Copyright © 2012 Elsevier Masson SAS. All rights reserved.
Incidence, Pattern and Management of Ovarian Cancer at a Tertiary ...
African Journals Online (AJOL)
the commonest type of ovarian cancer and is known to be a disease of postmenopausal women.[12]. A global ... received surgery and chemotherapy, as well as the estimated case‑fatality rate for ovarian cancer. Ethical ... The mean ages (SD) at presentation of the different types of ovarian cancer were epithelial 50.3 (13.2).
Etiology and Pathogenesis of Epithelial Ovarian Cancer
Directory of Open Access Journals (Sweden)
Samuel C. Mok
2007-01-01
Full Text Available Ovarian cancer is complex disease composed of different histological grades and types. However, the underlying molecular mechanisms involved in the development of different phenotypes remain largely unknown. Epidemiological studies identified multiple exogenous and endogenous risk factors for ovarian cancer development. Among them, an inflammatory stromal microenvironment seems to play a critical role in the initiation of the disease. The interaction between such a microenvironment, genetic polymorphisms, and different epithelial components such as endosalpingiosis, endometriosis, and ovarian inclusion cyst in the ovarian cortex may induce different genetic changes identified in the epithelial component of different histological types of ovarian tumors. Genetic studies on different histological grades and types provide insight into the pathogenetic pathways for the development of different disease phenotypes. However, the link between all these genetic changes and the etiological factors remains to be established.
de Almeida Chuffa, Luiz Gustavo; de Moura Ferreira, Grazielle; Lupi, Luiz Antonio; da Silva Nunes, Iseu; Fávaro, Wagner José
2018-01-17
Toll-like receptors (TLRs) are transmembrane proteins expressed on the surface of ovarian cancer (OC) and immune cells. Identifying the specific roles of the TLR-mediated signaling pathways in OC cells is important to guide new treatments. Because immunotherapies have emerged as the adjuvant treatment for patients with OC, we investigated the effect of a promising immunotherapeutic strategy based on protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) combined with cisplatin (CIS) on the TLR2 and TLR4 signaling pathways via myeloid differentiation factor 88 (MyD88) and TLR-associated activator of interferon (TRIF) in an in vivo model of OC. Tumors were chemically induced by a single injection of 100 μg of 7,12-dimethylbenz(a)anthracene (DMBA) directly under the left ovarian bursa in Fischer 344 rats. After the rats developed serous papillary OC, they were given P-MAPA, CIS or the combination P-MAPA+CIS as therapies. To understand the effects of the treatments, we assessed the tumor size, histopathology, and the TLR2- and TLR4-mediated inflammatory responses. Although CIS therapy was more effective than P-MAPA in reducing the tumor size, P-MAPA immunotherapy significantly increased the expressions of TLR2 and TLR4. More importantly, the combination of P-MAPA with CIS showed a greater survival rate compared to CIS alone, and exhibited a significant reduction in tumor volume compared to P-MAPA alone. The combination therapy also promoted the increase in the levels of the following OC-related proteins: TLR4, MyD88, TRIF, inhibitor of phosphorylated NF-kB alpha (p-IkBα), and nuclear factor kappa B (NF-kB p65) in both cytoplasmic and nuclear sites. While P-MAPA had no apparent effect on tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6, it seems to increase interferon-γ (IFN-γ), which may induce the Thelper (Th1)-mediated immune response. Collectively, our results suggest that P-MAPA immunotherapy combined with cisplatin
Minlikeeva, Albina N; Freudenheim, Jo L; Cannioto, Rikki A; Eng, Kevin H; Szender, J Brian; Mayor, Paul; Etter, John L; Cramer, Daniel W; Diergaarde, Brenda; Doherty, Jennifer A; Dörk, Thilo; Edwards, Robert; deFazio, Anna; Friel, Grace; Goodman, Marc T; Hillemanns, Peter; Høgdall, Estrid; Jensen, Allan; Jordan, Susan J; Karlan, Beth Y; Kjær, Susanne K; Klapdor, Rüdiger; Matsuo, Keitaro; Mizuno, Mika; Nagle, Christina M; Odunsi, Kunle; Paddock, Lisa; Rossing, Mary Anne; Schildkraut, Joellen M; Schmalfeldt, Barbara; Segal, Brahm H; Starbuck, Kristen; Terry, Kathryn L; Webb, Penelope M; Zsiros, Emese; Ness, Roberta B; Modugno, Francesmary; Bandera, Elisa V; Chang-Claude, Jenny; Moysich, Kirsten B
2017-09-26
Findings from in vitro studies suggest that increased exposure to thyroid hormones can influence progression of ovarian tumours. However, epidemiologic evidence on this topic is limited. We pooled data from 11 studies from the Ovarian Cancer Association Consortium. Using multivariate Cox proportional hazards models, we estimated associations between hyper- and hypothyroidism and medications prescribed for these conditions with 5-year all-cause survival among women diagnosed with invasive ovarian cancer. Overall, there was a nonsignificant association with history of hyperthyroidism (n=160 cases) and mortality (HR=1.22; 95% CI=0.97-1.53). Furthermore, diagnosis of hyperthyroidism within the 5 years before ovarian cancer diagnosis was associated with an increased risk of death (HR=1.94; 95% CI=1.19-3.18). A more modest association was observed with history of hypothyroidism (n=624 cases) and mortality (HR=1.16; 95% CI=1.03-1.31). Neither duration of hypothyroidism nor use of thyroid medications was associated with survival. In this large study of women with ovarian cancer, we found that recent history of hyperthyroidism and overall history of hypothyroidism were associated with worse 5-year survival.
Circulating soluble Fas levels and risk of ovarian cancer
International Nuclear Information System (INIS)
Akhmedkhanov, Arslan; Lenner, Per; Muti, Paola; Rinaldi, Sabina; Kaaks, Rudolf; Berrino, Franco; Hallmans, Göran; Toniolo, Paolo; Lundin, Eva; Guller, Seth; Lukanova, Annekatrin; Micheli, Andrea; Ma, Yuehong; Afanasyeva, Yelena; Zeleniuch-Jacquotte, Anne; Krogh, Vittorio
2003-01-01
Dysregulation of apoptosis, specifically overexpression of soluble Fas (sFas), has been proposed to play a role in the development of ovarian cancer. The main objective of the present study was to evaluate serum sFas as a potential biomarker of ovarian cancer risk. The association between serum sFas levels and the risk of ovarian cancer was examined in a case-control study nested within three prospective cohorts in New York (USA), Umeå (Sweden), and Milan (Italy). Case subjects were 138 women with primary invasive epithelial ovarian cancer diagnosed between 2 months and 13.2 years after the initial blood donation. Control subjects were 263 women who were free of cancer, and matched the case on cohort, menopausal status, age, and enrollment date. Serum sFas levels were determined using a quantitative sandwich enzyme immunoassay. Serum sFas levels were similar in women subsequently diagnosed with ovarian cancer (median, 6.5 ng/mL; range, 4.4 – 10.2) and in controls (median, 6.8 ng/mL; range, 4.5 – 10.1). Statistically significant trends of increasing serum sFas with age were observed among cases (r = 0.39, p < 0.0001) and controls (r = 0.42, p < 0.0001). Compared to women in the lowest third, women in the highest third of serum sFas were not at increased risk of ovarian cancer after adjustment for potential confounders (odd ratio (OR), 0.87; 95% confidence interval (CI), 0.42 – 1.82). The results suggest that serum sFas may not be a suitable marker for identification of women at increased risk of ovarian cancer
Tubal ligation and risk of ovarian cancer subtypes
DEFF Research Database (Denmark)
Sieh, Weiva; Salvador, Shannon; McGuire, Valerie
2013-01-01
Tubal ligation is a protective factor for ovarian cancer, but it is unknown whether this protection extends to all invasive histological subtypes or borderline tumors. We undertook an international collaborative study to examine the association between tubal ligation and ovarian cancer subtypes....
2017-01-05
Chemotherapeutic Agent Toxicity; Neuropathy; Neurotoxicity Syndrome; Pain; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer
PARP Inhibitors in Ovarian Cancer.
Mittica, Gloria; Ghisoni, Eleonora; Giannone, Gaia; Genta, Sofia; Aglietta, Massimo; Sapino, Anna; Valabrega, Giorgio
2018-03-05
Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients. To highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis. We performed a review on Pubmed using 'ovarian cancer' and the name of each PARPi (PARP inhibitor) discussed in the review as Medical Subject Headings (MeSH) keywords. The same search was performed on "clinicaltrial.gov" to identify ongoing clinical trials and on "google.com/patents" and "uspto.gov" for recent patents exploring PARPIs in ovarian cancer. Olaparib, Niraparib and Rucaparib are already approved for treatment of recurrent EOC and their indications are partially overlapping. Talazoparib and Veliparib are promising PARPis, but currently under investigation in early phase trials. Several studies are evaluating PARPis in monotherapy or in associations, in a wide range of settings (i.e. first line, neoadjuvant, platinum-sensitive and resistant disease). PARPis are valuable options in patients with recurrent ovarian cancer with promising activity in different stages of this disease. Further studies are required to better define optimal clinical settings, predictors of response beyond BRCA mutations and strategies to overcome secondary resistance of PARPis therapy in EOC. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
van der Steen, Sophieke C H A; Bulten, Johan; Van de Vijver, Koen K; van Kuppevelt, Toin H; Massuger, Leon F A G
2017-07-01
The identification of a marker for early progression of preinvasive lesions into invasive pelvic high-grade serous carcinoma (HGSC) may provide novel handles for innovative screening and prevention strategies. The interplay between cancer cells and the extracellular matrix (ECM) is one of the main principles in cancer development and growth, but has been largely neglected in preinvasive lesions. This is the first study addressing the involvement of the ECM in the "step-by-step" transition of normal fallopian tube epithelium into preinvasive lesions, and eventually the progression of preinvasive lesions into invasive HGSC. The expression of highly sulfated chondroitin sulfate (CS-E), a characteristic glycosaminoglycan of the cancer-associated ECM, was assessed by immunohistochemistry in a large cohort of precursor lesions of the full spectrum of HGSC development, including 97 serous tubal intraepithelial carcinomas (STICs), 27 serous tubal intraepithelial lesions, and 24 p53 signatures. In addition, the immunological reactivity in the microenvironment was evaluated. Increased stromal expression of highly sulfated CS-E was observed in 3.7%, 57.7%, and 90.6% of serous tubal intraepithelial lesions, STICs, and invasive HGSCs, respectively (P STIC, P STIC and paired HGSC was demonstrated. Intense stromal CS-E expression in STIC was significantly associated with an immune infiltrate (P < 0.001). Our study showed that increased stromal CS-E expression is related to the degree of the tubal epithelium abnormality. Specific alterations in the ECM (ie, CS-E expression) occur early in pelvic HGSC development and may represent a novel biomarker of early cancer progression, useful for the identification of novel clinical strategies.
Ovarian and cervical cancer awareness: development of two validated measurement tools.
Simon, Alice E; Wardle, Jane; Grimmett, Chloe; Power, Emily; Corker, Elizabeth; Menon, Usha; Matheson, Lauren; Waller, Jo
2012-07-01
The aim of the study was to develop and validate measures of awareness of symptoms and risk factors for ovarian and cervical cancer (Ovarian and Cervical Cancer Awareness Measures). Potentially relevant items were extracted from the literature and generated by experts. Four validation studies were carried out to establish reliability and validity. Women aged 21-67 years (n=146) and ovarian and cervical cancer experts (n=32) were included in the studies. Internal reliability was assessed psychometrically. Test-retest reliability was assessed over a 1-week interval. To establish construct validity, Cancer Awareness Measure (CAM) scores of cancer experts were compared with equally well-educated comparison groups. Sensitivity to change was tested by randomly assigning participants to read either a leaflet giving information about ovarian/cervical cancer or a leaflet with control information, and then completing the ovarian/cervical CAM. Internal reliability (Cronbach's α=0.88 for the ovarian CAM and α=0.84 for the cervical CAM) and test-retest reliability (r=0.84 and r=0.77 for the ovarian and cervical CAMs, respectively) were both high. Validity was demonstrated with cancer experts achieving higher scores than controls [ovarian CAM: t(36)= -5.6, pcancer leaflet scored higher than those who received a control leaflet [ovarian CAM: t(49)=7.5, pcancer awareness in the general population.
Incidence of ovarian cancer after hysterectomy: a nationwide controlled follow up.
Loft, A; Lidegaard, O; Tabor, A
1997-11-01
To estimate the risk of developing ovarian cancer after abdominal (total or subtotal) hysterectomy on benign indication. Prospective historical cohort study with 12.5 years of follow up. Denmark, nationwide. All Danish women (aged 0 to 99 years) having undergone hysterectomy with conservation of at least one ovary for a benign indication from 1977 to 1981 (n = 22,135). Follow up was conducted from 1977 to 1991. The reference group included all Danish women who had not undergone hysterectomy, age-standardised according to the hysterectomy group (n = 2,554,872). Registry data derived from the Danish National Register of Patients (diagnoses and operation codes) and the Civil Registration System (information about general population, including time of death). Incidence rate of ovarian cancer, lifetime risk of ovarian cancer, relative risk of ovarian cancer. Seventy-one women developed ovarian cancer on average 7.0 years after hysterectomy and 10,659 women in the reference group had ovarian cancer diagnosed after on average 6.4 years. The incidence rate of ovarian cancer was 0.27 per 1000 person-years in the group that had undergone hysterectomy and 0.34 per 1000 person-years in the general population (age-standardised). The extrapolated lifetime risk of developing ovarian cancer was 2.1% after hysterectomy and 2.7% in the general population (RR 0.78; 95% CI 0.60-0.96). The risk of ovarian cancer is lower among women who have undergone hysterectomy compared with those who have not. The protection seems to decrease with time.
The relation between endometriosis and ovarian cancer - a review
DEFF Research Database (Denmark)
Nyhøj Heidemann, Lene; Hartwell, Dorthe; Heidemann, Christian Hamilton
2014-01-01
Endometriosis is known to harbor characteristics substantiating that it is a possible precursor of ovarian cancer.......Endometriosis is known to harbor characteristics substantiating that it is a possible precursor of ovarian cancer....
Targeting HOX and PBX transcription factors in ovarian cancer
International Nuclear Information System (INIS)
Morgan, Richard; Plowright, Lynn; Harrington, Kevin J; Michael, Agnieszka; Pandha, Hardev S
2010-01-01
Ovarian cancer still has a relatively poor prognosis due to the frequent occurrence of drug resistance, making the identification of new therapeutic targets an important goal. We have studied the role of HOX genes in the survival and proliferation of ovarian cancer cells. These are a family of homeodomain-containing transcription factors that determine cell and tissue identity in the early embryo, and have an anti-apoptotic role in a number of malignancies including lung and renal cancer. We used QPCR to determine HOX gene expression in normal ovary and in the ovarian cancer cell lines SK-OV3 and OV-90. We used a short peptide, HXR9, to disrupt the formation of HOX/PBX dimers and alter transcriptional regulation by HOX proteins. In this study we show that the ovarian cancer derived line SK-OV3, but not OV-90, exhibits highly dysregulated expression of members of the HOX gene family. Disrupting the interaction between HOX proteins and their co-factor PBX induces apoptosis in SK-OV3 cells and retards tumour growth in vivo. HOX/PBX binding is a potential target in ovarian cancer
Menopausal hormone use and ovarian cancer risk
DEFF Research Database (Denmark)
Beral, V; Gaitskell, K; Hermon, C
2015-01-01
BACKGROUND: Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy...... on ovarian cancer risk. METHODS: Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies....... Adjusted Poisson regressions yielded relative risks (RRs) versus never-use. FINDINGS: During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with
Claudin-containing exosomes in the peripheral circulation of women with ovarian cancer
Directory of Open Access Journals (Sweden)
Bristow Robert E
2009-07-01
Full Text Available Abstract Background The absence of highly sensitive and specific serum biomarkers makes mass screening for ovarian cancer impossible. The claudin proteins are frequently overexpressed in ovarian cancers, but their potential as prognostic, diagnostic, or detection markers remains unclear. Here, we have explored the possible use of these proteins as screening biomarkers for ovarian cancer detection. Methods Claudin protein shedding from cells was examined by immunoblotting of conditioned culture media. The presence of claudins in exosomes released from ovarian cancer cells was demonstrated by sucrose gradient separation and immunogold electron microscopy experiments. Claudin-4-containing exosomes in the plasma of ovarian cancer patients were evaluated in a pilot panel of 63 ovarian cancer patients and 50 healthy volunteers. The CA125 marker was also assessed in these samples and compared with claudin-4 positivity. Results We show that full-length claudins can be shed from ovarian cancer cells in culture and found in the media as part of small lipid vesicles known as exosomes. Moreover, 32 of 63 plasma samples from ovarian cancer patients exhibited the presence of claudin-4-containing exosomes. In contrast, only one of 50 samples from individuals without cancer exhibited claudin-4-positive exosomes. In our small panel, at a specificity of 98%, the claudin-4 and CA125 tests had sensitivities of 51% and 71%, respectively. The two tests did not appear to be independent and were strongly correlated. Conclusion Our work shows for the first time that claudin-4 can be released from ovarian cancer cells and can be detected in the peripheral circulation of ovarian cancer patients. The development of sensitive assays for the detection of claudin-4 in blood will be crucial in determining whether this approach can be useful, alone or in combination with other screening methods, for the detection of ovarian cancer.
Claudin-containing exosomes in the peripheral circulation of women with ovarian cancer
International Nuclear Information System (INIS)
Li, Jianghong; Sherman-Baust, Cheryl A; Tsai-Turton, Miyun; Bristow, Robert E; Roden, Richard B; Morin, Patrice J
2009-01-01
The absence of highly sensitive and specific serum biomarkers makes mass screening for ovarian cancer impossible. The claudin proteins are frequently overexpressed in ovarian cancers, but their potential as prognostic, diagnostic, or detection markers remains unclear. Here, we have explored the possible use of these proteins as screening biomarkers for ovarian cancer detection. Claudin protein shedding from cells was examined by immunoblotting of conditioned culture media. The presence of claudins in exosomes released from ovarian cancer cells was demonstrated by sucrose gradient separation and immunogold electron microscopy experiments. Claudin-4-containing exosomes in the plasma of ovarian cancer patients were evaluated in a pilot panel of 63 ovarian cancer patients and 50 healthy volunteers. The CA125 marker was also assessed in these samples and compared with claudin-4 positivity. We show that full-length claudins can be shed from ovarian cancer cells in culture and found in the media as part of small lipid vesicles known as exosomes. Moreover, 32 of 63 plasma samples from ovarian cancer patients exhibited the presence of claudin-4-containing exosomes. In contrast, only one of 50 samples from individuals without cancer exhibited claudin-4-positive exosomes. In our small panel, at a specificity of 98%, the claudin-4 and CA125 tests had sensitivities of 51% and 71%, respectively. The two tests did not appear to be independent and were strongly correlated. Our work shows for the first time that claudin-4 can be released from ovarian cancer cells and can be detected in the peripheral circulation of ovarian cancer patients. The development of sensitive assays for the detection of claudin-4 in blood will be crucial in determining whether this approach can be useful, alone or in combination with other screening methods, for the detection of ovarian cancer
Fertility drugs, reproductive strategies and ovarian cancer risk.
Tomao, Federica; Lo Russo, Giuseppe; Spinelli, Gian Paolo; Stati, Valeria; Prete, Alessandra Anna; Prinzi, Natalie; Sinjari, Marsela; Vici, Patrizia; Papa, Anselmo; Chiotti, Maria Stefania; Benedetti Panici, Pierluigi; Tomao, Silverio
2014-01-01
Several adverse effects have been related to infertility treatments, such as cancer development. In particular, the relationship between infertility, reproductive strategies, and risk of gynecological cancers has aroused much interest in recent years. The evaluation of cancer risk among women treated for infertility is very complex, mainly because of many factors that can contribute to occurrence of cancer in these patients (including parity status). This article addresses the possible association between the use of fertility treatments and the risk of ovarian cancer, through a scrupulous search of the literature published thus far in this field. Our principal objective was to give more conclusive answers on the question whether the use of fertility drug significantly increases ovarian cancer risk. Our analysis focused on the different types of drugs and different treatment schedules used. This study provides additional insights regarding the long-term relationships between fertility drugs and risk of ovarian cancer.
International Nuclear Information System (INIS)
Kelemen, Linda E; Köbel, Martin; Lurie, Galina; Thompson, Pamela J; Carney, Michael E; Moysich, Kirsten; Edwards, Robert; Bunker, Clare; Jensen, Allan; Høgdall, Estrid; Cramer, Daniel W; Bandera, Elisa V; Vitonis, Allison F; Olson, Sara H; King, Melony; Chandran, Urmila; Lissowska, Jolanta; Garcia-Closas, Montserrat; Yang, Hannah; Webb, Penelope M; Schildkraut, Joellen M; Goodman, Marc T; Terry, Kathryn L; Risch, Harvey A; Rossing, Mary Anne; Brinton, Louise A; Doherty, Jennifer A; Ness, Roberta B; Kjær, Susanne Krüger; Chang-Claude, Jenny
2013-01-01
Studies evaluating the association between alcohol intake and ovarian carcinoma (OC) are inconsistent. Because OC and ovarian borderline tumor histologic types differ genetically, molecularly and clinically, large numbers are needed to estimate risk associations. We pooled data from 12 case-control studies in the Ovarian Cancer Association Consortium comprising 5,342 OC cases, 1,455 borderline tumors and 10,358 controls with quantitative information on recent alcohol intake to estimate odds ratios (OR) and 95% confidence intervals (CI) according to frequencies of average daily intakes of beer, wine, liquor and total alcohol. Total alcohol intake was not associated with all OC: consumption of >3 drinks per day compared to none, OR=0.92, 95% CI=0.76-1.10, P trend=0.27. Among beverage types, a statistically non-significant decreased risk was observed among women who consumed >8 oz/d of wine compared to none (OR=0.83, 95% CI=0.68-1.01, P trend=0.08). This association was more apparent among women with clear cell OC (OR, 0.43; 95% CI, 0.22-0.83; P trend=0.02), although based on only 10 cases and not statistically different from the other histologic types (P value for statistical heterogeneity between histologic types = 0.09). Statistical heterogeneity of the alcohol- and wine-OC associations was seen among three European studies, but not among eight North American studies. No statistically significant associations were observed in separate analyses evaluating risk with borderline tumors of serous or mucinous histology. Smoking status did not significantly modify any of the associations. We found no evidence that recent moderate alcohol drinking is associated with increased risk for overall OC, or that variation in risk is associated strongly with specific histologic types. Understanding modifiable causes of these elusive and deadly cancers remains a priority for the research community
The Roles of Laparoscopy in Treating Ovarian Cancer
Directory of Open Access Journals (Sweden)
Chyi-Long Lee
2009-03-01
Full Text Available Great advances in technology offer meticulous options of minimally invasive surgery to empower the gynecologists to manage patients of early ovarian cancer. Laparoscopy affords improved visualization of the pelvic peritoneum, diaphragm and the deep pelvic structures, and offers many advantages in the avoidance of long abdominal incision, including shorter hospital stay and a more rapid recovery time. Most studies showed that laparoscopy did not compromise the survival and recurrence prognosis in comparison with open abdominal approach of staging surgery. Contrarily, laparoscopy precludes the advantage of open surgery, such as manual examination of the full extent of the bowel and palpation of lymph nodes. Besides, laparoscopy technically hampers the removal of large ovarian mass, and laparoscopic cancer surgery has a potential risk of trocar site metastasis. As the trend shows that laparoscopy has been playing an important role in treating early ovarian cancer, we could expect laparoscopy to become an attractive surgical option in the future for ovarian cancers.
Use of fertility drugs and risk of ovarian cancer.
Diergaarde, Brenda; Kurta, Michelle L
2014-06-01
The purpose of this review is to highlight recent research and insights into the relationship between fertility drug use and ovarian cancer risk. Results from two large case-control studies provided further evidence that fertility drug use does not significantly contribute to risk of ovarian cancer among the majority of women when adjusting for known confounding factors. However, questions regarding the effect on certain subgroups, including long-term fertility drug users, women who remain nulligravid after fertility treatment, women with BRCA1 or BRCA2 mutations and borderline ovarian tumours, still remain. In addition, it may currently just be too early to determine whether there is an association between fertility drug use and ovarian cancer risk given that many of the exposed women are only now beginning to reach the ovarian cancer age range. Whether use of fertility drugs increases the risk of ovarian cancer is an important question that requires further investigation, in particular given the large number of women utilizing fertility treatments. Fortunately, results from recent studies have been mainly reassuring. Large well designed studies with sufficient follow-up time are needed to further evaluate the effects of fertility treatments within subgroups defined by patient and tumour characteristics.
Expression of Stem Cell Markers in Preinvasive Tubal Lesions of Ovarian Carcinoma.
Chene, G; Ouellet, V; Rahimi, K; Barres, V; Meunier, L; De Ladurantaye, M; Provencher, D; Mes-Masson, A M
2015-01-01
In order to better understand the ovarian serous carcinogenic process with tubal origin, we investigated the expression of stem cell markers in premalignant tubal lesions (serous tubal intraepithelial carcinoma or STIC). We found an increased stem cell marker density in the normal fallopian tube followed by a high CD117 and a low ALDH and CD44 expression in STICs raising the question of the role of the stem cell markers in the serous carcinogenic process.
Expression of Stem Cell Markers in Preinvasive Tubal Lesions of Ovarian Carcinoma
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G. Chene
2015-01-01
Full Text Available In order to better understand the ovarian serous carcinogenic process with tubal origin, we investigated the expression of stem cell markers in premalignant tubal lesions (serous tubal intraepithelial carcinoma or STIC. We found an increased stem cell marker density in the normal fallopian tube followed by a high CD117 and a low ALDH and CD44 expression in STICs raising the question of the role of the stem cell markers in the serous carcinogenic process.
Risk for Sporadic Breast Cancer in Ataxia Telangiectasia Heterozygotes
2001-08-01
cervix , kidney and colon cancer ) and 1 large benign ovarian tumour (serous cystadenoma), DNp73 was specifically upregulated 3 to 78-fold in 10...solos, alliances and feuds among family members. This article is in press in Biochimica and Biophysica Acta Reviews on Cancer . Appendix: manuscript...role in carcinogenesis, no related genes were known for HPV -mediated cancers (23). However, the adenovirus E4orf6 20 years. In 1997, two novel family
Does Breast or Ovarian Cancer Run in Your Family?
... Does Breast or Ovarian Cancer Run in Your Family? Recommend on Facebook Tweet Share Compartir If you ... get ovarian cancer by age 70. Does Your Family Health History Put You At Risk? Collect your ...
Polycystic ovary syndrome, oligomenorrhea, and risk of ovarian cancer histotypes
DEFF Research Database (Denmark)
Harris, Holly R; Babic, Ana; Webb, Penelope M
2018-01-01
BACKGROUND: Polycystic ovary syndrome (PCOS), and one if its distinguishing characteristics, oligomenorrhea, have both been associated with ovarian cancer risk in some but not all studies. However, these associations have been rarely been examined by ovarian cancer histotypes which may explain...... the lack of clear associations reported in previous studies. METHODS: We analyzed data from 14 case-control studies including 16,594 women with invasive ovarian cancer (n=13,719) or borderline ovarian disease (n=2,875) and 17,718 controls. Adjusted study-specific odds ratios (ORs) were calculated using...... logistic regression and combined using random-effects meta-analysis. Pooled histotype-specific ORs were calculated using polytomous logistic regression. RESULTS: Women reporting menstrual cycle length >35 days had decreased risk of invasive ovarian cancer compared to women reporting cycle length
Acute onset of ovarian dysfunction in young females after start of cancer treatment
DEFF Research Database (Denmark)
Mörse, Helena; Elfving, Maria; Lindgren, Anna
2013-01-01
Female childhood cancer survivors are at risk of ovarian failure and premature ovarian insufficiency. We hereby present an interim analysis of a prospective observational study of ovarian function during cancer treatment of young females in relation to clinical factors.......Female childhood cancer survivors are at risk of ovarian failure and premature ovarian insufficiency. We hereby present an interim analysis of a prospective observational study of ovarian function during cancer treatment of young females in relation to clinical factors....
Chlamydia trachomatis Serology in Women with and without Ovarian Cancer
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Roberta B. Ness
2008-01-01
Full Text Available Pelvic inflammation has been implicated in the genesis of ovarian cancer. We conducted serologic measurements of Chlamydia trachomatis antibodies as a surrogate marker of chlamydial pelvic inflammatory disease. Women with ovarian cancer (n=521 and population-based controls (n=766 were tested. IgG antibodies to serovar D of chlamydia elementary bodies (EBs were detected using an ELISA assay. The odds of having ovarian cancer among women with the highest titers (≥0.40 OD units were 0.6 (95% CI 0.4–0.9. These data do not support our earlier finding of elevated titers for antibodies to C. trachomatis among women with ovarian cancer.
McGee, Jacob; Giannakeas, Vasily; Karlan, Beth; Lubinski, Jan; Gronwald, Jacek; Rosen, Barry; McLaughlin, John; Risch, Harvey; Sun, Ping; Foulkes, William D; Neuhausen, Susan L; Kotsopoulos, Joanne; Narod, Steven A
2017-05-01
Preventive breast surgery and MRI screening are offered to unaffected BRCA mutation carriers. The clinical benefit of these two modalities has not been evaluated among mutation carriers with a history of ovarian cancer. Thus, we sought to determine whether or not BRCA mutation carriers with ovarian cancer would benefit from preventive mastectomy or from MRI screening. First, the annual mortality rate for ovarian cancer patients was estimated for a cohort of 178 BRCA mutation carriers from Ontario, Canada. Next, the actuarial risk of developing breast cancer was estimated using an international registry of 509 BRCA mutation carriers with ovarian cancer. A series of simulations was conducted to evaluate the reduction in the probability of death (from all causes) associated with mastectomy and with MRI-based breast surveillance. Cox proportional hazards models were used to evaluate the impacts of mastectomy and MRI screening on breast cancer incidence as well as on all-cause mortality. Twenty (3.9%) of the 509 patients developed breast cancer within ten years following ovarian cancer diagnosis. The actuarial risk of developing breast cancer at ten years post-diagnosis, conditional on survival from ovarian cancer and other causes of mortality was 7.8%. Based on our simulation results, among all BRCA mutation-carrying patients diagnosed with stage III/IV ovarian cancer at age 50, the chance of dying before age 80 was reduced by less than 1% with MRI and by less than 2% with mastectomy. Greater improvements in survival with MRI or mastectomy were observed for women who had already survived 10years after ovarian cancer, and for women with stage I or II ovarian cancer. Among BRCA mutation-carrying ovarian cancer patients without a personal history of breast cancer, neither preventive mastectomy nor MRI screening is warranted, except for those who have survived ovarian cancer without recurrence for ten years and for those with early stage ovarian cancer. Copyright © 2017
Distinct gene expression profiles in ovarian cancer linked to Lynch syndrome
DEFF Research Database (Denmark)
Jönsson, Jenny-Maria; Bartuma, Katarina; Dominguez-Valentin, Mev
2014-01-01
Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer...... with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic...... ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified...
Completeness of pedigree and family cancer history for ovarian cancer patients.
Son, Yedong; Lim, Myong Cheol; Seo, Sang Soo; Kang, Sokbom; Park, Sang Yoon
2014-10-01
To investigate the completeness of pedigree and of number of pedigree analysis to know the acceptable familial history in Korean women with ovarian cancer. Interview was conducted in 50 ovarian cancer patients for obtaining familial history three times over the 6 weeks. The completeness of pedigree is estimated in terms of familial history of disease (cancer), health status (health living, disease and death), and onset age of disease and death. The completion of pedigree was 79.3, 85.1, and 85.6% at the 1st, 2nd, and 3rd time of interview and the time for pedigree analysis was 34.3, 10.8, and 3.1 minutes, respectively. The factors limiting pedigree analysis were as follows: out of contact with their relatives (38%), no living ancestors who know the family history (34%), dispersed family member because of the Korean War (16%), unknown cause of death (12%), reluctance to ask medical history of relatives (10%), and concealing their ovarian cancer (10%). The percentage of cancers revealed in 1st (2%) and 2nd degree (8%) relatives were increasing through surveys, especially colorectal cancer related with Lynch syndrome (4%). Analysis of pedigree at least two times is acceptable in Korean woman with ovarian cancer from the first study. The completion of pedigree is increasing, while time to take family history is decreasing during three time survey.
Chemotherapy-induced hyaluronan production: a novel chemoresistance mechanism in ovarian cancer
International Nuclear Information System (INIS)
Ricciardelli, Carmela; Ween, Miranda P; Lokman, Noor A; Tan, Izza A; Pyragius, Carmen E; Oehler, Martin K
2013-01-01
Hyaluronan (HA) an important component of the extracellular matrix, has been linked to tumor progression and drug resistance in several malignancies. However, limited data is available for ovarian cancer. This study investigated the role of hyaluronan (HA) and a potential link between the HA-CD44 pathway and membrane ATP binding cassette (ABC) transporter proteins in ovarian cancer chemoresistance. We investigated the ability of HA to block the cytotoxic effects of the chemotherapy drug carboplatin, and to regulate the expression of ABC transporters in ovarian cancer cells. We also examined HA serum levels in ovarian cancer patients prior to and following chemotherapy and assessed its prognostic relevance. HA increased the survival of carboplatin treated ovarian cancer cells expressing the HA receptor, CD44 (OVCAR-5 and OV-90). Carboplatin significantly increased expression of HAS2, HAS3 and ABCC2 and HA secretion in ovarian cancer cell conditioned media. Serum HA levels were significantly increased in patients following platinum based chemotherapy and at both 1st and 2nd recurrence when compared with HA levels prior to treatment. High serum HA levels (>50 μg/ml) prior to chemotherapy treatment were associated with significantly reduced progression-free (P = 0.014) and overall survival (P = 0.036). HA production in ovarian cancer cells was increased in cancer tissues collected following chemotherapy treatment and at recurrence. Furthermore HA treatment significantly increased the expression of ABC drug transporters (ABCB3, ABCC1, ABCC2, and ABCC3), but only in ovarian cancer cells expressing CD44. The effects of HA and carboplatin on ABC transporter expression in ovarian cancer cells could be abrogated by HA oligomer treatment. Importantly, HA oligomers increased the sensitivity of chemoresistant SKOV3 cells to carboplatin. Our findings indicate that carboplatin chemotherapy induces HA production which can contribute to chemoresistance by regulating ABC
Directory of Open Access Journals (Sweden)
Yun-Jie Zhang
2015-01-01
Full Text Available Objective: To investigate the value of lysophosphatidic acid (LPA in the diagnosis of ovarian cancer. Materials and Methods: We first performed a hospital-based, case-control study involving 123 ovarian cancer patients and 101 benign ovarian tumor patients, and then conducted a meta-analysis with 19 case-control studies to assess the correlation between ovarian cancer and plasma LPA levels. Results: The case-control study results demonstrated that ovarian cancer patients have increased LPA and cancer antigen (CA-125 levels compared to patients with benign ovarian tumor (LPA: Ovarian cancer vs benign ovarian tumor: 5.28 ± 1.52 vs 1.82 ± 0.77 μmol/L; CA-125: Ovarian cancer vs benign ovarian tumor: 87.17 ± 45.81 vs. 14.03 ± 10.14 U/mL, which showed statistically significant differences (both P < 0.05. LPA with advanced sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate of diagnosis excelled CA-125 in the diagnosis of ovarian cancer (both P < 0.05. The areas under the receiver operating characteristic (ROC curve in the diagnosis of ovarian cancer (LPA: 0.983; CA-125: 0.910 were statistically significant compared with the reference (both P < 0.001 and the difference of the areas of ROC curve between LPA and CA-125 in the diagnosis of ovarian cancer showed statistically significant difference (P < 0.05. The meta-analysis results suggested that plasma LPA levels were higher in ovarian cancer tissues than in benign tissues (standardized mean difference (SMD =2.36, 95% confidence interval (CI: 1.61-3.11, P < 0.001 and normal tissues (SMD = 2.32, 95% CI: 1.77-2.87, P < 0.001. Conclusion: LPA shows greater value in the diagnosis of ovarian cancer compared to CA-125 and may be employed as a biological index to diagnose ovarian cancer.
General Information About Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
... black women, but have decreased in both groups. Women who have a family history of ovarian cancer and/or certain inherited gene ... ovarian, fallopian tube, and primary peritoneal cancer: Personal history of breast cancer A woman who has had breast cancer has an increased ...
Ovarian Cancer Risk Prediction Models
Developing statistical models that estimate the probability of developing ovarian cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.
Niekerk, G.C. van; Bulten, J.; Verbeek, A.L.M.
2011-01-01
Background. Patients with epithelial ovarian cancer have a high risk of (non-)melanoma skin cancer. The association between histological variants of primary ovarian cancer and skin cancer is poorly documented. Objectives. To further evaluate the risk of skin cancer based on the histology of the
Jacobs, Ian J; Menon, Usha; Ryan, Andy; Gentry-Maharaj, Aleksandra; Burnell, Matthew; Kalsi, Jatinderpal K; Amso, Nazar N; Apostolidou, Sophia; Benjamin, Elizabeth; Cruickshank, Derek; Crump, Danielle N; Davies, Susan K; Dawnay, Anne; Dobbs, Stephen; Fletcher, Gwendolen; Ford, Jeremy; Godfrey, Keith; Gunu, Richard; Habib, Mariam; Hallett, Rachel; Herod, Jonathan; Jenkins, Howard; Karpinskyj, Chloe; Leeson, Simon; Lewis, Sara J; Liston, William R; Lopes, Alberto; Mould, Tim; Murdoch, John; Oram, David; Rabideau, Dustin J; Reynolds, Karina; Scott, Ian; Seif, Mourad W; Sharma, Aarti; Singh, Naveena; Taylor, Julie; Warburton, Fiona; Widschwendter, Martin; Williamson, Karin; Woolas, Robert; Fallowfield, Lesley; McGuire, Alistair J; Campbell, Stuart; Parmar, Mahesh; Skates, Steven J
2016-01-01
Summary Background Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality. Methods In this randomised controlled trial, we recruited postmenopausal women aged 50–74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. Findings Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202 638 women: 50 640 (25·0%) to MMS, 50 639 (25·0%) to USS, and 101 359 (50·0%) to no screening. 202 546 (>99·9%) women were eligible for analysis: 50 624 (>99·9%) women in the MMS group, 50 623 (>99·9%) in the USS group, and 101 299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345 570 MMS and 327 775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0–12·0), we diagnosed ovarian cancer in
Use of analgesic drugs and risk of ovarian cancer
DEFF Research Database (Denmark)
Ammundsen, Henriette B; Faber, Mette T; Jensen, Allan
2012-01-01
The role of analgesic drug use in development of ovarian cancer is not fully understood. We examined the association between analgesic use and risk of ovarian cancer. In addition, we examined whether the association differed according to histological types....
Appendectomy in primary and secondary staging operations for ovarian malignancy.
Rose, P G; Reale, F R; Fisher, A; Hunter, R E
1991-01-01
Appendectomy was performed at primary or secondary staging operations in 100 patients with ovarian malignancies. Of 80 patients who underwent appendectomy at the time of their primary surgery, 25 (31.2%) had appendiceal metastases. Among 47 patients who were believed to have disease limited to the pelvis at the time of surgery--stage I (N = 34), II (N = 7), IIIA (N = 5), and those designated stage IIIC solely on the basis of microscopic para-aortic nodal metastasis (N = 1)--the appendix was involved with disease in only two patients (4.3%). However, among 33 patients with advanced disease--stage IIIB (N = 6), IIIC except those designated IIIC solely on the basis of microscopic paraaortic nodal metastasis (N = 19), and IV (N = 8)--the appendix was involved with disease in 23 patients (69.7%) (P less than .001). Poorly differentiated tumors and serous histologic cell types more frequently metastasized to the appendix (64, 15, 6, and 8% for grades 3, 2, and 1 and borderline histology, respectively; P less than .001; and 48, 13, and 8% for serous, endometrioid, and mucinous; P less than .001). Of 20 patients who underwent appendectomy at their secondary staging procedure, two had metastases. Metastatic disease in the appendix was microscopic in nine of 27 patients. Because the frequency of appendiceal metastasis is similar to that of other metastatic sites in stages I and II ovarian cancer, it should be removed at primary staging procedures. Appendectomy should also be performed in patients with advanced ovarian malignancies if it contributes to cytoreduction or at the time of secondary staging procedures.
Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer.
Lawrenson, Kate; Iversen, Edwin S; Tyrer, Jonathan; Weber, Rachel Palmieri; Concannon, Patrick; Hazelett, Dennis J; Li, Qiyuan; Marks, Jeffrey R; Berchuck, Andrew; Lee, Janet M; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Bandera, Elisa V; Bean, Yukie; Beckmann, Matthias W; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Ann; Chen, Zhihua; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Plisiecka-Halasa, Joanna; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Eccles, Diana; Easton, Douglas T; Edwards, Robert P; Eilber, Ursula; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Gronwald, Jacek; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Jakubowska, Anna; Paul, James; Jensen, Allan; Karlan, Beth Y; Kjaer, Susanne Kruger; Kelemen, Linda E; Kellar, Melissa; Kelley, Joseph L; Kiemeney, Lambertus A; Krakstad, Camilla; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Cannioto, Rikki; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; Nevanlinna, Heli; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Narod, Steven A; Nedergaard, Lotte; Ness, Roberta B; Noor Azmi, Mat Adenan; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jennifer; Phelan, Catherine M; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Budzilowska, Agnieszka; Sellers, Thomas A; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Sucheston, Lara; Tangen, Ingvild L; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Timorek, Agnieszka; Tworoger, Shelley S; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Coetzee, Gerhard A; Freedman, Matthew L; Monteiro, Alvaro N A; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta; Pharoah, Paul D; Gayther, Simon A; Schildkraut, Joellen M
2015-11-01
Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
DEFF Research Database (Denmark)
Phelan, Catherine M; Tsai, Ya-Yu; Goode, Ellen L
2010-01-01
Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism...... in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming...... the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92-1.07). When a recessive model was fit, the results were unchanged. Test for heterogeneity of the odds ratios revealed consistency across the 14 replication...
Metabolomic Characterization of Ovarian Epithelial Carcinomas by HRMAS-NMR Spectroscopy
Directory of Open Access Journals (Sweden)
D. Ben Sellem
2011-01-01
Full Text Available Objectives. The objectives of the present study are to determine if a metabolomic study by HRMAS-NMR can (i discriminate between different histological types of epithelial ovarian carcinomas and healthy ovarian tissue, (ii generate statistical models capable of classifying borderline tumors and (iii establish a potential relationship with patient's survival or response to chemotherapy. Methods. 36 human epithelial ovarian tumor biopsies and 3 healthy ovarian tissues were studied using 1H HRMAS NMR spectroscopy and multivariate statistical analysis. Results. The results presented in this study demonstrate that the three histological types of epithelial ovarian carcinomas present an effective metabolic pattern difference. Furthermore, a metabolic signature specific of serous (N-acetyl-aspartate and mucinous (N-acetyl-lysine carcinomas was found. The statistical models generated in this study are able to predict borderline tumors characterized by an intermediate metabolic pattern similar to the normal ovarian tissue. Finally and importantly, the statistical model of serous carcinomas provided good predictions of both patient's survival rates and the patient's response to chemotherapy. Conclusions. Despite the small number of samples used in this study, the results indicate that metabolomic analysis of intact tissues by HRMAS-NMR is a promising technique which might be applicable to the therapeutic management of patients.
DEFF Research Database (Denmark)
Ricardo, Sara; da Silva, Lara Patricia Marcos; Pereira, Daniela
2015-01-01
The CA125 assay detects circulating MUC16 and is one of the most widely used cancer biomarkers for the follow-up of ovarian cancer. We previously demonstrated that detection of aberrant cancer-associated glycoforms of MUC16 as well as MUC1 in circulation could improve the yield of these serum ass...
The utility of serum N-ERC/mesothelin as a biomarker of ovarian carcinoma.
Saeki, Harumi; Hashizume, Akane; Izumi, Hiroshi; Suzuki, Fujihiko; Ishi, Kazuhisa; Nojima, Michio; Maeda, Masahiro; Hino, Okio
2012-10-01
Ovarian carcinoma has been difficult to diagnose at an early stage. Recently, it has been recognized that the measurement of blood N-ERC/mesothelin levels aids early detection in and postoperative therapeutic monitoring of patients with mesothelioma, who have been exposed to asbestos. ERC/mesothelin has also been reported to be expressed in ovarian carcinoma. We determined serum N-ERC/mesothelin levels in patients with ovarian carcinoma using an enzyme-linked immunosorbent assay (ELISA). In addition, we immunohistochemically evaluated surgically resected specimens for C-ERC/mesothelin expression. As a result, of the 32 patients with ovarian tumors (18 carcinoma, 2 borderline tumors), one patient with serous adenocarcinoma showed increased N-ERC/ mesothelin levels. Immunohistochemically, of the 20 ovarian tumor (carcinoma and borderline tumor) specimens evaluated for serum N-ERC/mesothelin, 9 (45.0%) were positive for C-ERC/mesothelin. The C-ERC/mesothelin-positive specimens were found to be serous and clear cell adenocarcinomas. If serum N-ERC/mesothelin, which is considered useful for early detection in and therapeutic monitoring of patients with mesothelioma, may also be used for ovarian carcinoma monitoring, it may be a valuable serum tumor marker for the early detection of ovarian carcinoma.
Prescription Use of Paracetamol and Risk for Ovarian Cancer in Denmark
DEFF Research Database (Denmark)
Baandrup, Louise; Friis, Søren; Dehlendorff, Christian
2014-01-01
It has been suggested that paracetamol reduces the risk for ovarian cancer. We examined the association between prescription use of paracetamol and ovarian cancer risk in a nationwide case-control study nested within the Danish female population. Case patients (n = 3471) were all women with a first......% confidence intervals (CIs) for ovarian cancer associated with use of paracetamol or nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs). All statistical tests were two-sided. Use of paracetamol was associated with a reduced odds ratio for ovarian cancer (OR = 0.82; 95% CI = 0.74 to 0.92; P ...) compared with nonuse, and the odds ratio decreased further with long-term (≥10 years), high-intensity paracetamol use (OR = 0.45; 95% CI = 0.24 to 0.86; P = .02). Use of nonaspirin NSAIDs was not associated with ovarian cancer risk....
Targeting the urokinase plasminogen activator receptor inhibits ovarian cancer metastasis.
Kenny, Hilary A; Leonhardt, Payton; Ladanyi, Andras; Yamada, S Diane; Montag, Anthony; Im, Hae Kyung; Jagadeeswaran, Sujatha; Shaw, David E; Mazar, Andrew P; Lengyel, Ernst
2011-02-01
To understand the functional and preclinical efficacy of targeting the urokinase plasminogen activator receptor (u-PAR) in ovarian cancer. Expression of u-PAR was studied in 162 epithelial ovarian cancers, including 77 pairs of corresponding primary and metastatic tumors. The effect of an antibody against u-PAR (ATN-658) on proliferation, adhesion, invasion, apoptosis, and migration was assessed in 3 (SKOV3ip1, HeyA8, and CaOV3) ovarian cancer cell lines. The impact of the u-PAR antibody on tumor weight, number, and survival was examined in corresponding ovarian cancer xenograft models and the mechanism by which ATN-658 blocks metastasis was explored. Only 8% of all ovarian tumors were negative for u-PAR expression. Treatment of SKOV3ip1, HeyA8, and CaOV3 ovarian cancer cell lines with the u-PAR antibody inhibited cell invasion, migration, and adhesion. In vivo, anti-u-PAR treatment reduced the number of tumors and tumor weight in CaOV3 and SKOV3ip1 xenografts and reduced tumor weight and increased survival in HeyA8 xenografts. Immunostaining of CaOV3 xenograft tumors and ovarian cancer cell lines showed an increase in active-caspase 3 and TUNEL staining. Treatment with u-PAR antibody inhibited α(5)-integrin and u-PAR colocalization on primary human omental extracellular matrix. Anti-u-PAR treatment also decreased the expression of urokinase, u-PAR, β(3)-integrin, and fibroblast growth factor receptor-1 both in vitro and in vivo. This study shows that an antibody against u-PAR reduces metastasis, induces apoptosis, and reduces the interaction between u-PAR and α(5)-integrin. This provides a rationale for targeting the u-PAR pathway in patients with ovarian cancer and for further testing of ATN-658 in this indication. ©2010 AACR.
[Screening of ovarian cancer : not for tomorrow].
Vuilleumier, Aurélie; Labidi-Galy, Intidhar
2017-05-17
As the worldwide incidence of cancer continuously rises, one of the measures to reduce mortality is early diagnosis while the disease is still curable. Colonoscopy screening and PAP-smears are worthwhile examples illustrating the impact of early diagnosis on mortality. Ovarian cancer is the first cause of mortality by gynecological cancers in Switzerland (incidence of 600 new cases / year), mostly diagnosed at advanced stages with a poor prognosis. Could surveillance measures improve survival ? Three large-scale randomized control trials failed to show mortality reduction from ovarian cancer with the methods currently available. A better comprehension of pathogenesis can allow the development of new strategies of screening.
Are ovarian cancer stem cells the target for innovative immunotherapy?
Directory of Open Access Journals (Sweden)
Wang L
2018-05-01
Full Text Available Liang Wang, Tianmin Xu, Manhua Cui Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, Changchun, Jilin, People’s Republic of China Abstract: Cancer stem cells (CSCs, a subpopulation of cancer cells with the ability of self-renewal and differentiation, are believed to be responsible for tumor generation, progression, metastasis, and relapse. Ovarian cancer, the most malignant gynecological cancer, has consistent pathology behavior with CSC model, which suggests that therapies based on ovarian cancer stem cells (OCSCs can gain a more successful prognosis. Much evidence has proved that epigenetic mechanism played an important role in tumor formation and sustainment. Since CSCs are generally resistant to conventional therapies (chemotherapy and radiotherapy, immunotherapy is a more effective method that has been implemented in the clinic. Chimeric antigen receptor (CAR- T cell, an adoptive cellular immunotherapy, which results in apparent elimination of tumor in both hematologic and solid cancers, could be used for ovarian cancer. This review covers the basic conception of CSCs and OCSCs, the implication of epigenetic mechanism underlying cancer evolution considering CSC model, the immunotherapies reported for ovarian cancer targeting OCSCs currently, and the relationship between immune system and hierarchy cancer organized by CSCs. Particularly, the promising prospects and potential pitfalls of targeting OCSC surface markers to design CAR-T cellular immunotherapy are discussed here. Keywords: cancer stem cells, ovarian cancer, epigenetics, tumor cell surface marker, immunotherapy, CAR
Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup
DEFF Research Database (Denmark)
Wilson, M K; Pujade-Lauraine, E; Aoki, D
2017-01-01
This manuscript reports the consensus statements regarding recurrent ovarian cancer (ROC), reached at the fifth Ovarian Cancer Consensus Conference (OCCC), which was held in Tokyo, Japan, in November 2015. Three important questions were identified: (i) What are the subgroups for clinical trials i...... including pre-defined patient reported outcomes (PROs), time to second subsequent therapy (TSST), or time until definitive deterioration of quality of life (TUDD)....
Directory of Open Access Journals (Sweden)
Fanayan Susan
2010-09-01
Full Text Available Abstract Background The four-transmembrane MAL2 protein is frequently overexpressed in breast carcinoma, and MAL2 overexpression is associated with gain of the corresponding locus at chromosome 8q24.12. Independent expression microarray studies predict MAL2 overexpression in ovarian carcinoma, but these had remained unconfirmed. MAL2 binds tumor protein D52 (TPD52, which is frequently overexpressed in ovarian carcinoma, but the clinical significance of MAL2 and TPD52 overexpression was unknown. Methods Immunohistochemical analyses of MAL2 and TPD52 expression were performed using tissue microarray sections including benign, borderline and malignant epithelial ovarian tumours. Inmmunohistochemical staining intensity and distribution was assessed both visually and digitally. Results MAL2 and TPD52 were significantly overexpressed in high-grade serous carcinomas compared with serous borderline tumours. MAL2 expression was highest in serous carcinomas relative to other histological subtypes, whereas TPD52 expression was highest in clear cell carcinomas. MAL2 expression was not related to patient survival, however high-level TPD52 staining was significantly associated with improved overall survival in patients with stage III serous ovarian carcinoma (log-rank test, p Conclusions MAL2 is frequently overexpressed in ovarian carcinoma, and TPD52 overexpression is a favourable independent prognostic marker of potential value in the management of ovarian carcinoma patients.
Advances in circulating microRNAs as diagnostic and prognostic markers for ovarian cancer
International Nuclear Information System (INIS)
Zheng, Hong; Liu, Jia-Yu; Song, Feng-Ju; Chen, Ke-Xin
2013-01-01
Ovarian cancer is one of the most lethal malignant gynecological tumors. More than 70% of patients with ovarian cancer are diagnosed at advanced stage. The 5-year survival in patients with advanced ovarian cancer is less than 30% because of the lack of effective biomarkers for diagnosis, prognosis, and personalized treatment. MicroRNA (miR) is a class of small noncoding RNAs that negatively regulate gene expression primarily through post-transcriptional repression. Many studies on tissue miR in ovarian cancer have been carried out and show great potential in clinical practice. However, tissue samples are not easily available because sampling causes injury. Researchers have started to focus on plasma/serum miR, assuming that blood samples may replace tissue samples in miR research in the future. Plasma/serum miR research is still in its early stages. Studies on its function in the early diagnosis of ovarian cancer have achieved some progress, but plasma/serum miR profiling for prognosis and personalized treatment of ovarian cancer remains unknown. A thorough understanding of the function of plasma/serum miR in ovarian cancer will facilitate early diagnosis and improve treatment for ovarian cancer
Ovarian Autoantibodies Predict Ovarian Cancer
2010-11-01
Expression of thymidine 459 phosphorylase in epithelial ovarian cancer: correlation with angiogenesis, apoptosis , and 460 ultrasound-derived peak...trafficking, activation of S1P1 can promote or inhibit apoptosis of 41 immune cells depending on the balance of cytokines [7]. Knockout of S1P1 (LP(B1...EDG-1) in 42 mice is embryologically lethal [8]. S1P1 also has a role in inflammatory disease such as graft 43 versus host disease and multiple
Benefits and risks of ovarian function and reproduction for cancer development and prevention.
Schindler, Adolf E
2011-12-01
Ovarian function and menstrual cycle disturbances, pregnancy, and reproductive medicine procedures can either increase gynecological cancer risk or prevent cancer development. For ovarian cancer development, there are two hypotheses, which are connected with ovulation and gonadotropin secretion. Most of the ovarian cancers seem to be derived from displaced ovarian surfice epithelial cells. One year of ovulatory cycles increases the ovarian cancer risk by 6%. Ovulation between 22 and 29 years of age causes the highest risk increase per year. In contrast, progesterone or progestins appear to create protection. Lifestyle can affect or modify ovarian cancer risk. Breast cancer risk is very much related to age of menarche and menopause, pregnancy, and breast feeding. All of which are related to ovarian function and progestogenic impact that translates either into breast cancer risk increase or decrease. This is modified by body mass index, physical activity, and lifestyle in general. The risk of endometrial cancer is most closely related to endogenous progesterone during the menstrual cycle and pregnancy or by exogenous progestogens as in oral contraceptives. These effects are progestogen dose and time dependent. Endometrial cancer risk can also be increased by estrogen-producing tumors or long-term estrogen treatment.
Obesity and risk of ovarian cancer subtypes
DEFF Research Database (Denmark)
Olsen, Catherine M; Nagle, Christina M; Whiteman, David C
2013-01-01
Whilst previous studies have reported that higher BMI increases a woman's risk of developing ovarian cancer, associations for the different histological subtypes have not been well defined. As the prevalence of obesity has increased dramatically, and classification of ovarian histology has improv...
Ovarian cancer and the immune system - The role of targeted therapies.
Turner, Taylor B; Buchsbaum, Donald J; Straughn, J Michael; Randall, Troy D; Arend, Rebecca C
2016-08-01
The majority of patients with epithelial ovarian cancer are diagnosed with advanced disease. While many of these patients will respond initially to chemotherapy, the majority will relapse and die of their disease. Targeted therapies that block or activate specific intracellular signaling pathways have been disappointing. In the past 15years, the role of the immune system in ovarian cancer has been investigated. Patients with a more robust immune response, as documented by the presence of lymphocytes infiltrating within their tumor, have increased survival and better response to chemotherapy. In addition, a strong immunosuppressive environment often accompanies ovarian cancer. Recent research has identified potential therapies that leverage the immune system to identify and destroy tumor cells that previously evaded immunosurveillance mechanisms. In this review, we discuss the role of the immune system in ovarian cancer and focus on specific pathways and molecules that show a potential for targeted therapy. We also review the ongoing clinical trials using targeted immunotherapy in ovarian cancer. The role of targeted immunotherapy in patients with ovarian cancer represents a field of growing research and clinical importance. Copyright © 2016 Elsevier Inc. All rights reserved.
DEFF Research Database (Denmark)
Domanska, K; Malander, S; Måsbäck, A
2007-01-01
age is a hallmark of heredity, and ovarian cancers associated with HNPCC have been demonstrated to develop at a particularly early age. We used the Swedish Cancer Registry to identify a population-based series of 98 invasive epithelial ovarian cancers that developed before 40 years. Mucinous......At least one of ten patients with ovarian cancer is estimated to develop their tumor because of heredity with the breast and ovarian cancer syndrome due to mutations in the BRCA1 and BRCA2 genes and hereditary nonpolyposis colorectal cancer (HNPCC) being the major genetic causes. Cancer at young...... and endometrioid cancers were overrepresented and were diagnosed in 27% and 16% of the tumors, respectively. Immunostaining using antibodies against MLH1, PMS2, MSH2, and MSH6 was used to assess the mismatch-repair status and revealed loss of expression of MLH1/PMS2 in two cases, loss of MSH2/MSH6 in one case...
RNA-based ovarian cancer research from 'a gene to systems biomedicine' perspective.
Gov, Esra; Kori, Medi; Arga, Kazim Yalcin
2017-08-01
Ovarian cancer remains the leading cause of death from a gynecologic malignancy, and treatment of this disease is harder than any other type of female reproductive cancer. Improvements in the diagnosis and development of novel and effective treatment strategies for complex pathophysiologies, such as ovarian cancer, require a better understanding of disease emergence and mechanisms of progression through systems medicine approaches. RNA-level analyses generate new information that can help in understanding the mechanisms behind disease pathogenesis, to identify new biomarkers and therapeutic targets and in new drug discovery. Whole RNA sequencing and coding and non-coding RNA expression array datasets have shed light on the mechanisms underlying disease progression and have identified mRNAs, miRNAs, and lncRNAs involved in ovarian cancer progression. In addition, the results from these analyses indicate that various signalling pathways and biological processes are associated with ovarian cancer. Here, we present a comprehensive literature review on RNA-based ovarian cancer research and highlight the benefits of integrative approaches within the systems biomedicine concept for future ovarian cancer research. We invite the ovarian cancer and systems biomedicine research fields to join forces to achieve the interdisciplinary caliber and rigor required to find real-life solutions to common, devastating, and complex diseases such as ovarian cancer. CAF: cancer-associated fibroblasts; COG: Cluster of Orthologous Groups; DEA: disease enrichment analysis; EOC: epithelial ovarian carcinoma; ESCC: oesophageal squamous cell carcinoma; GSI: gamma secretase inhibitor; GO: Gene Ontology; GSEA: gene set enrichment analyzes; HAS: Hungarian Academy of Sciences; lncRNAs: long non-coding RNAs; MAPK/ERK: mitogen-activated protein kinase/extracellular signal-regulated kinases; NGS: next-generation sequencing; ncRNAs: non-coding RNAs; OvC: ovarian cancer; PI3K
International Nuclear Information System (INIS)
Sun, Fei; Ding, Wen; He, Jie-Hua; Wang, Xiao-Jing; Ma, Ze-Biao; Li, Yan-Fang
2015-01-01
Stomatin-like protein 2 (SLP-2, also known as STOML2) is a stomatin homologue of uncertain function. SLP-2 overexpression has been suggested to be associated with cancer progression, resulting in adverse clinical outcomes in patients. Our study aim to investigate SLP-2 expression in epithelial ovarian cancer cells and its correlation with patient survival. SLP-2 mRNA and protein expression levels were analysed in five epithelial ovarian cancer cell lines and normal ovarian epithelial cells using real-time PCR and western blotting analysis. SLP-2 expression was investigated in eight matched-pair samples of epithelial ovarian cancer and adjacent noncancerous tissues from the same patients. Using immunohistochemistry, we examined the protein expression of paraffin-embedded specimens from 140 patients with epithelial ovarian cancer, 20 cases with borderline ovarian tumours, 20 cases with benign ovarian tumours, and 20 cases with normal ovarian tissues. Statistical analyses were applied to evaluate the clinicopathological significance of SLP-2 expression. SLP-2 mRNA and protein expression levels were significantly up-regulated in epithelial ovarian cancer cell lines and cancer tissues compared with normal ovarian epithelial cells and adjacent noncancerous ovarian tissues. Immunohistochemistry analysis revealed that the relative overexpression of SLP-2 was detected in 73.6 % (103/140) of the epithelial ovarian cancer specimens, 45.0 % (9/20) of the borderline ovarian specimens, 30.0 % (6/20) of the benign ovarian specimens and none of the normal ovarian specimens. SLP-2 protein expression in epithelial ovarian cancer was significantly correlated with the tumour stage (P < 0.001). Epithelial ovarian cancer patients with higher SLP-2 protein expression levels had shorter progress free survival and overall survival times compared to patients with lower SLP-2 protein expression levels. Multivariate analyses showed that SLP-2 expression levels were an independent prognostic
Identifying novel hypoxia-associated markers of chemoresistance in ovarian cancer.
LENUS (Irish Health Repository)
McEvoy, Lynda M
2015-01-01
Ovarian cancer is associated with poor long-term survival due to late diagnosis and development of chemoresistance. Tumour hypoxia is associated with many features of tumour aggressiveness including increased cellular proliferation, inhibition of apoptosis, increased invasion and metastasis, and chemoresistance, mostly mediated through hypoxia-inducible factor (HIF)-1α. While HIF-1α has been associated with platinum resistance in a variety of cancers, including ovarian, relatively little is known about the importance of the duration of hypoxia. Similarly, the gene pathways activated in ovarian cancer which cause chemoresistance as a result of hypoxia are poorly understood. This study aimed to firstly investigate the effect of hypoxia duration on resistance to cisplatin in an ovarian cancer chemoresistance cell line model and to identify genes whose expression was associated with hypoxia-induced chemoresistance.
Mathematical Models of Breast and Ovarian Cancers
Botesteanu, Dana-Adriana; Lipkowitz, Stanley; Lee, Jung-Min; Levy, Doron
2016-01-01
Women constitute the majority of the aging United States (US) population, and this has substantial implications on cancer population patterns and management practices. Breast cancer is the most common women's malignancy, while ovarian cancer is the most fatal gynecological malignancy in the US. In this review we focus on these subsets of women's cancers, seen more commonly in postmenopausal and elderly women. In order to systematically investigate the complexity of cancer progression and response to treatment in breast and ovarian malignancies, we assert that integrated mathematical modeling frameworks viewed from a systems biology perspective are needed. Such integrated frameworks could offer innovative contributions to the clinical women's cancers community, since answers to clinical questions cannot always be reached with contemporary clinical and experimental tools. Here, we recapitulate clinically known data regarding the progression and treatment of the breast and ovarian cancers. We compare and contrast the two malignancies whenever possible, in order to emphasize areas where substantial contributions could be made by clinically inspired and validated mathematical modeling. We show how current paradigms in the mathematical oncology community focusing on the two malignancies do not make comprehensive use of, nor substantially reflect existing clinical data, and we highlight the modeling areas in most critical need of clinical data integration. We emphasize that the primary goal of any mathematical study of women's cancers should be to address clinically relevant questions. PMID:27259061
International Nuclear Information System (INIS)
Byrne, Jennifer A; Sutherland, Robert L; Fazio, Anna de; O'Brien, Philippa M; Maleki, Sanaz; Hardy, Jayne R; Gloss, Brian S; Murali, Rajmohan; Scurry, James P; Fanayan, Susan; Emmanuel, Catherine; Hacker, Neville F
2010-01-01
The four-transmembrane MAL2 protein is frequently overexpressed in breast carcinoma, and MAL2 overexpression is associated with gain of the corresponding locus at chromosome 8q24.12. Independent expression microarray studies predict MAL2 overexpression in ovarian carcinoma, but these had remained unconfirmed. MAL2 binds tumor protein D52 (TPD52), which is frequently overexpressed in ovarian carcinoma, but the clinical significance of MAL2 and TPD52 overexpression was unknown. Immunohistochemical analyses of MAL2 and TPD52 expression were performed using tissue microarray sections including benign, borderline and malignant epithelial ovarian tumours. Inmmunohistochemical staining intensity and distribution was assessed both visually and digitally. MAL2 and TPD52 were significantly overexpressed in high-grade serous carcinomas compared with serous borderline tumours. MAL2 expression was highest in serous carcinomas relative to other histological subtypes, whereas TPD52 expression was highest in clear cell carcinomas. MAL2 expression was not related to patient survival, however high-level TPD52 staining was significantly associated with improved overall survival in patients with stage III serous ovarian carcinoma (log-rank test, p < 0.001; n = 124) and was an independent predictor of survival in the overall carcinoma cohort (hazard ratio (HR), 0.498; 95% confidence interval (CI), 0.34-0.728; p < 0.001; n = 221), and in serous carcinomas (HR, 0.440; 95% CI, 0.294-0.658; p < 0.001; n = 182). MAL2 is frequently overexpressed in ovarian carcinoma, and TPD52 overexpression is a favourable independent prognostic marker of potential value in the management of ovarian carcinoma patients
Laparoscopic optical coherence tomographic imaging of human ovarian cancer
Hariri, Lida P.; Bonnema, Garret T.; Schmidt, Kathy; Korde, Vrushali; Winkler, Amy M.; Hatch, Kenneth; Brewer, Molly; Barton, Jennifer K.
2009-02-01
Ovarian cancer is the fourth leading cause of cancer-related death among women. If diagnosed at early stages, 5-year survival rate is 94%, but drops to 68% for regional disease and 29% for distant metastasis; only 19% of cases are diagnosed at early, localized stages. Optical coherence tomography is a recently emerging non-destructive imaging technology, achieving high axial resolutions (10-20 µm) at imaging depths up to 2 mm. Previously, we studied OCT in normal and diseased human ovary ex vivo. Changes in collagen were suggested with several images that correlated with changes in collagen seen in malignancy. Areas of necrosis and blood vessels were also visualized using OCT, indicative of an underlying tissue abnormality. We recently developed a custom side-firing laparoscopic OCT (LOCT) probe fabricated for in vivo imaging. The LOCT probe, consisting of a 38 mm diameter handpiece terminated in a 280 mm long, 4.6 mm diameter tip for insertion into the laparoscopic trocar, is capable of obtaining up to 9.5 mm image lengths at 10 µm axial resolution. In this pilot study, we utilize the LOCT probe to image one or both ovaries of 17 patients undergoing laparotomy or transabdominal endoscopy and oophorectomy to determine if OCT is capable of differentiating normal and neoplastic ovary. We have laparoscopically imaged the ovaries of seventeen patients with no known complications. Initial data evaluation reveals qualitative distinguishability between the features of undiseased post-menopausal ovary and the cystic, non-homogenous appearance of neoplastic ovary such as serous cystadenoma and endometroid adenocarcinoma.
Update on fertility preservation in young women undergoing breast cancer and ovarian cancer therapy.
Lambertini, Matteo; Ginsburg, Elizabeth S; Partridge, Ann H
2015-02-01
The purpose of the article is to review the available options for fertility preservation in patients with breast and ovarian cancer, and the special issues faced by BRCA mutation carriers. Future fertility is an important consideration for many young patients with cancer. There are both experimental and standard available strategies for patients with breast and ovarian cancer to preserve fertility, and each has potential advantages and disadvantages. Embryo cryopreservation is widely available with a highly successful track record. Improvements in laboratory techniques have led to oocyte cryopreservation recently being recategorized as nonexperimental. Conservative gynecologic surgery is a standard consideration for patients with stage I ovarian cancer who desire future fertility. Ovarian tissue cryopreservation as well as ovarian suppression with luteinizing hormone-releasing hormone analogs during chemotherapy are considered experimental methods at this time, although recent data suggest both safety and efficacy for the use of luteinizing hormone-releasing hormone analogs in women receiving (neo)adjuvant chemotherapy for breast cancer. Special issues should be considered for women with BRCA mutations because of the need to undergo preventive surgery at young age. Multidisciplinary teams and well functioning relationships between the oncology and reproductive units are crucial to manage the fertility issues of young women with cancer.
Levels of Distress in Women at Risk for Ovarian Cancer
National Research Council Canada - National Science Library
Kash, Kathryn M
2008-01-01
The overall goal of this study was to determine the levels of distress in women with a family history of ovarian cancer and to identify the mediating factors between risk of developing ovarian cancer and distress...
Carter, Rebecca R; DiFeo, Analisa; Bogie, Kath; Zhang, Guo-Qiang; Sun, Jiayang
2014-01-01
Ovarian cancer is the most lethal gynecologic disease in the United States, with more women dying from this cancer than all gynecological cancers combined. Ovarian cancer has been termed the "silent killer" because some patients do not show clear symptoms at an early stage. Currently, there is a lack of approved and effective early diagnostic tools for ovarian cancer. There is also an apparent severe knowledge gap of ovarian cancer in general and of its indicative symptoms among both public and many health professionals. These factors have significantly contributed to the late stage diagnosis of most ovarian cancer patients (63% are diagnosed at Stage III or above), where the 5-year survival rate is less than 30%. The paucity of knowledge concerning ovarian cancer in the United States is unknown. The present investigation examined current public awareness and knowledge about ovarian cancer. The study implemented design strategies to develop an unbiased survey with quality control measures, including the modern application of multiple statistical analyses. The survey assessed a reasonable proxy of the US population by crowdsourcing participants through the online task marketplace Amazon Mechanical Turk, at a highly condensed rate of cost and time compared to traditional recruitment methods. Knowledge of ovarian cancer was compared to that of breast cancer using repeated measures, bias control and other quality control measures in the survey design. Analyses included multinomial logistic regression and categorical data analysis procedures such as correspondence analysis, among other statistics. We confirmed the relatively poor public knowledge of ovarian cancer among the US population. The simple, yet novel design should set an example for designing surveys to obtain quality data via Amazon Mechanical Turk with the associated analyses.
Tumor necrosis factor-alpha and its receptors in epithelial ovarian cancer.
Directory of Open Access Journals (Sweden)
Jacek Nikliński
2010-05-01
Full Text Available The aim of the present study was to characterize the expression pattern of tumor necrosis factor (TNF-alpha and its receptors (TNF-Rs in the epithelial ovarian cancer (EOC and compare these results with the outcome of 126 patients. Presence of TNF-alpha, TNFR-1 and TNFR-2 were studied by Western blotting and immunohistochemistry. The proportion of samples positive for TNF-alpha and TNF-R2 was higher in epithelial ovarian cancer patients than in benign ovarian diseases (p<0.001 and p=0.016, respectively. Immunostaining intensity of TNF-R2 were correlated with tumor stage (p<0.001 and with reduced mean survival time (MST (p=0.002. The results of the present study suggested that tissue expression of TNF-R2 in epithelial ovarian cancer was correlated with the highest risk of cancer progression. Thus, the clinical value of activated TNF system in epithelial ovarian cancer needs to be further investigated.
Bogani, Giorgio; Tagliabue, Elena; Signorelli, Mauro; Chiappa, Valentina; Carcangiu, Maria Luisa; Paolini, Biagio; Casarin, Jvan; Scaffa, Cono; Gennaro, Massimiliano; Martinelli, Fabio; Borghi, Chiara; Ditto, Antonino; Lorusso, Domenica; Raspagliesi, Francesco
To investigate the incidence and predictive factors of 30-day surgery-related morbidity and occult precancerous and cancerous conditions for women undergoing risk-reducing surgery. A prospective study (Canadian Task Force classification II-1). A gynecologic oncology referral center. Breast-related cancer antigen (BRCA) mutation carriers and BRCAX patients (those with a significant family history of breast and ovarian cancer). Minimally invasive risk-reduction surgery. Overall, 85 women underwent risk-reducing surgery: 30 (35%) and 55 (65%) had hysterectomy plus bilateral salpingo-oophorectomy (BSO) and BSO alone, respectively. Overall, in 6 (7%) patients, the final pathology revealed unexpected cancer: 3 early-stage ovarian/fallopian tube cancers, 2 advanced-stage ovarian cancers (stage IIIA and IIIB), and 1 serous endometrial carcinoma. Additionally, 3 (3.6%) patients had incidental finding of serous tubal intraepithelial carcinoma. Four (4.7%) postoperative complications within 30 days from surgery were registered, including fever (n = 3) and postoperative ileus (n = 1); no severe (grade 3 or more) complications were observed. All complications were managed conservatively. The presence of occult cancer was the only factor predicting the development of postoperative complications (p = .02). Minimally invasive risk-reducing surgery is a safe and effective strategy to manage BRCA mutation carriers. Patients should benefit from an appropriate counseling about the high prevalence of undiagnosed cancers observed at the time of surgery. Copyright © 2017 AAGL. Published by Elsevier Inc. All rights reserved.
Self-production of tissue factor-coagulation factor VII complex by ovarian cancer cells.
Yokota, N; Koizume, S; Miyagi, E; Hirahara, F; Nakamura, Y; Kikuchi, K; Ruf, W; Sakuma, Y; Tsuchiya, E; Miyagi, Y
2009-12-15
Thromboembolic events are a major complication in ovarian cancer patients. Tissue factor (TF) is frequently overexpressed in ovarian cancer tissue and correlates with intravascular thrombosis. TF binds to coagulation factor VII (fVII), changing it to its active form, fVIIa. This leads to activation of the extrinsic coagulation cascade. fVII is produced by the liver and believed to be supplied from blood plasma at the site of coagulation. However, we recently showed that ovarian cancer cells express fVII transcripts under normoxia and that this transcription is inducible under hypoxia. These findings led us to hypothesise that ovarian cancer cells are intrinsically associated with TF-fVIIa coagulation activity, which could result in thrombosis. In this study, we examined whether ectopically expressed fVII could cause thrombosis by means of immunohistochemistry, RT-PCR, western blotting and flow cytometry. Ectopic fVII expression occurs frequently in ovarian cancers, particularly in clear cell carcinoma. We further showed that ovarian cancer cells express TF-fVIIa on the cell surface under normoxia and that this procoagulant activity is enhanced by hypoxic stimuli. Moreover, we showed that ovarian cancer cells secrete microparticles (MPs) with TF-fVIIa activity. Production of this procoagulant secretion is enhanced under hypoxia. These results raise the possibility that cancer cell-derived TF-fVIIa could cause thrombotic events in ovarian cancer patients.
Konishi, Haruhisa; Takehara, Kazuhiro; Kojima, Atsumi; Okame, Shinichi; Yamamoto, Yasuko; Shiroyama, Yuko; Yokoyama, Takashi; Nogawa, Takayoshi; Sugawara, Yoshifumi
2014-09-01
Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is useful for diagnosing malignant tumors. Intracellular FDG uptake is measured as the standardized uptake value (SUV), which differs depending on tumor characteristics. This study investigated differences in maximum SUV (SUVmax) according to histologic type in ovarian epithelial cancer and the relationship of SUVmax with prognosis. This study included 80 patients with ovarian epithelial cancer based on histopathologic findings at surgery and who had undergone PET/CT before treatment. Maximum SUV on PET/CT of primary lesions and histopathology were compared based on histologic type, and the prognosis associated with different SUVmax was evaluated. Clinical tumor stage was I in 35 patients, II in 8, III in 25, and IV in 12. Histologic type was serous adenocarcinoma (AC) in 33 patients, clear cell AC in 27, endometrioid AC in 15, and mucinous AC in 5. Median SUVmax was lower in mucinous AC (2.76) and clear cell AC (4.9) than in serous AC (11.4) or endometrioid AC (11.4). Overall, median SUVmax was lower in clinical stage I (5.37) than in clinical stage ≥II (10.3). However, in both clear cell AC and endometrioid AC, when histologic evaluation was possible, no difference was seen between stage I and stage ≥II. Moreover, in clear cell AC, the 5-year survival rate was significantly higher in the low-SUVmax group (100%) than in the high-SUVmax group (43.0%, P = 0.009). Maximum SUV on preoperative FDG-PET/CT in ovarian epithelial cancer differs according to histologic type. In clear cell AC, SUVmax may represent a prognostic factor.
Sharatz, Steven M; Treviño, Taína A; Rodriguez, Luís; West, Jared H
2008-01-18
Ectopic ovarian tissue is an unusual entity, especially if it is an isolated finding thought to be of embryological origin. An 11-year-old, morbidly obese female presented with left flank pain, nausea, and irregular menses. Various diagnostic procedures suggested a large ovarian cyst, and surgical resection was performed. Histologically, the resected mass was not of tubal origin as suspected, but a serous cystadenoma arising from ovarian tissue. The patient's two normal, eutopic ovaries were completely uninvolved and unaffected. A tumor arising from ectopic ovarian tissue of embryological origin seems the most likely explanation. We suggest refining the descriptive nomenclature so as to more precisely characterize the various presentations of ovarian ectopia.
Low 25-OH vitamin D levels at time of diagnosis and recurrence of ovarian cancer.
Granato, Teresa; Manganaro, Lucia; Petri, Luca; Porpora, Maria Grazia; Viggiani, Valentina; Angeloni, Antonio; Anastasi, Emanuela
2016-02-01
The objective of this study was to evaluate the correlation between 25-OH vitamin D and ovarian cancer as a diagnostic marker or recurrence disease marker. We studied the following: (1) 61 women without gynecologic diseases, (2) 45 women affected by benign ovarian disease, (3) 46 women with recent diagnosis of ovarian cancer, (4) 26 follow-up women with recurrent ovarian cancer, and (5) 32 follow-up women with stable ovarian cancer. The 25-OH vitamin D was quantified with LUMIPULSE® G 25-OH vitamin D on LUMIPULSE® G 1200 (Fujirebio, Japan). As a threshold value, identified by ROC curve analysis, 20.2 ng/mL (sensitivity 73.3 %, specificity 84 %) was chosen corresponding to the limit between sufficient and insufficient 25-OH vitamin D according to the WHO. Low 25-OH vitamin D levels were observed in 26 % of women without gynecologic diseases, in 80 % of women with recent diagnosis of ovarian cancer and in 24 % women affected by benign ovarian diseases (p < 0.001). The follow-up study showed an insufficient level of 25-OH vitamin D in 73 % women with recurrent ovarian cancer and in 47 % women with stable ovarian cancer (p < 0.0003). This study showed that patients with ovarian cancer are often insufficient in 25-OH vitamin D compared to women with benign ovarian diseases. The women with recurrent ovarian cancer presented more often low levels compared to women with stable ovarian cancer. This study suggests that 25-OH vitamin D, due to its antiproliferative properties, can be a good marker for ovarian cancer also.
Clinical Trials with Pegylated Liposomal Doxorubicin in the Treatment of Ovarian Cancer
Directory of Open Access Journals (Sweden)
Carmela Pisano
2013-01-01
Full Text Available Among the pharmaceutical options available for treatment of ovarian cancer, increasing attention has been progressively focused on pegylated liposomal doxorubicin (PLD, whose unique formulation prolongs the persistence of the drug in the circulation and potentiates intratumor accumulation. Pegylated liposomal doxorubicin (PLD has become a major component in the routine management of epithelial ovarian cancer. In 1999 it was first approved for platinum-refractory ovarian cancer and then received full approval for platinum-sensitive recurrent disease in 2005. PLD remains an important therapeutic tool in the management of recurrent ovarian cancer in 2012. Recent interest in PLD/carboplatin combination therapy has been the object of phase III trials in platinum-sensitive and chemonaïve ovarian cancer patients reporting response rates, progressive-free survival, and overall survival similar to other platinum-based combinations, but with a more favorable toxicity profile and convenient dosing schedule. This paper summarizes data clarifying the role of pegylated liposomal doxorubicin (PLD in ovarian cancer, as well as researches focusing on adding novel targeted drugs to this cytotoxic agent.
Is sphere assay useful for the identification of cancer initiating cells of the ovary?
Martínez-Serrano, María José; Caballero-Baños, Miguel; Vilella, Ramon; Vidal, Laura; Pahisa, Jaume; Martínez-Roman, Sergio
2015-01-01
Current evidence suggests that the presence of tumor-initiating cells (TICs) in epithelial ovarian cancer (EOC) has a role in chemoresistance and relapse. Surface markers such as CD44(+)/CD24(-), CD117(+), and CD133(+) expression have been reported as potential markers for TICs related to ovarian cancer and tumorigenic cell lines. In this study, we have investigated if spheroid forms are TIC specific or whether they can also be produced by somatic stem cells from healthy tissue in vitro. In addition, we also investigated the specificity of surface markers to identify TICs from papillary serous EOC patients. Cells were obtained from fresh tumors from 10 chemotherapy-naive patients with EOC, and cells from ovarian and tubal epithelium were obtained from 5 healthy menopausal women undergoing surgery for benign pathology and cultured in standard and in selective medium. Cells forming nonadherent spheroids were considered TICs, and the adherent cells were considered as non-TIC-like. Percentages of CD24(+), CD44(+), CD117(+), CD133(+), and vascular endothelial growth factor receptor (VEGF-R)(+) cell surface markers were analyzed by flow cytometry. Four of 10 EOC cell tissues were excluded from the study. Tumor cells cultured in selective medium developed spheroid forms after 1 to 7 weeks in 5 of 6 EOC patients. No spheroid forms were observed in cultures of cells from healthy women. Unlike previously published data, low levels of CD24(+), CD44(+), CD117(+), and VEGF-R(+) expression were observed in spheroid cells, whereas expression of CD133(+) was moderate but higher in adherent cells from papillary serous EOC cells in comparison with adherent cells from controls. Papillary serous EOC contains TICs that form spheroids with low expression of CD44(+), CD24(+), CD117(+) and VEGF-R(+). Further research is required to find specific surface markers to identify papillary serous TICs.
2014-12-18
Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Stage III Pancreatic Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Ovarian Germ Cell Tumor; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Pancreatic Cancer
Rasmussen, C.B.; Kjaer, S.K.; Albieri, V.; Bandera, E.V.; Doherty, J.A.; Hogdall, E.; Webb, P.M.; Jordan, S.J.; Rossing, M.A.; Wicklund, K.G.; Goodman, M.T.; Modugno, F.; Moysich, K.B.; Ness, R.B.; Edwards, R.P.; Schildkraut, J.M.; Berchuck, A.; Olson, S.H.; Kiemeney, L.A.L.M.; Massuger, L.F.A.G.; Narod, S.A.; Phelan, C.M.; Anton-Culver, H.; Ziogas, A.; Wu, A.H.; Pearce, C.L.; Risch, H.A.; Jensen, A.
2017-01-01
Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to
No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
Hollestelle, Antoinette; van der Baan, Frederieke H.; Berchuck, Andrew; Johnatty, Sharon E.; Aben, Katja K.; Agnarsson, Bjarni A.; Aittomäki, Kristiina; Alducci, Elisa; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Antoniou, Antonis C.; Apicella, Carmel; Arndt, Volker; Arnold, Norbert; Arun, Banu K.; Arver, Brita; Ashworth, Alan; Baglietto, Laura; Balleine, Rosemary; Bandera, Elisa V.; Barrowdale, Daniel; Bean, Yukie T.; Beckmann, Lars; Beckmann, Matthias W.; Benitez, Javier; Berger, Andreas; Berger, Raanan; Beuselinck, Benoit; Bisogna, Maria; Bjorge, Line; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Anders; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Brand, Judith S.; Brauch, Hiltrud; Brenner, Hermann; Brinton, Louise; Brooks-Wilson, Angela; Bruinsma, Fiona; Brunet, Joan; Brüning, Thomas; Budzilowska, Agnieszka; Bunker, Clareann H.; Burwinkel, Barbara; Butzow, Ralf; Buys, Saundra S.; Caligo, Maria A.; Campbell, Ian; Carter, Jonathan; Chang-Claude, Jenny; Chanock, Stephen J.; Claes, Kathleen B.M.; Collée, J. Margriet; Cook, Linda S.; Couch, Fergus J.; Cox, Angela; Cramer, Daniel; Cross, Simon S.; Cunningham, Julie M.; Cybulski, Cezary; Czene, Kamila; Damiola, Francesca; Dansonka-Mieszkowska, Agnieszka; Darabi, Hatef; de la Hoya, Miguel; deFazio, Anna; Dennis, Joseph; Devilee, Peter; Dicks, Ed M.; Diez, Orland; Doherty, Jennifer A.; Domchek, Susan M.; Dorfling, Cecilia M.; Dörk, Thilo; Santos Silva, Isabel Dos; du Bois, Andreas; Dumont, Martine; Dunning, Alison M.; Duran, Mercedes; Easton, Douglas F.; Eccles, Diana; Edwards, Robert P.; Ehrencrona, Hans; Ejlertsen, Bent; Ekici, Arif B.; Ellis, Steve D.; Engel, Christoph; Eriksson, Mikael; Fasching, Peter A.; Feliubadalo, Lidia; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Fontaine, Annette; Fortuzzi, Stefano; Fostira, Florentia; Fridley, Brooke L.; Friebel, Tara; Friedman, Eitan; Friel, Grace; Frost, Debra; Garber, Judy; García-Closas, Montserrat; Gayther, Simon A.; Gentry-Maharaj, Aleksandra; Gerdes, Anne-Marie; Giles, Graham G.; Glasspool, Rosalind; Glendon, Gord; Godwin, Andrew K.; Goodman, Marc T.; Gore, Martin; Greene, Mark H.; Grip, Mervi; Gronwald, Jacek; Kaulich, Daphne Gschwantler; Guénel, Pascal; Guzman, Starr R.; Haeberle, Lothar; Haiman, Christopher A.; Hall, Per; Halverson, Sandra L.; Hamann, Ute; Hansen, Thomas V.O.; Harter, Philipp; Hartikainen, Jaana M.; Healey, Sue; Hein, Alexander; Heitz, Florian; Henderson, Brian E.; Herzog, Josef; Hildebrandt, Michelle A. T.; Høgdall, Claus K.; Høgdall, Estrid; Hogervorst, Frans B.L.; Hopper, John L.; Humphreys, Keith; Huzarski, Tomasz; Imyanitov, Evgeny N.; Isaacs, Claudine; Jakubowska, Anna; Janavicius, Ramunas; Jaworska, Katarzyna; Jensen, Allan; Jensen, Uffe Birk; Johnson, Nichola; Jukkola-Vuorinen, Arja; Kabisch, Maria; Karlan, Beth Y.; Kataja, Vesa; Kauff, Noah; Kelemen, Linda E.; Kerin, Michael J.; Kiemeney, Lambertus A.; Kjaer, Susanne K.; Knight, Julia A.; Knol-Bout, Jacoba P.; Konstantopoulou, Irene; Kosma, Veli-Matti; Krakstad, Camilla; Kristensen, Vessela; Kuchenbaecker, Karoline B.; Kupryjanczyk, Jolanta; Laitman, Yael; Lambrechts, Diether; Lambrechts, Sandrina; Larson, Melissa C.; Lasa, Aadriana; Laurent-Puig, Pierre; Lazaro, Conxi; Le, Nhu D.; Le Marchand, Loic; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Li, Jingmei; Liang, Dong; Lindblom, Annika; Lindor, Noralane; Lissowska, Jolanta; Long, Jirong; Lu, Karen H.; Lubinski, Jan; Lundvall, Lene; Lurie, Galina; Mai, Phuong L.; Mannermaa, Arto; Margolin, Sara; Mariette, Frederique; Marme, Frederik; Martens, John W.M.; Massuger, Leon F.A.G.; Maugard, Christine; Mazoyer, Sylvie; McGuffog, Lesley; McGuire, Valerie; McLean, Catriona; McNeish, Iain; Meindl, Alfons; Menegaux, Florence; Menéndez, Primitiva; Menkiszak, Janusz; Menon, Usha; Mensenkamp, Arjen R.; Miller, Nicola; Milne, Roger L.; Modugno, Francesmary; Montagna, Marco; Moysich, Kirsten B.; Müller, Heiko; Mulligan, Anna Marie; Muranen, Taru A.; Narod, Steven A.; Nathanson, Katherine L.; Ness, Roberta B.; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Nielsen, Finn C.; Nielsen, Sune F.; Nordestgaard, Børge G.; Nussbaum, Robert L.; Odunsi, Kunle; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I.; Olson, Janet E.; Olson, Sara H.; Oosterwijk, Jan C.; Orlow, Irene; Orr, Nick; Orsulic, Sandra; Osorio, Ana; Ottini, Laura; Paul, James; Pearce, Celeste L.; Pedersen, Inge Sokilde; Peissel, Bernard; Pejovic, Tanja; Pelttari, Liisa M.; Perkins, Jo; Permuth-Wey, Jenny; Peterlongo, Paolo; Peto, Julian; Phelan, Catherine M.; Phillips, Kelly-Anne; Piedmonte, Marion; Pike, Malcolm C.; Platte, Radka; Plisiecka-Halasa, Joanna; Poole, Elizabeth M.; Poppe, Bruce; Pylkäs, Katri; Radice, Paolo; Ramus, Susan J.; Rebbeck, Timothy R.; Reed, Malcolm W.R.; Rennert, Gad; Risch, Harvey A.; Robson, Mark; Rodriguez, Gustavo C.; Romero, Atocha; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo; Salani, Ritu; Salvesen, Helga B.; Sawyer, Elinor J.; Schildkraut, Joellen M.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Schneeweiss, Andreas; Schoemaker, Minouk J.; Schrauder, Michael G.; Schumacher, Fredrick; Schwaab, Ira; Scuvera, Giulietta; Sellers, Thomas A.; Severi, Gianluca; Seynaeve, Caroline M.; Shah, Mitul; Shrubsole, Martha; Siddiqui, Nadeem; Sieh, Weiva; Simard, Jacques; Singer, Christian F.; Sinilnikova, Olga M.; Smeets, Dominiek; Sohn, Christof; Soller, Maria; Song, Honglin; Soucy, Penny; Southey, Melissa C.; Stegmaier, Christa; Stoppa-Lyonnet, Dominique; Sucheston, Lara; Swerdlow, Anthony; Tangen, Ingvild L.; Tea, Muy-Kheng; Teixeira, Manuel R.; Terry, Kathryn L.; Terry, Mary Beth; Thomassen, Madas; Thompson, Pamela J.; Tihomirova, Laima; Tischkowitz, Marc; Toland, Amanda Ewart; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Tsimiklis, Helen; Tung, Nadine; Tworoger, Shelley S.; Tyrer, Jonathan P.; Vachon, Celine M.; Van 't Veer, Laura J.; van Altena, Anne M.; Van Asperen, C.J.; van den Berg, David; van den Ouweland, Ans M.W.; van Doorn, Helena C.; Van Nieuwenhuysen, Els; van Rensburg, Elizabeth J.; Vergote, Ignace; Verhoef, Senno; Vierkant, Robert A.; Vijai, Joseph; Vitonis, Allison F.; von Wachenfeldt, Anna; Walsh, Christine; Wang, Qin; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weischer, Maren; Weitzel, Jeffrey N.; Weltens, Caroline; Wentzensen, Nicolas; Whittemore, Alice S.; Wilkens, Lynne R.; Winqvist, Robert; Wu, Anna H.; Wu, Xifeng; Yang, Hannah P.; Zaffaroni, Daniela; Zamora, M. Pilar; Zheng, Wei; Ziogas, Argyrios; Chenevix-Trench, Georgia; Pharoah, Paul D.P.; Rookus, Matti A.; Hooning, Maartje J.; Goode, Ellen L.
2015-01-01
Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR= 0.99, 95% CI 0.94–1.04,p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94–1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97–1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97–1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71–1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94–1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83–1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87–1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers. PMID:25940428
No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer.
Hollestelle, Antoinette; van der Baan, Frederieke H; Berchuck, Andrew; Johnatty, Sharon E; Aben, Katja K; Agnarsson, Bjarni A; Aittomäki, Kristiina; Alducci, Elisa; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Antoniou, Antonis C; Apicella, Carmel; Arndt, Volker; Arnold, Norbert; Arun, Banu K; Arver, Brita; Ashworth, Alan; Baglietto, Laura; Balleine, Rosemary; Bandera, Elisa V; Barrowdale, Daniel; Bean, Yukie T; Beckmann, Lars; Beckmann, Matthias W; Benitez, Javier; Berger, Andreas; Berger, Raanan; Beuselinck, Benoit; Bisogna, Maria; Bjorge, Line; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Anders; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Brand, Judith S; Brauch, Hiltrud; Brenner, Hermann; Brinton, Louise; Brooks-Wilson, Angela; Bruinsma, Fiona; Brunet, Joan; Brüning, Thomas; Budzilowska, Agnieszka; Bunker, Clareann H; Burwinkel, Barbara; Butzow, Ralf; Buys, Saundra S; Caligo, Maria A; Campbell, Ian; Carter, Jonathan; Chang-Claude, Jenny; Chanock, Stephen J; Claes, Kathleen B M; Collée, J Margriet; Cook, Linda S; Couch, Fergus J; Cox, Angela; Cramer, Daniel; Cross, Simon S; Cunningham, Julie M; Cybulski, Cezary; Czene, Kamila; Damiola, Francesca; Dansonka-Mieszkowska, Agnieszka; Darabi, Hatef; de la Hoya, Miguel; deFazio, Anna; Dennis, Joseph; Devilee, Peter; Dicks, Ed M; Diez, Orland; Doherty, Jennifer A; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; Silva, Isabel Dos Santos; du Bois, Andreas; Dumont, Martine; Dunning, Alison M; Duran, Mercedes; Easton, Douglas F; Eccles, Diana; Edwards, Robert P; Ehrencrona, Hans; Ejlertsen, Bent; Ekici, Arif B; Ellis, Steve D; Engel, Christoph; Eriksson, Mikael; Fasching, Peter A; Feliubadalo, Lidia; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Fontaine, Annette; Fortuzzi, Stefano; Fostira, Florentia; Fridley, Brooke L; Friebel, Tara; Friedman, Eitan; Friel, Grace; Frost, Debra; Garber, Judy; García-Closas, Montserrat; Gayther, Simon A; Gentry-Maharaj, Aleksandra; Gerdes, Anne-Marie; Giles, Graham G; Glasspool, Rosalind; Glendon, Gord; Godwin, Andrew K; Goodman, Marc T; Gore, Martin; Greene, Mark H; Grip, Mervi; Gronwald, Jacek; Gschwantler Kaulich, Daphne; Guénel, Pascal; Guzman, Starr R; Haeberle, Lothar; Haiman, Christopher A; Hall, Per; Halverson, Sandra L; Hamann, Ute; Hansen, Thomas V O; Harter, Philipp; Hartikainen, Jaana M; Healey, Sue; Hein, Alexander; Heitz, Florian; Henderson, Brian E; Herzog, Josef; T Hildebrandt, Michelle A; Høgdall, Claus K; Høgdall, Estrid; Hogervorst, Frans B L; Hopper, John L; Humphreys, Keith; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Jakubowska, Anna; Janavicius, Ramunas; Jaworska, Katarzyna; Jensen, Allan; Jensen, Uffe Birk; Johnson, Nichola; Jukkola-Vuorinen, Arja; Kabisch, Maria; Karlan, Beth Y; Kataja, Vesa; Kauff, Noah; Kelemen, Linda E; Kerin, Michael J; Kiemeney, Lambertus A; Kjaer, Susanne K; Knight, Julia A; Knol-Bout, Jacoba P; Konstantopoulou, Irene; Kosma, Veli-Matti; Krakstad, Camilla; Kristensen, Vessela; Kuchenbaecker, Karoline B; Kupryjanczyk, Jolanta; Laitman, Yael; Lambrechts, Diether; Lambrechts, Sandrina; Larson, Melissa C; Lasa, Adriana; Laurent-Puig, Pierre; Lazaro, Conxi; Le, Nhu D; Le Marchand, Loic; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Li, Jingmei; Liang, Dong; Lindblom, Annika; Lindor, Noralane; Lissowska, Jolanta; Long, Jirong; Lu, Karen H; Lubinski, Jan; Lundvall, Lene; Lurie, Galina; Mai, Phuong L; Mannermaa, Arto; Margolin, Sara; Mariette, Frederique; Marme, Frederik; Martens, John W M; Massuger, Leon F A G; Maugard, Christine; Mazoyer, Sylvie; McGuffog, Lesley; McGuire, Valerie; McLean, Catriona; McNeish, Iain; Meindl, Alfons; Menegaux, Florence; Menéndez, Primitiva; Menkiszak, Janusz; Menon, Usha; Mensenkamp, Arjen R; Miller, Nicola; Milne, Roger L; Modugno, Francesmary; Montagna, Marco; Moysich, Kirsten B; Müller, Heiko; Mulligan, Anna Marie; Muranen, Taru A; Narod, Steven A; Nathanson, Katherine L; Ness, Roberta B; Neuhausen, Susan L; Nevanlinna, Heli; Neven, Patrick; Nielsen, Finn C; Nielsen, Sune F; Nordestgaard, Børge G; Nussbaum, Robert L; Odunsi, Kunle; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Olson, Sara H; Oosterwijk, Jan C; Orlow, Irene; Orr, Nick; Orsulic, Sandra; Osorio, Ana; Ottini, Laura; Paul, James; Pearce, Celeste L; Pedersen, Inge Sokilde; Peissel, Bernard; Pejovic, Tanja; Pelttari, Liisa M; Perkins, Jo; Permuth-Wey, Jenny; Peterlongo, Paolo; Peto, Julian; Phelan, Catherine M; Phillips, Kelly-Anne; Piedmonte, Marion; Pike, Malcolm C; Platte, Radka; Plisiecka-Halasa, Joanna; Poole, Elizabeth M; Poppe, Bruce; Pylkäs, Katri; Radice, Paolo; Ramus, Susan J; Rebbeck, Timothy R; Reed, Malcolm W R; Rennert, Gad; Risch, Harvey A; Robson, Mark; Rodriguez, Gustavo C; Romero, Atocha; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo; Salani, Ritu; Salvesen, Helga B; Sawyer, Elinor J; Schildkraut, Joellen M; Schmidt, Marjanka K; Schmutzler, Rita K; Schneeweiss, Andreas; Schoemaker, Minouk J; Schrauder, Michael G; Schumacher, Fredrick; Schwaab, Ira; Scuvera, Giulietta; Sellers, Thomas A; Severi, Gianluca; Seynaeve, Caroline M; Shah, Mitul; Shrubsole, Martha; Siddiqui, Nadeem; Sieh, Weiva; Simard, Jacques; Singer, Christian F; Sinilnikova, Olga M; Smeets, Dominiek; Sohn, Christof; Soller, Maria; Song, Honglin; Soucy, Penny; Southey, Melissa C; Stegmaier, Christa; Stoppa-Lyonnet, Dominique; Sucheston, Lara; Swerdlow, Anthony; Tangen, Ingvild L; Tea, Muy-Kheng; Teixeira, Manuel R; Terry, Kathryn L; Terry, Mary Beth; Thomassen, Mads; Thompson, Pamela J; Tihomirova, Laima; Tischkowitz, Marc; Toland, Amanda Ewart; Tollenaar, Rob A E M; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Tsimiklis, Helen; Tung, Nadine; Tworoger, Shelley S; Tyrer, Jonathan P; Vachon, Celine M; Van 't Veer, Laura J; van Altena, Anne M; Van Asperen, C J; van den Berg, David; van den Ouweland, Ans M W; van Doorn, Helena C; Van Nieuwenhuysen, Els; van Rensburg, Elizabeth J; Vergote, Ignace; Verhoef, Senno; Vierkant, Robert A; Vijai, Joseph; Vitonis, Allison F; von Wachenfeldt, Anna; Walsh, Christine; Wang, Qin; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weischer, Maren; Weitzel, Jeffrey N; Weltens, Caroline; Wentzensen, Nicolas; Whittemore, Alice S; Wilkens, Lynne R; Winqvist, Robert; Wu, Anna H; Wu, Xifeng; Yang, Hannah P; Zaffaroni, Daniela; Pilar Zamora, M; Zheng, Wei; Ziogas, Argyrios; Chenevix-Trench, Georgia; Pharoah, Paul D P; Rookus, Matti A; Hooning, Maartje J; Goode, Ellen L
2016-05-01
Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations. rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers. Copyright © 2015 Elsevier Inc. All rights reserved.
Ovarian failure due to cancer treatment and fertility preservation options
Directory of Open Access Journals (Sweden)
Soheila Aminimoghaddam
2016-04-01
Full Text Available Primary ovarian insufficiency (POI, commonly referred to premature ovarian failure, is defined as ovarian failure before the age of 40 years. It is the loss of ovarian function caused by a process directly affecting ovaries. Cancer therapy which includes surgery, radiotherapy, and chemotherapy influence ovarian function, leading to premature menopause and loss of fertility. POI is idiopathic in most cases (74-90%. The known causes, in addition to anticancer treatment, are other processes like chromosomal abnormalities, autoimmunity, and natural aging can result in secondary ovarian failure, which is detected by an increase in serum gonadotropin levels (FSH and LH. There are evident risks of POI in women treated for cancer. Those who receive anticancer treatments have an increased risk of developing POI. There by, anticancer drugs and radiation therapy are considered as the most common toxins of ovaries. Although cancer incidence rates in women less than 50 years old continue to increase during recent years, mortality rates are dramatically decreasing due to modern advances in treatment. Increasing numbers of survivors are now confronted with the long-term consequences of exposure to these treatments. The pool of primordial follicles in the ovary is fixed and any injury to the ovary can potentially reduce this ovarian reserve, effectively advancing the patient’s reproductive age, thus narrowing the window of reproductive opportunity. Ovarian failure occurs in a significant percentage of childhood cancer survivors and many of them will seek care for reproductive dysfunction. Nevertheless, Embryo cryopreservation, oocyte cryopreservation, ovary tissue cryopreservation, ovarian suppression and oophoro-pexy are some options to preserve fertility in these groups. As a result, having foreknowledge of potential treatment related ovarian failure will allow the physician to give a better counsel to patients and their family regarding the importance and
Synthetic Lethal Therapeutic Approaches for ARID1A-Mutated Ovarian Cancer
2017-10-01
Award Number: W81XWH-16-1-0496 TITLE: Synthetic lethal therapeutic approaches for ARID1A-mutated ovarian cancer PRINCIPAL INVESTIGATOR: Rugang...AND SUBTITLE Synthetic lethal therapeutic approaches for ARID1A-mutated ovarian cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0496 5c...Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological
Directory of Open Access Journals (Sweden)
Rebecca R Carter
Full Text Available BACKGROUND: Ovarian cancer is the most lethal gynecologic disease in the United States, with more women dying from this cancer than all gynecological cancers combined. Ovarian cancer has been termed the "silent killer" because some patients do not show clear symptoms at an early stage. Currently, there is a lack of approved and effective early diagnostic tools for ovarian cancer. There is also an apparent severe knowledge gap of ovarian cancer in general and of its indicative symptoms among both public and many health professionals. These factors have significantly contributed to the late stage diagnosis of most ovarian cancer patients (63% are diagnosed at Stage III or above, where the 5-year survival rate is less than 30%. The paucity of knowledge concerning ovarian cancer in the United States is unknown. METHODS: The present investigation examined current public awareness and knowledge about ovarian cancer. The study implemented design strategies to develop an unbiased survey with quality control measures, including the modern application of multiple statistical analyses. The survey assessed a reasonable proxy of the US population by crowdsourcing participants through the online task marketplace Amazon Mechanical Turk, at a highly condensed rate of cost and time compared to traditional recruitment methods. CONCLUSION: Knowledge of ovarian cancer was compared to that of breast cancer using repeated measures, bias control and other quality control measures in the survey design. Analyses included multinomial logistic regression and categorical data analysis procedures such as correspondence analysis, among other statistics. We confirmed the relatively poor public knowledge of ovarian cancer among the US population. The simple, yet novel design should set an example for designing surveys to obtain quality data via Amazon Mechanical Turk with the associated analyses.
Morphologic 3D scanning of fallopian tubes to assist ovarian cancer diagnosis
Madore, Wendy-Julie; De Montigny, Etienne; Deschênes, Andréanne; Benboujja, Fouzi; Leduc, Mikael; Mes-Masson, Anne-Marie; Provencher, Diane M.; Rahimi, Kurosh; Boudoux, Caroline; Godbout, Nicolas
2016-02-01
Pathological evaluation of the fallopian tubes is an important diagnostic result but tumors can be missed using routine approaches. As the majority of high-grade serous ovarian cancers are now believed to originate in the fallopian tubes, pathological examination should include in a thorough examination of the excised ovaries and fallopian tubes. We present an dedicated imaging system for diagnostic exploration of human fallopian tubes. This system is based on optical coherence tomography (OCT), a laser imaging modality giving access to sub- epithelial tissue architecture. This system produces cross-sectional images up to 3 mm in depth, with a lateral resolution of ≍15μm and an axial resolution of ≍12μm. An endoscopic single fiber probe was developed to fit in a human fallopian tube. This 1.2 mm probe produces 3D volume data of the entire inner tube within a few minutes. To demonstrate the clinical potential of OCT for lesion identification, we studied 5 different ovarian lesions and healthy fallopian tubes. We imaged 52 paraffin-embedded human surgical specimens with a benchtop system and compared these images with histology slides. We also imaged and compared healthy oviducts from 3 animal models to find one resembling the human anatomy and to develop a functional ex vivo imaging procedure with the endoscopic probe. We also present an update on an ongoing clinical pilot study on women undergoing prophylactic or diagnostic surgery in which we image ex vivo fallopian tubes with the endoscopic probe.
Directory of Open Access Journals (Sweden)
Xinlei Chen
2007-06-01
Full Text Available Little is known about the behavior of the ovarian surface epithelium (OSE, which plays a central role in ovarian cancer etiology. It has been suggested that incessant ovulation causes OSE changes leading to transformation and that high gonadotropin levels during postmenopause activate OSE receptors, inducing proliferation. We examined the chronology of OSE changes, including tumor appearance, in a mouse model where ovulation never occurs due to deletion of follitropin receptor. Changes in epithelial cells were marked by pan-cytokeratin (CK staining. Histologic changes and CK staining in the OSE increased from postnatal day 2. CK staining was observed inside the ovary by 24 days and increased thereafter in tumor-bearing animals. Ovaries from a third of aged (1 year mutant mice showed CK deep inside, indicating cell migration. These tumors resembled serous papillary adenoma of human ovaries. Weak expression of GATA-4 and elevation of PCNA, cyclooxygenase-1, cyclooxygenase-2, and plateletderived growth factor receptors α and β in mutants indicated differences in cell proliferation, differentiation, and inflammation. Thus, we report that OSE changes occur long before epithelial tumors appear in FORKO mice. Our results suggest that neither incessant ovulation nor follicle-stimulating hormone receptor presence in the OSE is required for inducing ovarian tumors; thus, other mechanisms must contribute to ovarian tumorigenesis.
Xiang, Libing; Tu, Yunxia; He, Tiancong; Shen, Xuxia; Li, Ziting; Wu, Xiaohua; Yang, Huijuan
2016-11-01
Distal pancreatectomy with splenectomy may be required for optimal cytoreductive surgery in patients with epithelial ovarian cancer (EOC) metastasized to splenic hilum. This study evaluates the morbidity and treatment outcomes of the uncommon procedure in the management of advanced or recurrent EOC. This study recruited 18 patients who underwent distal pancreatectomy with splenectomy during cytoreductive surgery of EOC. Their clinicopathological characteristics and follow-up data were retrospectively analyzed. All tumors were confirmed as high-grade serous carcinomas. The median diameter of metastatic tumors located in splenic hilum was 3.5 cm (range, 1 to 10 cm). Optimal cytoreduction was achieved in all patients. Eight patients (44.4%) suffered from postoperative complications. The morbidity associated with distal pancreatectomy and splenectomy included pancreatic leakage (22.2%), encapsulated effusion in the left upper quadrant (11.1%), intra-abdominal infection (11.1%), pleural effusion with or without pulmonary atelectasis (11.1%), intestinal obstruction (5.6%), pneumonia (5.6%), postoperative hemorrhage (5.6%), and pancreatic pseudocyst (5.6%). There was no perioperative mortality. The majority of complications were treated successfully with conservative management. During the median follow-up duration of 25 months, nine patients experienced recurrence, and three patients died of the disease. The 2-year progression-free survival and overall survival were 40.2% and 84.8%, respectively. The inclusion of distal pancreatectomy with splenectomy as part of cytoreduction for the management of ovarian cancer was associated with high morbidity; however, the majority of complications could be managed with conservative therapy.
The Prevention of Hereditary Breast and Ovarian Cancer: A Personal View
Directory of Open Access Journals (Sweden)
Narod Steven
2004-02-01
Full Text Available Abstract Options for the prevention of hereditary breast and ovarian cancer include screening, preventive surgery and chemoprevention. Screening studies with magnetic resonance imaging of the breast are promising but the technology is not widespread and MRI is unlikely to be available as a screening tool in the near future. Prophylactic oophorectomy and mastectomy are effective preventive measures and are gaining in acceptance by patients and physicians. Preventive mastectomy is effective against both primary and contralateral breast cancer. Oophorectomy prevents ovarian cancer, and if done prior to menopause, will prevent breast cancer as well. Tamoxifen has been shown to prevent contralateral breast cancers in BRCA1 and BRCA2 carriers but is not widely accepted as a means of primary prevention. Oral contraceptives and tubal ligation will reduce the risk of hereditary ovarian cancer and should be considered in women who wish to retain ovarian function.
A case-control study of risk factors for epithelial ovarian cancer
Directory of Open Access Journals (Sweden)
Ghaem Maghami Noori F
2001-09-01
Full Text Available Ovarian cancer is second prevalent cancer among gynecologic malignancies and the most common type of ovarian cancer is epithelial form (85-90 percent. To detect the risk factors for the epithelial ovarian cancer, a case-control study was conducted in Valieasr hospital in 1988. In this study, 118 cases with epithelial ovarian cancer (according histological records and 240 controls without any gynecological cancer in gynecologic clinic had been interviewed. For data analysis, T-test, Chi2 test and logistic regression have been used at a =0.05 as level of significance. The mean age in cases was 50±13 and in controls was 49.9±12 years, without significant different. The mean number of pregnancies and parity in cases was less than controls, significantly (P<0.03. The mean months of breast feeding in cases was less than controls (54.9±71.2 versus 82.4±62.7 (P<0.001. The cases had a lower mean age of menarch than controls (P=0.03. 58 percent of cases and 21.3 percent of controls hadn't used any contraception methods (P=0.00001. The mean years of contraception was significantly less in cases versus controls (P<0.001. The odds ratio for epithelial ovarian cancer was 0.24 (95 percent CI: 0.13-0.48 in OCP users, 0.47 (95 percent CI: 0.005-0.43 in TL method, and was 0.41 (95 percent CI: 0.22-0.76 in other contraception methods, relative to women who hadn't used any contraception methods. This study reveals that epithelial ovarian cancer risk increases significantly with earlier menarch, decreasing number of pregnancy, deliveries duration of breast feeding and use of contraception methods. Use of contraception pill and tubal ligation method decreases risk of epithelial ovarian cancer.
Targeting Insulin and Insulin-Like Growth Factor Pathways in Epithelial Ovarian Cancer
Directory of Open Access Journals (Sweden)
Marie-Claude Beauchamp
2010-01-01
Full Text Available Ovarian cancer is the most lethal of all gynecological malignancies, due in part to the diagnosis at an advanced stage caused by the lack of specific signs and symptoms and the absence of reliable tests for screening and early detection. Most patients will respond initially to treatment but about 70% of them will suffer a recurrence. Therefore, new therapeutic modalities are urgently needed to overcome chemoresistance observed in ovarian cancer patients. Evidence accumulates suggesting that the insulin/insulin growth factor (IGF pathways could act as a good therapeutic target in several cancers, including ovarian cancer. In this paper, we will focus on the role of insulin/IGF in ovarian cancer tumorigenesis and treatment.
Serum tumor marker CA 125 for monitoring ovarian cancer during follow-up
DEFF Research Database (Denmark)
Tuxen, Malgorzata K.; Sölétormos, G; Dombernowsky, P
2002-01-01
CA 125 is currently widely applied in the management of patients with ovarian cancer. However, a change in results of CA 125, which should be considered significant, has not been defined. The aim of this study was to investigate the ability of CA 125 to signal progressive ovarian cancer during fo...... utility of serological tumor markers in patients with ovarian cancer....
Lifescience Database Archive (English)
Full Text Available leading cause of cancer-related death among women in developed countries. Approximately 90% of human ovaria...nous, serous, endometrioid, and clear cell subtypes. Approximately 10% of ovarian cancers arise in women who
Kadour-Peero, Einav; Sagi-Dain, Lena; Cohen, Gil; Korobochka, Roman; Agbarya, Abed; Bejar, Jacob; Sagi, Shlomi
2018-05-07
BACKGROUND There is now evidence to support that some cases of high-grade serous papillary carcinoma arise from the fallopian tubes rather than the ovaries. Common symptoms at presentation include abdominal pain and swelling, vomiting, altered bowel habit and urinary symptoms. To our knowledge, this is the first case of serous papillary carcinoma presenting as a vaginal mass lesion. CASE REPORT A 41-year-old woman was referred to the Bnai-Zion Medical Center with the main complaint of irregular vaginal bleeding, vaginal mucous discharge, and suspected pelvic mass. Physical examination showed a soft, painless mass, measuring about 10 cm in diameter located mainly in the recto-vaginal septum, but not involving the uterus. Ultrasound examination showed no abnormal ovarian or uterine findings. Transvaginal biopsies of the mass showed a poorly differentiated serous papillary carcinoma of ovarian, tubal, or peritoneal origin. The physical examination and imaging findings strongly indicated an inoperable tumor, and the patient was treated with neoadjuvant (pre-surgical) chemotherapy. Pre-operative computed tomography (CT) imaging showed the partial involvement of the colon, and so surgical treatment included total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, partial vaginectomy, anterior rectal resection, and lymph node dissection. Histopathology of the surgical specimens showed a poorly differentiated serous carcinoma originating from the fimbria of the right fallopian tube. CONCLUSIONS To the best of our knowledge, this is the first report to describe primary fallopian tube papillary serous carcinoma presenting as a vaginal mass. Therefore, physicians should be aware of this possible diagnosis.
Ding, Yuan C.; McGuffog, Lesley; Healey, Sue; Friedman, Eitan; Laitman, Yael; Shani-Shimon–Paluch; Kaufman, Bella; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Gronwald, Jacek; Huzarski, Tomasz; Cybulski, Cezary; Byrski, Tomasz; Osorio, Ana; Cajal, Teresa Ramóny; Stavropoulou, Alexandra V; Benítez, Javier; Hamann, Ute; Rookus, Matti; Aalfs, Cora M.; de Lange, Judith L.; Meijers-Heijboer, Hanne E.J.; Oosterwijk, Jan C.; van Asperen, Christi J.; García, Encarna B. Gómez; Hoogerbrugge, Nicoline; Jager, Agnes; van der Luijt, Rob B.; Easton, Douglas F.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Brewer, Carole; Tischkowitz, Marc; Godwin, Andrew K.; Pathak, Harsh; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M.; Mazoyer, Sylvie; Barjhoux, Laure; Léoné, Mélanie; Gauthier-Villars, Marion; Caux-Moncoutier, Virginie; de Pauw, Antoine; Hardouin, Agnès; Berthet, Pascaline; Dreyfus, Hélène; Ferrer, Sandra Fert; Collonge-Rame, Marie-Agnès; Sokolowska, Johanna; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Maria, Muy-Kheng Tea; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Hansen, Thomas v. O.; Ejlertsen, Bent; Johannsson, Oskar Th.; Offit, Kenneth; Sarrel, Kara; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion R; Andrews, Lesley; Cohn, David; DeMars, Leslie R.; DiSilvestro, Paul; Rodriguez, Gustavo; Toland, Amanda Ewart; Montagna, Marco; Agata, Simona; Imyanitov, Evgeny; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Ramus, Susan J; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Ganz, Patricia A.; Beattie, Mary S.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Meindl, Alfons; Arnold, Norbert; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Nevanlinna, Heli; Aittomäki, Kristiina; Simard, Jacques; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Tomlinson, Gail E.; Weitzel, Jeffrey; Garber, Judy E.; Olopade, Olufunmilayo I.; Rubinstein, Wendy S.; Tung, Nadine; Blum, Joanne L.; Narod, Steven A.; Brummel, Sean; Gillen, Daniel L.; Lindor, Noralane; Fredericksen, Zachary; Pankratz, Vernon S.; Couch, Fergus J.; Radice, Paolo; Peterlongo, Paolo; Greene, Mark H.; Loud, Jennifer T.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Gerdes, Anne-Marie; Thomassen, Mads; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Lee, Andrew; Chenevix-Trench, Georgia; Antoniou, Antonis C; Neuhausen, Susan L.
2012-01-01
Background We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. Results Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 [Hazard ratio (HR) = 1.43; 95% CI: 1.06–1.92; p = 0.019] and BRCA2 mutation carriers (HR=2.21; 95% CI: 1.39–3.52, p=0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class 2 mutations than class 1 (mutations (class 2 HR=1.86, 95% CI: 1.28–2.70; class 1 HR=0.86, 95%CI:0.69–1.09; p-for difference=0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class 2 mutation carriers (HR = 2.42; p = 0.03). Conclusion The IRS1 Gly972Arg SNP, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class 2 mutation carriers. Impact These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers. PMID:22729394
Investigation of mammographic breast density as a risk factor for ovarian cancer.
Wernli, Karen J; O'Meara, Ellen S; Kerlikowske, Karla; Miglioretti, Diana L; Muller, Carolyn Y; Onega, Tracy; Sprague, Brian L; Henderson, Louise M; Buist, Diana S M
2014-01-01
Endogenous hormones and growth factors that increase mammographic breast density could increase ovarian cancer risk. We examined whether high breast density is associated with ovarian cancer risk. We conducted a cohort study of 724,603 women aged 40 to 79 years with 2,506,732 mammograms participating in the Breast Cancer Surveillance Consortium from 1995 to 2009. Incident epithelial ovarian cancer was diagnosed in 1373 women. We used partly conditional Cox regression to estimate the association between breast density and 5-year risk of incident epithelial ovarian cancer overall and stratified by 10-year age group. All statistical tests were two-sided. Compared with women with scattered fibroglandular densities, women with heterogeneously dense and extremely dense breast tissue had 20% and 18% increased 5-year risk of incident epithelial ovarian cancer (hazard ratio [HR] = 1.20, 95% confidence interval [CI] = 1.06 to 1.36; HR = 1.18, 95% CI = 0.93 to 1.50, respectively; P(trend) = .01). Among women aged 50 to 59 years, we observed a trend in elevated risk associated with increased breast density (P(trend) = .02); women with heterogeneously and extremely dense breast tissue had 30% (HR = 1.30; 95% CI = 1.03 to 1.64) and 65% (HR = 1.65; 95% CI = 1.12 to 2.44) increased risk, respectively, compared with women with scattered fibroglandular densities. The pattern was similar but not statistically significant at age 40 to 49 years. There were no consistent patterns of breast density and ovarian cancer risk at age 60 to 79 years. Dense breast tissue was associated with a modest increase in 5-year ovarian cancer risk in women aged 50 to 59 years but was not associated with ovarian cancer at ages 40 to 49 or 60 to 79 years.
Clinical Application of 18F-FDG PET in Ovarian Cancer
International Nuclear Information System (INIS)
Oh, So Won; Kim, Seok Ki
2008-01-01
Ovarian cancer is often fatal since it is difficult to diagnose early and recurrence is quite frequent despite successful implementation of cytoreductive surgery and chemotherapy, thus exact diagnosis and early detection of recurrence are crucial to patient management. For pre-treatment staging, FDG PET could be helpful in a limited patient group possessing high risks of ovarian cancer. Besides, FDG PET could be recommended to patients with a high suspicion of recurrence i.e. rise of CA-125, especially in cases of conventional diagnostic imaging modalities presenting no evidence of disease because FDG PET provides critical information for treatment planning such as recurrence site or pattern. In order to expand the use of FDG PET to general population at staging or routine surveillance of ovarian cancer, more investigation is needed. The usefulness of FDG PET in evaluating treatment response and prognosis of ovarian cancer has not yet been determined, but it has been reported that FDG PET could evaluate treatment response early and show a close relationship with overall survival. PET/CT has been actively adopted in management of ovarian cancer. Not only in detecting tumor recurrence and evaluating treatment response but also in pre-treatment staging, FDG PET/CT is expected to play a role due to available anatomical information
Hereditary Ovarian Cancer: Not Only BRCA 1 and 2 Genes
Directory of Open Access Journals (Sweden)
Angela Toss
2015-01-01
Full Text Available More than one-fifth of ovarian tumors have hereditary susceptibility and, in about 65–85% of these cases, the genetic abnormality is a germline mutation in BRCA genes. Nevertheless, several other suppressor genes and oncogenes have been associated with hereditary ovarian cancers, including the mismatch repair (MMR genes in Lynch syndrome, the tumor suppressor gene, TP53, in the Li-Fraumeni syndrome, and several other genes involved in the double-strand breaks repair system, such as CHEK2, RAD51, BRIP1, and PALB2. The study of genetic discriminators and deregulated pathways involved in hereditary ovarian syndromes is relevant for the future development of molecular diagnostic strategies and targeted therapeutic approaches. The recent development and implementation of next-generation sequencing technologies have provided the opportunity to simultaneously analyze multiple cancer susceptibility genes, reduce the delay and costs, and optimize the molecular diagnosis of hereditary tumors. Particularly, the identification of mutations in ovarian cancer susceptibility genes in healthy women may result in a more personalized cancer risk management with tailored clinical and radiological surveillance, chemopreventive approaches, and/or prophylactic surgeries. On the other hand, for ovarian cancer patients, the identification of mutations may provide potential targets for biologic agents and guide treatment decision-making.
Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis
DEFF Research Database (Denmark)
Cunningham, J M; Vierkant, R A; Sellers, T A
2009-01-01
BACKGROUND: Dysregulation of the cell cycle is a hallmark of many cancers including ovarian cancer, a leading cause of gynaecologic cancer mortality worldwide. METHODS: We examined single nucleotide polymorphisms (SNPs) (n=288) from 39 cell cycle regulation genes, including cyclins, cyclin......-dependent kinases (CDKs) and CDK inhibitors, in a two-stage study. White, non-Hispanic cases (n=829) and ovarian cancer-free controls (n=941) were genotyped using an Illumina assay. RESULTS: Eleven variants in nine genes (ABL1, CCNB2, CDKN1A, CCND3, E2F2, CDK2, E2F3, CDC2, and CDK7) were associated with risk...... of ovarian cancer in at least one genetic model. Seven SNPs were then assessed in four additional studies with 1689 cases and 3398 controls. Association between risk of ovarian cancer and ABL1 rs2855192 found in the original population [odds ratio, OR(BB vs AA) 2.81 (1.29-6.09), P=0.01] was also observed...
Calcium Intake and the Risk of Ovarian Cancer: A Meta-Analysis.
Song, Xingxing; Li, Zongyao; Ji, Xinqiang; Zhang, Dongfeng
2017-06-30
Several epidemiological studies have evaluated the association between calcium intake and the risk of ovarian cancer. However, the results of these studies remain controversial. Thus, we performed a meta-analysis to explore the association between calcium intake and the risk of ovarian cancer. Pubmed, Embase and Web of Science were searched for eligible publications up to April 2017. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using the random-effects model. Small-study effect was estimated using Egger's test and the funnel plot. Among 15 epidemiological studies involving 493,415 participants and 7453 cases eligible for this meta-analysis, 13 studies were about dietary calcium intake, 4 studies about dairy calcium intake and 7 studies about dietary plus supplemental calcium intake. When comparing the highest with the lowest intake, the pooled RRs of ovarian cancer were 0.80 (95% CI 0.72-0.89) for dietary calcium, 0.80 (95% CI 0.66-0.98) for dairy calcium and 0.90 (95% CI 0.65-1.24) for dietary plus supplemental calcium, respectively. Dietary calcium was significantly associated with a reduced risk of ovarian cancer among cohort studies (RR = 0.86, 95% CI 0.74-0.99) and among case-control studies ( RR = 0.75, 95% CI 0.64-0.89). In subgroup analysis by ovarian cancer subtypes, we found a statistically significant association between the dietary calcium ( RR = 0.78, 95% CI 0.69-0.88) and the risk of epithelial ovarian cancer (EOC). This meta-analysis indicated that increased calcium intake might be inversely associated with the risk of ovarian cancer; this still needs to be confirmed by larger prospective cohort studies.
Directory of Open Access Journals (Sweden)
Kelemen Linda E
2013-01-01
Full Text Available Abstract Background Studies evaluating the association between alcohol intake and ovarian carcinoma (OC are inconsistent. Because OC and ovarian borderline tumor histologic types differ genetically, molecularly and clinically, large numbers are needed to estimate risk associations. Methods We pooled data from 12 case-control studies in the Ovarian Cancer Association Consortium comprising 5,342 OC cases, 1,455 borderline tumors and 10,358 controls with quantitative information on recent alcohol intake to estimate odds ratios (OR and 95% confidence intervals (CI according to frequencies of average daily intakes of beer, wine, liquor and total alcohol. Results Total alcohol intake was not associated with all OC: consumption of >3 drinks per day compared to none, OR=0.92, 95% CI=0.76-1.10, P trend=0.27. Among beverage types, a statistically non-significant decreased risk was observed among women who consumed >8 oz/d of wine compared to none (OR=0.83, 95% CI=0.68-1.01, P trend=0.08. This association was more apparent among women with clear cell OC (OR, 0.43; 95% CI, 0.22-0.83; P trend=0.02, although based on only 10 cases and not statistically different from the other histologic types (P value for statistical heterogeneity between histologic types = 0.09. Statistical heterogeneity of the alcohol- and wine-OC associations was seen among three European studies, but not among eight North American studies. No statistically significant associations were observed in separate analyses evaluating risk with borderline tumors of serous or mucinous histology. Smoking status did not significantly modify any of the associations. Conclusions We found no evidence that recent moderate alcohol drinking is associated with increased risk for overall OC, or that variation in risk is associated strongly with specific histologic types. Understanding modifiable causes of these elusive and deadly cancers remains a priority for the research community.
Radioimmunoimaging of ovarian cancer with 131I labelled CEA monoclonal antibody
International Nuclear Information System (INIS)
Hu Likuan; Li Zhen; Huo Zhenguo; Jiang Sen; Jia Shiquan
2001-01-01
Objective: To investigate radioimmunoimaging with 131 I labelled CEA McAb and its value in diagnosis and treatment of ovarian cancer. Methods: CEA McAb was labelled with 131 I by standard chloramine T procedure. The radiolabeled McAb was given intravenously to the patients. The scintigraphy was performed at different time. Results: In 105 patients with histopathology proved ovarian cancers, for 96 patients the lesions were well located with RII (true positives), for the remaining 9 patients, the results were false negative. 22/23 cases with RII diagnosed benign ovarian tumors were proved to be true negative by surgical pathology in RII. Of 96 ovarian cancers 87 were stratified into identical stages by surgical pathology all RII. 141/151 metastatic tumors were found in RII and the positive rate was as high as 93.4%. The smallest tumor defected by RII was of 1 cm in diameter. Conclusions: RII is as good as ultrasonography and CT in distinguishing benignancy and malignancy. The location, size and number of the lesions can also be determined with RII. RII of ovarian cancer with 131 I-CEA McAb is valuable and helpful in early detection of ovarian cancer. It is also helpful for clinical staging, treatment programing and prognosticating
Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper
Herzog, Thomas J.; Armstrong, Deborah K.; Brady, Mark F.; Coleman, Robert L.; Einstein, Mark H.; Monk, Bradley J.; Mannel, Robert S.; Thigpen, J. Tate; Umpierre, Sharee A.; Villella, Jeannine A.; Alvarez, Ronald D.
2015-01-01
Objective To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. Methods A clinical trial workgroup was established by the Society of Gynecologic Oncology to develop a consensus statement via multiple conference calls, meetings and white paper drafts. Results Clinical trial endpoints have profound effects on late phase clinical trial design, result interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented. Conclusions Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect