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  1. Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    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.

  2. 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.

  3. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    Directory of Open Access Journals (Sweden)

    Miller Dianne M

    2008-01-01

    Full Text Available Background 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. Methods 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. Results 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. Conclusion 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.

  4. Loss of the BRCA1-interacting helicase BRIP1 results in abnormal mammary acinar morphogenesis.

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    Kazuhiro Daino

    Full Text Available BRIP1 is a DNA helicase that directly interacts with the C-terminal BRCT repeat of the breast cancer susceptibility protein BRCA1 and plays an important role in BRCA1-dependent DNA repair and DNA damage-induced checkpoint control. Recent studies implicate BRIP1 as a moderate/low-penetrance breast cancer susceptibility gene. However, the phenotypic effects of BRIP1 dysfunction and its role in breast cancer tumorigenesis remain unclear. To explore the function of BRIP1 in acinar morphogenesis of mammary epithelial cells, we generated BRIP1-knockdown MCF-10A cells by short hairpin RNA (shRNA-mediated RNA interference and examined its effect in a three-dimensional culture model. Genome-wide gene expression profiling by microarray and quantitative RT-PCR were performed to identify alterations in gene expression in BRIP1-knockdown cells compared with control cells. The microarray data were further investigated using the pathway analysis and Gene Set Enrichment Analysis (GSEA for pathway identification. BRIP1 knockdown in non-malignant MCF-10A mammary epithelial cells by RNA interference induced neoplastic-like changes such as abnormal cell adhesion, increased cell proliferation, large and irregular-shaped acini, invasive growth, and defective lumen formation. Differentially expressed genes, including MCAM, COL8A1, WIPF1, RICH2, PCSK5, GAS1, SATB1, and ELF3, in BRIP1-knockdown cells compared with control cells were categorized into several functional groups, such as cell adhesion, polarity, growth, signal transduction, and developmental process. Signaling-pathway analyses showed dysregulation of multiple cellular signaling pathways, involving LPA receptor, Myc, Wnt, PI3K, PTEN as well as DNA damage response, in BRIP1-knockdown cells. Loss of BRIP1 thus disrupts normal mammary morphogenesis and causes neoplastic-like changes, possibly via dysregulating multiple cellular signaling pathways functioning in the normal development of mammary glands.

  5. Analysis of loss of heterozygosity of the tumor suppressor genes p53 and BRCA1 in ovarial carcinomas

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    Luković Ljiljana

    2006-01-01

    Full Text Available Background/aim: Among the genes involved in ovarian carcinogenesis, there has been increased interest in tumor-suppressor genes p53 and BRCA1. Both of the genes make control of cell cycle, DNA repair and apoptosis. The p53 is a "genome guardian" inactivated in more than 50% of human cancers, while BRCA1 mutations are found mostly in breast and ovarian cancer. The aim of this investigation was to establish the frequency of loss of heterozygosity (LOH in the regions of the genes p53 and BRCA1 in ovarian carcinomas, and to analyze the association of LOH with the disease stage and prognosis. Methods. We analyzed 20 patients with a confirmed diagnosis of epithelilal ovarian carcinoma. DNA for molecular-genetic analysis was extracted from the tumor tissue and blood as normal tissue of each person. Microsatellite markers of the regions of genes p53 and BRCA1 were amplified by PCR method. The determination of allelic status of microsatellites and detection of LOH was performed after PAA gel electroforesis. Results. Both of the analyzed microsatellite markers were informative in 13/20 (65% cases. In the region of gene p53, LOH was established in 4/13 (30.7% tumors. One of them had histological gradus G1, one had gradus G2, and two of them had gradus G3, while all were with the International Federation of Gynecology and Obstetrics (FIGO IIIc stage. In the region of gene BRCA1, LOH was detected in 5/13 (38.5% tumors. Four of them had histological gradus G2, and one had gradus G3, while by the (FIGO classification one was with stage Ib, one was with stage IIIb, while the three were with stage IIIc. LOH in both of the analyzed regions was detected in one tumor (7.7%, with histological gradus G3 and the FIGO IIIc stage. Conclusion. The frequency of LOH in epthelial ovarian carcinomas was 30.7% and 38.5% for p53 and BRCA1 gene regions, respectively. Most of tumors with LOH had histological gradus G2 or G3, and the clinical FIGO stage IIIc, suggesting the

  6. BRCA1 loss pre-existing in small subpopulations of prostate cancer is associated with advanced disease and metastatic spread to lymph nodes and peripheral blood

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    Bednarz, Natalia; Eltze, Elke; Semjonow, Axel; Rink, Michael; Andreas, Antje; Mulder, Lennart; Hannemann, Juliane; Fisch, Margit; Pantel, Klaus; Weier, Heinz-Ulrich G.; Bielawski, Krzysztof P.; Brandt, Burkhard

    2010-03-19

    A recent study concluded that serum prostate specific antigen (PSA)-based screening is beneficial for reducing the lethality of PCa, but was also associated with a high risk of 'overdiagnosis'. Nevertheless, also PCa patients who suffered from organ confined tumors and had negative bone scans succumb to distant metastases after complete tumor resection. It is reasonable to assume that those tumors spread to other organs long before the overt manifestation of metastases. Our current results confirm that prostate tumors are highly heterogeneous. Even a small subpopulation of cells bearing BRCA1 losses can initiate PCa cell regional and distant dissemination indicating those patients which might be at high risk of metastasis. A preliminary study performed on a small cohort of multifocal prostate cancer (PCa) detected BRCA1 allelic imbalances (AI) among circulating tumor cells (CTCs). The present analysis was aimed to elucidate the biological and clinical role of BRCA1 losses on metastatic spread and tumor progression in prostate cancer patients. Experimental Design: To map molecular progression in PCa outgrowth we used FISH analysis of tissue microarrays (TMA), lymph node sections and CTC from peripheral blood. We found that 14% of 133 tested patients carried monoallelic BRCA1 loss in at least one tumor focus. Extended molecular analysis of chr17q revealed that this aberration was often a part of larger cytogenetic rearrangement involving chr17q21 accompanied by AI of the tumor suppressor gene PTEN and lack of the BRCA1 promoter methylation. The BRCA1 losses correlated with advanced T stage (p < 0.05), invasion to pelvic lymph nodes (LN, p < 0.05) as well as BR (p < 0.01). Their prevalence was twice as high within 62 LN metastases (LNMs) as in primary tumors (27%, p < 0.01). The analysis of 11 matched primary PCa-LNM pairs confirmed the suspected transmission of genetic abnormalities between those two sites. In 4 of 7 patients with metastatic disease, BRCA1

  7. Characterization of familial non-BRCA1/2 breast tumors by loss of heterozygosity and immunophenotyping.

    NARCIS (Netherlands)

    Oldenburg, R.A.; Kroeze-Jansema, K.; Meijers-Heijboer, H.; Asperen, C.J. van; Hoogerbrugge-van der Linden, N.; Leeuwen, I. van; Vasen, H.F.; Cleton-Jansen, A.M.; Kraan, J.; Houwing-Duistermaat, J.J.; Morreau, H.; Cornelisse, C.J.; Devilee, P.

    2006-01-01

    PURPOSE: Since the identification of BRCA1 and BRCA2, there has been no major breast cancer susceptibility gene discovered by linkage analysis in breast cancer families. This has been attributed to the heterogeneous genetic basis for the families under study. Recent studies have indicated that breas

  8. The mechanism of BRCA1 participate sporadic breast carcinomas genesis

    Institute of Scientific and Technical Information of China (English)

    WEI Min-jie; REN Jie

    2008-01-01

    Objective To elucidate the BRCA1 participated mechanism of genesis and development of sporadic breast cancer through detect the statues of BRCA1 and analysis the relationship with the pathologic and clinic parameters. Methods BRCA1 statues were respectively analyzed in frozen samples or paraffine fixed sporadic breast carcinoma and benign breast tissues by three methods: protein expression by immunohistochemistry (IHC), the methylation of BRCA 1 promoter by methylation specific PCR (MSP), gene copy number by interphase fluorescence in situ hybridization (FISH). Results 14.2 % (29/204) cases were detected hypermethylation of BRCA1 promoter in sporadic breast cancer. BRCA1 mean copy number in sporadic breast cancer (1.70±0.14) less than those in benign tissues (2.03±0.08, P<0.05), and in sporadic breast cancer with hypermethylation of BRCA1 (1.62±0.09) significantly less than in those without hypermethylation (1.84±0.26, P<0.05). The loss copy related to the methylation of BRCA1 promoter. There were significant of 41.1% (88/214) cases no BRCA1 nuclei expression in sporadic breast cancers. Loss expression of BRCA1 had significant correlation with higher histological stages, axillary' s lymph nodal metastasis (P<0.01), lower expression of ERα, and overexpression of HER-2 protein( P<0.01). Conclusions There are BRCA 1 methylations, loss BRCA 1 gene copy and loss protein expression in the sporadic breast cancer, the three statues of BRCA1 is correlated to each other;and the loss expression of BRCA1 protein related to part of pathology and clinic parameters.

  9. BRCA1 loses the ring but lords over resistance.

    Science.gov (United States)

    Powell, Simon N

    2016-08-01

    Germline breast cancer 1 (BRCA1) variants are associated with a high risk of breast and ovarian cancers. Many BRCA1-mediated cancers are initially responsive to platinum-based therapy; however, resistance commonly develops. The BRCA1185delAG mutation is common in the Ashkenazi Jewish population and has been thought to result in loss of function due to the introduction of a stop codon in the 5' region of the BRCA1 transcript. Two studies in this issue of the JCI reveal that the BRCA1185delAG mutation results in the production of BRCA1 that lacks the N-terminal really interesting new gene (RING) domain. RING-less BRCA1 was shown to directly mediate chemoresistance, while maintaining some homologous recombination function. These results provide important insight into BRCA1 function and indicate that other truncated proteins could arise through similar alterations in codon usage. PMID:27454288

  10. Transgenic expression of BRCA1 disturbs hematopoietic stem and progenitor cells quiescence and function

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    Bai, Lin; Shi, Guiying; Zhang, Xu; Dong, Wei; Zhang, Lianfeng, E-mail: zhanglf@cnilas.org

    2013-10-15

    The balance between quiescence and proliferation of HSCs is an important regulator of hematopoiesis. Loss of quiescence frequently results in HSCs exhaustion, which underscores the importance of tight regulation of proliferation in these cells. Studies have indicated that cyclin-dependent kinases are involved in the regulation of quiescence in HSCs. BRCA1 plays an important role in the repair of DNA double-stranded breaks, cell cycle, apoptosis and transcription. BRCA1 is expressed in the bone marrow. However, the function of BRCA1 in HSCs is unknown. In our study, we generated BRCA1 transgenic mice to investigate the effects of BRCA1 on the mechanisms of quiescence and differentiation in HSCs. The results demonstrate that over-expression of BRCA1 in the bone marrow impairs the development of B lymphocytes. Furthermore, BRCA1 induced an increase in the number of LSKs, LT-HSCs, ST-HSCs and MPPs. A competitive transplantation assay found that BRCA1 transgenic mice failed to reconstitute hematopoiesis. Moreover, BRCA1 regulates the expression of p21{sup waf1}/cip1 and p57{sup kip2}, which results in a loss of quiescence in LSKs. Together, over-expression of BRCA1 in bone marrow disrupted the quiescent of LSKs, induced excessive accumulation of LSKs, and disrupted differentiation of the HSCs, which acts through the down-regulated of p21{sup waf1}/cip1 and p57{sup kip2}. - Highlights: • Over-expression of BRCA1 results in impaired B lymphocyte development. • BRCA1 transgenic mice disrupted the quiescent of LSKs, induced excessive accumulation of LSKs. • BRCA1 impairs the function of HSCs through the down-regulated of p21{sup waf1/cip1} and p57{sup kip2}.

  11. BRCA1 Protein Expression Level and CD44+ Phenotype in Breast Cancer Patients

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    Saadat Molanae

    2011-01-01

    Full Text Available Objective: CD44+/CD24-/low breast cancer cells have tumour-initiating properties with stemcell-like features. Breast cancer gene 1 (BRCA1 is a tumour suppressor gene that playsa crucial role in DNA repair and maintenance of chromosome stability. The clinicopathologicalfeatures of breast cancer in BRCA1 mutation carriers suggest that BRCA1 mayfunction as a stem-cell regulator.Materials and Methods: In the present experimental study we examined the expressionand localization of the BRCA1 protein and investigated the prognostic value aswell as its relationship with the putative cancer stem cell (CSC marker (CD44 in 156tumour samples from a well-characterized series of unselected breast carcinomas usingimmunohistochemistry. Statistical analysis of the data was performed using SPSSsoftware version 16 (Chicago, IL, USA.Results: In breast tumours, the loss of nuclear expression was detected in 23 cases(15%, whereas cytoplasmic expression of BRCA1 was observed in 133 breast carcinomas(85%. Altered BRCA1 expression was significantly associated with high grade and poorprognosis breast tumours (p=0.006. We further established an inverse significant correlationbetween BRCA1 expression levels and CD44+ cancer cell phenotype (p=0.02Conclusion: Loss of BRCA1 expression is a marker of tumour aggressiveness andcorrelates with CD44+ tumour cell phenotype. Taken together, the present study supportsthe idea that the loss of BRCA1 results in persistent errors in DNA replication inbreast stem cells and provides targets for additional carcinogenic events.

  12. Identification of BRCA1-deficient ovarian cancers

    DEFF Research Database (Denmark)

    Skytte, Anne-Bine; Waldstrøm, Marianne; Rasmussen, Anders Aamann;

    2011-01-01

    . 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...... but no mutation detected, and 25 ovarian cancers with unknown BRCA1 status. Results. Abnormal BRCA1 IHC was found to indicate BRCA mutations with a sensitivity of 80%, a specificity of 93%, and an estimated positive predictive value of 73%. FISH analyses supported the diagnosis in most cases. Methylation analyses...... could indicate BRCA deficiency in combination with one of the other methods. Conclusions. BRCA1 IHC is a promising screening method for BRCA1 mutation detection....

  13. A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor negative and positive breast cancers

    Science.gov (United States)

    Weigelt, Britta; Wilkerson, Paul M; Manie, Elodie; Grigoriadis, Anita; A’Hern, Roger; van der Groep, Petra; Kozarewa, Iwanka; Popova, Tatiana; Mariani, Odette; Turaljic, Samra; Furney, Simon J; Marais, Richard; Rodruigues, Daniel-Nava; Flora, Adriana C; Wai, Patty; Pawar, Vidya; McDade, Simon; Carroll, Jason; Stoppa-Lyonnet, Dominique; Green, Andrew R; Ellis, Ian O; Swanton, Charles; van Diest, Paul; Delattre, Olivier; Lord, Christopher J; Foulkes, William D; Vincent-Salomon, Anne; Ashworth, Alan; Stern, Marc Henri; Reis-Filho, Jorge S

    2016-01-01

    BRCA1 encodes a tumour suppressor protein that plays pivotal roles in homologous recombination (HR) DNA repair, cell-cycle checkpoints, and transcriptional regulation. BRCA1 germline mutations confer a high risk of early-onset breast and ovarian cancer. In >80% of cases, tumours arising in BRCA1 germline mutation carriers are oestrogen receptor (ER)-negative, however up to 15% are ER-positive. It has been suggested that BRCA1 ER-positive breast cancers constitute sporadic cancers arising in the context of a BRCA1 germline mutation rather than being causally related to BRCA1 loss-of-function. Whole-genome massively parallel sequencing of ER-positive and ER-negative BRCA1 breast cancers, and their respective germline DNAs, was used to characterise the genetic landscape of BRCA1 cancers at base-pair resolution. Only BRCA1 germline mutations and somatic loss of the wild-type allele, and TP53 somatic mutations were recurrently found in the index cases. BRCA1 breast cancers displayed a mutational signature consistent with that caused by lack of HR DNA repair in both ER-positive and ER-negative cases. Sequencing analysis of independent cohorts of hereditary BRCA1 and sporadic non-BRCA1 breast cancers for the presence of recurrent pathogenic mutations and/or homozygous deletions found in the index cases revealed that DAPK3, TMEM135, KIAA1797, PDE4D and GATA4 are potential additional drivers of breast cancers. This study demonstrates that BRCA1 pathogenic germline mutations coupled with somatic loss of the wild-type allele are not sufficient for hereditary breast cancers to display an ER-negative phenotype, and has led to the identification of three potential novel breast cancer genes (i.e. DAPK3, TMEM135 and GATA4). PMID:22362584

  14. Breast Cancer Susceptibility Gene1 (BRCA1

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    Wasiksiri, S.

    2002-07-01

    Full Text Available Breast Cancer Susceptibility Gene1 (BRCA1 is a tumor suppressor gene for breast and ovarian cancers. The gene locates at chromosome 17q21 and encodes for 1863 amino acids protein. It is believed that BRCA1 protein is involved in many functions such as DNA repair, centrosome replication, cell cycle checkpoint and replication of other genes. More than 800 mutations have been found in the population with an increased risk of cancer incidence in their families. Germ-line mutation of BRCA1 accounts for 5-10 percent of all breast cancer cases. Epigenetic modifications also reduce the function of normal BRCA1 gene. Several methods are used for laboratory diagnosis of cancer-related mutations. The development of breast cancer in carriers at risk with BRCA1 mutations may be prevented by suitable prevention plans such as breast cancer screening, ovarian cancer screening, surgery and cancer chemotherapy.

  15. Association of BLM and BRCA1 during Telomere Maintenance in ALT Cells.

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    Samir Acharya

    Full Text Available Fifteen percent of tumors utilize recombination-based alternative lengthening of telomeres (ALT to maintain telomeres. The mechanisms underlying ALT are unclear but involve several proteins involved in homologous recombination including the BLM helicase, mutated in Bloom's syndrome, and the BRCA1 tumor suppressor. Cells deficient in either BLM or BRCA1 have phenotypes consistent with telomere dysfunction. Although BLM associates with numerous DNA damage repair proteins including BRCA1 during DNA repair, the functional consequences of BLM-BRCA1 association in telomere maintenance are not completely understood. Our earlier work showed the involvement of BRCA1 in different mechanisms of ALT, and telomere shortening upon loss of BLM in ALT cells. In order to delineate their roles in telomere maintenance, we studied their association in telomere metabolism in cells using ALT. This work shows that BLM and BRCA1 co-localize with RAD50 at telomeres during S- and G2-phases of the cell cycle in immortalized human cells using ALT but not in cells using telomerase to maintain telomeres. Co-immunoprecipitation of BRCA1 and BLM is enhanced in ALT cells at G2. Furthermore, BRCA1 and BLM interact with RAD50 predominantly in S- and G2-phases, respectively. Biochemical assays demonstrate that full-length BRCA1 increases the unwinding rate of BLM three-fold in assays using a DNA substrate that models a forked structure composed of telomeric repeats. Our results suggest that BRCA1 participates in ALT through its interactions with RAD50 and BLM.

  16. BRCA1 interacts with Smad3 and regulates Smad3-mediated TGF-beta signaling during oxidative stress responses.

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    Huchun Li

    Full Text Available BACKGROUND: BRCA1 is a key regulatory protein participating in cell cycle checkpoint and DNA damage repair networks. BRCA1 plays important roles in protecting numerous cellular processes in response to cell damaging signals. Transforming growth factor-beta (TGF-beta is a potent regulator of growth, apoptosis and invasiveness of tumor cells. TFG-beta activates Smad signaling via its two cell surface receptors, the TbetaRII and ALK5/TbetaRI, leading to Smad-mediated transcriptional regulation. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report an important role of BRCA1 in modulating TGF-beta signaling during oxidative stress responses. Wild-type (WT BRCA1, but not mutated BRCA1 failed to activate TGF-beta mediated transactivation of the TGF-beta responsive reporter, p3TP-Lux. Further, WT-BRCA1, but not mutated BRCA1 increased the expression of Smad3 protein in a dose-dependent manner, while silencing of WT-BRCA1 by siRNA decreased Smad3 and Smad4 interaction induced by TGF-beta in MCF-7 breast cancer cells. BRCA1 interacted with Smad3 upon TGF-beta1 stimulation in MCF-7 cells and this interaction was mediated via the domain of 298-436aa of BRCA1 and Smad3 domain of 207-426aa. In addition, H(2O(2 increased the colocalization and the interaction of Smad3 with WT-BRCA1. Interestingly, TGF-beta1 induced Smad3 and Smad4 interaction was increased in the presence of H(2O(2 in cells expressing WT-BRCA1, while the TGF-beta1 induced interaction between Smad3 and Smad4 was decreased upon H(2O(2 treatment in a dose-dependent manner in HCC1937 breast cancer cells, deficient for endogenous BRCA1. This interaction between Smad3 and Smad4 was increased in reconstituted HCC1937 cells expressing WT-BRCA1 (HCC1937/BRCA1. Further, loss of BRCA1 resulted in H(2O(2 induced nuclear export of phosphor-Smad3 protein to the cytoplasm, resulting decreased of Smad3 and Smad4 interaction induced by TGF-beta and in significant decrease in Smad3 and Smad4 transcriptional

  17. Analysis of BRCA1 involvement in breast cancer in Indian women

    Indian Academy of Sciences (India)

    P H Pestonjamasp; I Mittra

    2000-03-01

    The involvement of the familial breast-ovarian cancer gene (BRCA1) in the molecular pathogenesis of breast cancer among Indian women is unknown. We have used a set of microsatellite polymorphisms to examine the frequency of allele loss at the BRCA1 region on chromosome 17q21, in a panel of 80 human breast tumours. Tumour and blood leukocyte/normal tissue DNA from a series of 80 patients with primary breast cancer was screened by PCR-amplified microsatellite length polymorphisms to detect deletions at three polymorphic BRCA1 loci. PCR-allelotype was valuable in examining allele losses from archival and small tumour samples. Loss of alleles at BRCA1 in the patient set, confirmed a noteworthy role of this gene in the molecular pathogenesis of breast cancer and was in accordance with its well-documented tumour suppressive function.

  18. The Prognostic Value of BRCA1 and PARP Expression in Epithelial Ovarian Carcinoma

    DEFF Research Database (Denmark)

    Hjortkjær, Mette; Waldstrøm, Marianne; Jakobsen, Anders;

    2016-01-01

    BRCA1/2 mutation status in epithelial ovarian cancer (EOC) presently relies on genetic testing which is resource consuming. Immunohistochemistry is cheap, fairly reproducible, and may identify gene product alterations due to both germline and somatic mutations and other defects along the BRCA gene...... tissue from 170 patients with EOC was stained immunohistochemically with BRCA1 and PARP antibodies. Semiquantitative analyses were performed to determine loss of, equivocal, and retained BRCA1 and high versus low PARP protein expression. These parameters were analyzed for relation with patient and...

  19. BRCA1 and BRCA2 Mutations

    Science.gov (United States)

    ... risk of cancer of the ovary , fallopian tube , peritoneum , and pancreas. Men who have a BRCA1 or ... one of the previous criteria? *Cancer of the peritoneum and fallopian tubes should be considered a part ...

  20. Evidence for a pathogenic role of BRCA1 L1705P and W1837X germ-line mutations.

    Science.gov (United States)

    Sokolenko, Anna P; Volkov, Nikita M; Preobrazhenskaya, Elena V; Suspitsin, Evgeny N; Garifullina, Aigul R; Ivantsov, Alexandr V; Togo, Alexandr V; Imyanitov, Evgeny N

    2016-05-01

    BRCA1 L1705P (c.5114T>C) has been classified in the NCBI SNP database as the variant with uncertain significance and is absent in major BRCA1 databases. BRCA1 W1837X (c.5511G>A) results in a loss of only last 27 residues of BRCA1 protein, thus its pathogenic role still requires a confirmation. This report describes two breast cancer (BC) patients carrying BRCA1 L1705P and W1837X germ-line mutations, respectively. Significant evidence for BC-predisposing impact of the mentioned mutations have been obtained: (1) both index cases presented with the triple-negative receptor status of BC disease; (2) complete segregation with BRCA1-related cancers was observed in the families of these patients; (3) somatic loss of the remaining (wild-type) BRCA1 allele was detected in tumor tissues of the affected women. The results of this study have to be taken into account while providing genetic counseling to cancer patients and while considering the use of BRCA1-specific therapeutic compounds for BC treatment. PMID:26951538

  1. BRCA1-Dependent Translational Regulation in Breast Cancer Cells.

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    Estelle Dacheux

    Full Text Available BRCA1 (Breast Cancer 1 has been implicated in a number of cellular processes, including transcription regulation, DNA damage repair and protein ubiquitination. We previously demonstrated that BRCA1 interacts with PABP1 (Poly(A-Binding Protein 1 and that BRCA1 modulates protein synthesis through this interaction. To identify the mRNAs that are translationally regulated by BRCA1, we used a microarray analysis of polysome-bound mRNAs in BRCA1-depleted and non-depleted MCF7 cells. Our findings show that BRCA1 modifies the translational efficiency of approximately 7% of the mRNAs expressed in these cells. Further analysis revealed that several processes contributing to cell surveillance such as cell cycle arrest, cell death, cellular growth and proliferation, DNA repair and gene expression, are largely enriched for the mRNAs whose translation is impacted by BRCA1. The BRCA1-dependent translation of these species of mRNAs therefore uncovers a novel mechanism through which BRCA1 exerts its onco-suppressive role. In addition, the BRCA1-dependent translation of mRNAs participating in unexpected functions such as cellular movement, nucleic acid metabolism or protein trafficking is indicative of novel functions for BRCA1. Finally, this study contributes to the identification of several markers associated with BRCA1 deficiency and to the discovery of new potential anti-neoplastic therapeutic targets.

  2. Analysis list: Brca1 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Brca1 Blood + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Brca1.1.tsv... http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Brca1.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Brca...1.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Brca1.Blood.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Blood.gml ...

  3. Factors forming the BRCA1-A complex orchestrate BRCA1 recruitment to the sites of DNA damage

    Institute of Scientific and Technical Information of China (English)

    Joonyoung Her; Nam Soo Lee; Yonghwan Kim; Hongtae Kim

    2016-01-01

    Sustaining genomic integrity is essential for preventing onset of cancers.Therefore,human cells evolve to have refined biological pathways to defend genetic materials from various genomic insults.DNA damage response and DNA repair pathways essential for genome maintenance are accomplished by cooperative executions of multiple factors including breast cancer type 1 susceptibility protein (BRCA1).BRCAI is initially identified as an altered gene in the hereditary breast cancer patients.Since then,tremendous efforts to understand the functions of BRAC1 reveal that BRCA1 is found in distinct complexes,including BRCA1-A,BRCA1-B,BRCA1-C,and the BRCA1a PALB2aBRCA2 complex,and plays diverse roles in a context-dependent manner.Among the complexes,BRCA1-A is critical for BRCA1 recruitment to the sites of DNA damage.Factors comprising the BRCA1-A include RAP80,CCDC98aAbraxas,BRCC36,BRCC45,BARD1,BRCA1,and MERIT40,a RAP80-associated factor.In this review,we summarize recent findings of the factors that form the BRCA1-A complex.

  4. Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.

    Directory of Open Access Journals (Sweden)

    Christopher A Maxwell

    2011-11-01

    Full Text Available Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((wHR = 1.09 (95% CI 1.02-1.16, p(trend = 0.017; and n = 3,965, (wHR = 1.04 (95% CI 0.94-1.16, p(trend = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.

  5. Different Array CGH profiles within hereditary breast cancer tumors associated to BRCA1 expression and overall survival

    OpenAIRE

    Alvarez, Carolina; Aravena, Andrés; Tapia, Teresa; Rozenblum, Ester; Solís, Luisa; Corvalán, Alejandro; Camus, Mauricio; Alvarez, Manuel; Munroe, David; Maass, Alejandro; Carvallo, Pilar

    2016-01-01

    Background Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease. M...

  6. Survival in Norwegian BRCA1 mutation carriers with breast cancer

    OpenAIRE

    Hagen Anne; Tretli Steinar; Mæhle Lovise; Apold Jaran; Vedå Nina; Møller Pål

    2009-01-01

    Abstract Several studies of survival in women with BRCA1 mutations have shown either reduced survival or no difference compared to controls. Programmes for early detection and treatment of inherited breast cancer, have failed to demonstrate a significant improvement in survival in BRCA1 mutation carriers. One hundred and sixty-seven women with disease-associated germline BRCA1 mutations and breast cancer from 1980 to 2001 were identified. Tumour characteristics, treatment given and survival w...

  7. BRCA1-mediated repression of select X chromosome genes

    Directory of Open Access Journals (Sweden)

    Ropers H Hilger

    2004-09-01

    Full Text Available Abstract Recently BRCA1 has been implicated in the regulation of gene expression from the X chromosome. In this study the influence of BRCA1 on expression of X chromosome genes was investigated. Complementary DNA microarrays were used to compare the expression levels of X chromosome genes in 18 BRCA1-associated ovarian cancers to those of the 13 "BRCA1-like" and 14 "BRCA2-like" sporadic tumors (as defined by previously reported expression profiling. Significance was determined using parametric statistics with P

  8. Hemizygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis

    Directory of Open Access Journals (Sweden)

    Zhu Jiayun

    2010-02-01

    Full Text Available Abstract Background In recent years data from both mouse models and human tumors suggest that loss of one allele of genes involved in DNA repair pathways may play a central role in genomic instability and carcinogenesis. Additionally several examples in mouse models confirmed that loss of one allele of two functionally related genes may have an additive effect on tumor development. To understand some of the mechanisms involved, we examined the role of monoallelic loss or Atm and Brca1 on cell transformation and apoptosis induced by radiation. Methods Cell transformation and apoptosis were measured in mouse embryo fibroblasts (MEF and thymocytes respectively. Combinations of wild type and hemizygous genotypes for ATM and BRCA1 were tested in various comparisons. Results Haploinsufficiency of either ATM or BRCA1 resulted in an increase in the incidence of radiation-induced transformation of MEF and a corresponding decrease in the proportion of thymocytes dying an apoptotic death, compared with cells from wild-type animals. Combined haploinsufficiency for both genes resulted in an even larger effect on apoptosis. Conclusions Under stress, the efficiency and capacity for DNA repair mediated by the ATM/BRCA1 cell signalling network depends on the expression levels of both proteins.

  9. Hemizygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis

    International Nuclear Information System (INIS)

    In recent years data from both mouse models and human tumors suggest that loss of one allele of genes involved in DNA repair pathways may play a central role in genomic instability and carcinogenesis. Additionally several examples in mouse models confirmed that loss of one allele of two functionally related genes may have an additive effect on tumor development. To understand some of the mechanisms involved, we examined the role of monoallelic loss or Atm and Brca1 on cell transformation and apoptosis induced by radiation. Cell transformation and apoptosis were measured in mouse embryo fibroblasts (MEF) and thymocytes respectively. Combinations of wild type and hemizygous genotypes for ATM and BRCA1 were tested in various comparisons. Haploinsufficiency of either ATM or BRCA1 resulted in an increase in the incidence of radiation-induced transformation of MEF and a corresponding decrease in the proportion of thymocytes dying an apoptotic death, compared with cells from wild-type animals. Combined haploinsufficiency for both genes resulted in an even larger effect on apoptosis. Under stress, the efficiency and capacity for DNA repair mediated by the ATM/BRCA1 cell signalling network depends on the expression levels of both proteins

  10. BRCA1 mutations in Brazilian patients

    Directory of Open Access Journals (Sweden)

    Juliano Javert Lourenço

    2004-01-01

    Full Text Available BRCA1 mutations are known to be responsible for the majority of hereditary breast and ovarian cancers in women with early onset and a family history of the disease. In this paper we present a mutational survey conducted in 47 Brazilian patients with breast/ovarian cancer, selected based on age at diagnosis, family history, tumor laterality, and presence of breast cancer in male patients. All 22 coding exons and intron-exon junctions were sequenced. Constitutional mutations were found in seven families, consisting of one insertion (insC5382 in exon 20 (four patients, one four base-pair deletion (3450-3453delCAAG in exon 11 resulting in a premature stop codon (one patient, one transition (IVS17+2T> C in intron 17 affecting a mRNA splicing site (one patient, and a C> T transition resulting in a stop-codon (Q1135X in exon 11 (one patient. The identification of these mutations which are associated to hereditary breast and ovarian cancers will contribute to the characterization of the mutational spectrum of BRCA1 and to the improvement of genetic counseling for familial breast/ovarian cancer patients in Brazil.

  11. Comprehensive BRCA1 and BRCA2 mutational profile in Lithuania.

    Science.gov (United States)

    Janavičius, Ramūnas; Rudaitis, Vilius; Mickys, Ugnius; Elsakov, Pavel; Griškevičius, Laimonas

    2014-05-01

    There is limited knowledge about the BRCA1/2 mutational profile in Lithuania. We aimed to define the full BRCA1 and BRCA2 mutational spectrum and the clinically relevant prevalence of these gene mutations in Lithuania. A data set of 753 unrelated probands, recruited through a clinical setting, was used and consisted of 380 female breast cancer cases, 213 epithelial ovarian cancer cases, 20 breast and ovarian cancer cases, and 140 probands with positive family history of breast or ovarian cancer. A comprehensive mutation analysis of the BRCA1/2 genes by high resolution melting analysis coupled with Sanger sequencing and multiplex ligation-dependent probe amplification analysis was performed. Genetic analysis revealed 32 different pathogenic germline BRCA1/2 mutations: 20 in the BRCA1 gene and 12 in the BRCA2 gene, including four different large genomic rearrangements in the BRCA1 gene. In all, 10 novel BRCA1/2 mutations were found. Nine different recurrent BRCA1 mutations and two recurrent BRCA2 mutations were identified, which comprised 90.4% of all BRCA1/2 mutations. BRCA1 exon 1-3 deletion and BRCA2 c.658_659del are reported for the first time as recurrent mutations, pointing to a possible Baltic founder effect. Approximately 7% of breast cancer and 22% of ovarian cancer patients without family history and an estimated 0.5-0.6% of all Lithuanian women were found to be carriers of mutations in the BRCA1 or BRCA2 gene. PMID:25066507

  12. Distinct claudin expression characterizes BRCA1-related breast cancer

    NARCIS (Netherlands)

    van Voss, Marise R. Heerma; van Diest, Paul J.; Smolders, Yvonne H. C. M.; Bart, Joost; van der Wall, Elsken; van der Groep, Petra

    2014-01-01

    AimsMembers of the claudin family are involved in cancer progression and are differentially expressed in subtypes of breast cancer. Breast cancers in BRCA1 germ line mutation carriers have distinct clinicopathological characteristics. Biomarkers that discriminate between BRCA1-related and sporadic b

  13. BRCA1 in the DNA damage response and at telomeres

    Directory of Open Access Journals (Sweden)

    Eliot Michael Rosen

    2013-06-01

    Full Text Available Abstract. Mutations of the breast and ovarian cancer susceptibility gene 1 (BRCA1 account for about 40-45% of hereditary breast cancer cases. Moreover, a significant fraction of sporadic (non-hereditary breast and ovarian cancers exhibit reduced or absent expression of the BRCA1 protein, suggesting an additional role for BRCA1 in sporadic cancers. BRCA1 follows the classic pattern of a highly penetrant Knudsen-type tumor suppressor gene in which one allele is inactivated through a germ-line mutation and the other is mutated or deleted within the tumor. BRCA1 is a multi-functional protein but it is not fully understood which function(s is (are most important for tumor suppression, nor is it clear why BRCA1 mutations confer a high risk for breast and ovarian cancers and not a broad spectrum of tumor types. Here, we will review BRCA1 functions in the DNA damage response (DDR, which are likely to contribute to tumor suppression. In the process, we will highlight some of the controversies and unresolved issues in the field. We will also describe a recently identified and under-investigated role for BRCA1 in the regulation of telomeres and the implications of this role in the DDR and cancer suppression.

  14. BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation.

    LENUS (Irish Health Repository)

    Stordal, Britta

    2013-06-01

    Mutations in BRCA1\\/2 increase the risk of developing breast and ovarian cancer. Germline BRCA1\\/2 mutations occur in 8.6-13.7% of unselected epithelial ovarian cancers, somatic mutations are also frequent. BRCA1\\/2 mutated or dysfunctional cells may be sensitive to PARP inhibition by synthetic lethality. The aim of this study is to comprehensively characterise the BRCA1\\/2 status of a large panel of ovarian cancer cell lines available to the research community to assist in biomarker studies of novel drugs and in particular of PARP inhibitors. The BRCA1\\/2 genes were sequenced in 41 ovarian cell lines, mRNA expression of BRCA1\\/2 and gene methylation status of BRCA1 was also examined. The cytotoxicity of PARP inhibitors olaparib and veliparib was examined in 20 cell lines. The cell line SNU-251 has a deleterious BRCA1 mutation at 5564G > A, and is the only deleterious BRCA1\\/2 mutant in the panel. Two cell lines (UPN-251 and PEO1) had deleterious mutations as well as additional reversion mutations that restored the protein functionality. Heterozygous mutations in BRCA1\\/2 were relatively common, found in 14.6% of cell lines. BRCA1 was methylated in two cell lines (OVCAR8, A1847) and there was a corresponding decrease in gene expression. The BRCA1 methylated cell lines were more sensitive to PARP inhibition than wild-type cells. The SNU-251 deleterious mutant was more sensitive to PARP inhibition, but only in a long-term exposure to correct for its slow growth rate. Cell lines derived from metastatic disease are significantly more resistant to veliparib (2.0 fold p = 0.03) compared to those derived from primary tumours. Resistance to olaparib and veliparib was correlated Pearsons-R 0.5393, p = 0.0311. The incidence of BRCA1\\/2 deleterious mutations 1\\/41 cell lines derived from 33 different patients (3.0%) is much lower than the population incidence. The reversion mutations and high frequency of heterozygous mutations suggest that there is a selective

  15. A common Greenlandic Inuit BRCA1 RING domain founder mutation

    DEFF Research Database (Denmark)

    Hansen, T.v.O.; Ejlertsen, B.; Albrechtsen, Anders;

    2009-01-01

    of the families had members with ovarian cancer, suggesting that the RING domain may be an ovarian cancer hotspot. By SNP array analysis, we find that all 13 families share a 4.5 Mb genomic fragment containing the BRCA1 gene, showing that the mutation originates from a founder. Finally, analysis of 1152 Inuit......Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1...... exon 3 nucleotide 234 T > G mutation, which has not previously been reported in the breast cancer information core (BIC) database. The mutation changes a conserved cysteine 39 to a glycine in the Zn(2+) site II of the RING domain, which is essential for BRCA1 ubiquitin ligase activity. Eight...

  16. A common Greenlandic Inuit BRCA1 RING domain founder mutation

    DEFF Research Database (Denmark)

    Hansen, Thomas; Ejlertsen, Bent; Albrechtsen, Anders;

    2009-01-01

    Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1 e...... possibility to reduce mortality in gene carriers, may warrant screening of the Greenlandic Inuit population. Provided screening is efficient, about 5% of breast- and 13% of ovarian cancers, respectively, may be prevented.......Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1...... exon 3 nucleotide 234 T > G mutation, which has not previously been reported in the breast cancer information core (BIC) database. The mutation changes a conserved cysteine 39 to a glycine in the Zn(2+) site II of the RING domain, which is essential for BRCA1 ubiquitin ligase activity. Eight of the...

  17. BRCA1 tumor suppressor network: focusing on its tail

    Directory of Open Access Journals (Sweden)

    Wang Bin

    2012-02-01

    Full Text Available Abstract Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer. BRCA1 plays critical roles in the DNA damage response that regulates activities of multiple repair and checkpoint pathways for maintaining genome stability. The BRCT domains of BRCA1 constitute a phospho-peptide binding domain recognizing a phospho-SPxF motif (S, serine; P, proline; × varies; F, phenylalanine. The BRCT domains are frequently targeted by clinically important mutations and most of these mutations disrupt the binding surface of the BRCT domains to phosphorylated peptides. The BRCT domain and its capability to bind phosphorylated protein is required for the tumor suppressor function of BRCA1. Through its BRCT phospho-binding ability BRCA1 forms at least three mutually exclusive complexes by binding to phosphorylated proteins Abraxas, Bach1 and CTIP. The A, B and C complexes, at lease partially undertake BRCA1's role in mechanisms of cell cycle checkpoint and DNA repair that maintain genome stability, thus may play important roles in BRCA1's tumor suppressor function.

  18. Preliminary crystallographic studies of BRCA1 BRCT-ABRAXAS complex.

    Science.gov (United States)

    Badgujar, Dilip C; Sawant, Ulka; Yadav, Lumbini; Hosur, M V; Varma, Ashok K

    2013-12-01

    The BRCA1 holoenzyme complex plays an important role in DNA damage repair. ABRAXAS is a newly discovered component of this complex and its C-terminal region directly binds to the BRCA1 BRCT domain. Single crystals of the BRCA1 BRCT-ABRAXAS complex grown by co-crystallization belonged to space group P4(1)2(1)2, with unit-cell parameters a = b = 187.18, c = 85.31 Å. Diffraction data were collected on the BM-14 beamline at the ESRF. Molecular-replacement calculations using Phaser led to three molecules in the asymmetric unit and a high solvent content of 76%. PMID:24316840

  19. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    DEFF Research Database (Denmark)

    Cox, David G; Simard, Jacques; Sinnett, Daniel;

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly...... instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation...... carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence...

  20. BRCA1/2 associated hereditary breast cancer

    Institute of Scientific and Technical Information of China (English)

    Li-song TENG; Yi ZHENG; Hao-hao WANG

    2008-01-01

    Breast cancer is one of the leading causes of death in women today. Some of the patients are hereditary, with a large proportion characterized by mutation in BRCA1 and/or BRCA2 genes. In this review, we provide an overview of these two genes,focusing on their relationship with hereditary breast cancers. BRCA1/2 associated hereditary breast cancers have unique features that differ from the general breast cancers, including alterations in cellular molecules, pathological bases, biological behavior, and a different prevention strategy. But the outcome of BRCA1/2 associated hereditary breast cancers still remains controversial;further studies are needed to elucidate the nature of BRCA1/2 associated hereditary breast cancers.

  1. Evidence of a founder BRCA1 mutation in Scotland

    OpenAIRE

    Liede, A; Cohen, B.; Black, D. M.; Davidson, R H; Renwick, A; Hoodfar, E; Olopade, O.I.; Micek, M; Anderson, V.; Mey, R De; Fordyce, A; Warner, E.; Dann, J L; King, M-C; Weber, B.

    2000-01-01

    BRCA1 mutations have been identified in breast and ovarian cancer families from diverse ethnic backgrounds. We studied 17 different families with the BRCA1 2800delAA mutation; seven were ascertained in Scotland (Dundee, Edinburgh, Glasgow, St Andrews), five in Canada (Toronto, Victoria) and five in the United States (Chicago, Philadelphia, Seattle). Overall there was a clear preponderance of Scottish ancestry. Genotype analysis performed on key members from 17 families was consistent with a c...

  2. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    Science.gov (United States)

    Cox, David G.; Simard, Jacques; Sinnett, Daniel; Hamdi, Yosr; Soucy, Penny; Ouimet, Manon; Barjhoux, Laure; Verny-Pierre, Carole; McGuffog, Lesley; Healey, Sue; Szabo, Csilla; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Caligo, Maria A.; Friedman, Eitan; Laitman, Yael; Kaufman, Bella; Paluch, Shani S.; Borg, Åke; Karlsson, Per; Stenmark Askmalm, Marie; Barbany Bustinza, Gisela; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Benítez, Javier; Hamann, Ute; Rookus, Matti A.; van den Ouweland, Ans M.W.; Ausems, Margreet G.E.M.; Aalfs, Cora M.; van Asperen, Christi J.; Devilee, Peter; Gille, Hans J.J.P.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Adlard, Julian; Paterson, Joan; Eason, Jacqueline; Godwin, Andrew K.; Remon, Marie-Alice; Moncoutier, Virginie; Gauthier-Villars, Marion; Lasset, Christine; Giraud, Sophie; Hardouin, Agnès; Berthet, Pascaline; Sobol, Hagay; Eisinger, François; Bressac de Paillerets, Brigitte; Caron, Olivier; Delnatte, Capucine; Goldgar, David; Miron, Alex; Ozcelik, Hilmi; Buys, Saundra; Southey, Melissa C.; Terry, Mary Beth; Singer, Christian F.; Dressler, Anne-Catharina; Tea, Muy-Kheng; Hansen, Thomas V.O.; Johannsson, Oskar; Piedmonte, Marion; Rodriguez, Gustavo C.; Basil, Jack B.; Blank, Stephanie; Toland, Amanda E.; Montagna, Marco; Isaacs, Claudine; Blanco, Ignacio; Gayther, Simon A.; Moysich, Kirsten B.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Gadzicki, Dorothea; Fiebig, Britta; Caldes, Trinidad; Laframboise, Rachel; Nevanlinna, Heli; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan C.; Couch, Fergus J.; Wang, Xianshu; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Radice, Paolo; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Sinilnikova, Olga M.

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77–0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription. PMID:21890493

  3. BRCA1 regulates insulin-like growth factor 1 receptor levels in ovarian cancer

    OpenAIRE

    Liu, Bo; Li, Da; Guan, Yi-Fu

    2014-01-01

    Breast cancer 1 (BRCA1) and insulin-like growth factor 1 receptor (IGF1R) are critical in ovarian cancer progression. However, the crosstalk between the BRCA1 and IGF1R signaling pathways in ovarian cancer remains largely unknown. The effects of BRCA1 on IGF1R were assessed in 121 serous ovarian cancer patients (BRCA1 mutation, n=30; non-BRCA1 mutation, n=32; hypermethylated BRCA1 promoter, n=28; and non-methylation, n=31). BRCA1 promoter methylation was analyzed via bisulfite sequencing usin...

  4. First description of an acinic cell carcinoma of the breast in a BRCA1 mutation carrier: a case report

    International Nuclear Information System (INIS)

    Acinic cell carcinoma (ACC) is a rare malignant epithelial neoplasm characterized by the presence of malignant tubular acinar exocrine gland structures. Diagnosis is generally made in salivary glands and in the pancreas. ACC of the breast has been reported in few cases only. Carriers of inherited mutations in the BRCA1 gene are prone to the development of breast cancer, mainly invasive ductal or medullary type carcinomas. We describe for the first time a BRCA1 mutation carrier with a diagnosis of ACC of the breast. The patient developed an invasive ductal carcinoma (IDC) at the age of 40 years and an ACC in the contralateral breast at 44 years. Immunohistochemical examination of the ACC revealed a triple negative status (i.e., negativity for estrogen receptor, progesterone receptor and HER2 protein) and positivity for p53. Using a combination of loss of heterozygosity (LOH) and sequencing analyses, the loss of the wild-type BRCA1 allele was detected in both the ACC and the IDC. In addition, two different somatic TP53 mutations, one in the ACC only and another one in the IDC only, were observed. Both the immunohistochemical and molecular features observed in the ACC are typical of BRCA1-associated breast cancers and suggest an involvement of the patient’s germline mutation in the disease. The occurrence of rare histological types of breast cancers, including malignant phyllodes tumor, atypical medullary carcinoma and metaplastic carcinoma, in BRCA1 mutation carriers has been already reported. Our findings further broaden the spectrum of BRCA1-associated breast malignancies

  5. BRCA1 Mutation: A Predictive Marker for Radiation Therapy?

    International Nuclear Information System (INIS)

    DNA repair, in particular, DNA double-strand break (DSB) repair, is essential for the survival of both normal and cancer cells. An elaborate repair mechanism has been developed in cells to efficiently repair the damaged DNA. The pathways predominately involved in DSB repair are homologous recombination and classic nonhomologous end-joining, although the alternative NHEJ pathway, a third DSB repair pathway, could also be important in certain contexts. The protein of BRCA1 encoded by the tumor suppressor gene BRCA1 regulates all DSB repair pathways. Given that DSBs represent the most biologically significant lesions induced by ionizing radiation and that impaired DSB repair leads to radiation sensitivity, it has been expected that cancer patients with BRCA1 mutations should benefit from radiation therapy. However, the clinical data have been conflicting and inconclusive. We provide an overview about the current status of the data regarding BRCA1 deficiency and radiation therapy sensitivity in both experimental models and clinical investigations. In addition, we discuss a strategy to potentiate the effects of radiation therapy by poly(ADP-ribose) polymerase inhibitors, the pharmacologic drugs being investigated as monotherapy for the treatment of patients with BRCA1/2 mutations

  6. BRCA1 Mutation: A Predictive Marker for Radiation Therapy?

    Energy Technology Data Exchange (ETDEWEB)

    Kan, Charlene; Zhang, Junran, E-mail: Junran.zhang@case.edu

    2015-10-01

    DNA repair, in particular, DNA double-strand break (DSB) repair, is essential for the survival of both normal and cancer cells. An elaborate repair mechanism has been developed in cells to efficiently repair the damaged DNA. The pathways predominately involved in DSB repair are homologous recombination and classic nonhomologous end-joining, although the alternative NHEJ pathway, a third DSB repair pathway, could also be important in certain contexts. The protein of BRCA1 encoded by the tumor suppressor gene BRCA1 regulates all DSB repair pathways. Given that DSBs represent the most biologically significant lesions induced by ionizing radiation and that impaired DSB repair leads to radiation sensitivity, it has been expected that cancer patients with BRCA1 mutations should benefit from radiation therapy. However, the clinical data have been conflicting and inconclusive. We provide an overview about the current status of the data regarding BRCA1 deficiency and radiation therapy sensitivity in both experimental models and clinical investigations. In addition, we discuss a strategy to potentiate the effects of radiation therapy by poly(ADP-ribose) polymerase inhibitors, the pharmacologic drugs being investigated as monotherapy for the treatment of patients with BRCA1/2 mutations.

  7. BRCA1 founder mutations compared to ovarian cancer in Belarus.

    Science.gov (United States)

    Savanevich, Alena; Oszurek, Oleg; Lubiński, Jan; Cybulski, Cezary; Dębniak, Tadeusz; Narod, Steven A; Gronwald, Jacek

    2014-09-01

    In Belarus and other Slavic countries, founder mutations in the BRCA1 gene are responsible for a significant proportion of breast cancer cases, but the data on contribution of these mutations to ovarian cancers are limited. To estimate the proportion of ovarian cancers in Belarus, which are dependent on BRCA1 Slavic founder mutations, we sought the presence of three most frequent mutations (BRCA1: 5382insC, C61G and, 4153delA) in 158 consecutive unselected cases of ovarian cancer. One of the three founder mutations was present in 25 of 158 unselected cases of ovarian cancer (15.8 %). We recommend that all cases of ovarian cancer in Belarus be offered genetic testing for these founder mutations. Furthermore, genetic testing of the Belarusian population will provide the opportunity to prevent a significant proportion of ovarian cancer.

  8. Robust BRCA1-like classification of copy number profiles of samples repeated across different datasets and platforms

    NARCIS (Netherlands)

    Schouten, P.C.; Grigoriadis, A.; Kuilman, T.; Mirza, H.; Watkins, J.A.; Cooke, S.A.; Dyk, E. van; Severson, T.M.; Rueda, O.M.; Hoogstraat, M.; Verhagen, C.V.M.; Natrajan, R.; Chin, S.F.; Lips, E.H.; Kruizinga, J.; Velds, A.; Nieuwland, M.; Kerkhoven, R.M.; Krijgsman, O.; Vens, C.; Peeper, D.; Nederlof, P.M.; Caldas, C.; Tutt, A.N.; Wessels, L.F.; Linn, S.C.

    2015-01-01

    Breast cancers with BRCA1 germline mutation have a characteristic DNA copy number (CN) pattern. We developed a test that assigns CN profiles to be 'BRCA1-like' or 'non-BRCA1-like', which refers to resembling a BRCA1-mutated tumor or resembling a tumor without a BRCA1 mutation, respectively. Approxim

  9. The {Delta}Np63 Proteins Are Key Allies of BRCA1 in the Prevention of Basal-Like Breast Cancer.

    LENUS (Irish Health Repository)

    Buckley, Niamh E

    2011-03-01

    Little is known about the origin of basal-like breast cancers, an aggressive disease that is highly similar to BRCA1-mutant breast cancers. p63 family proteins that are structurally related to the p53 suppressor protein are known to function in stem cell regulation and stratified epithelia development in multiple tissues, and p63 expression may be a marker of basal-like breast cancers. Here we report that ΔNp63 isoforms of p63 are transcriptional targets for positive regulation by BRCA1. Our analyses of breast cancer tissue microarrays and BRCA1-modulated breast cancer cell lines do not support earlier reports that p63 is a marker of basal-like or BRCA1 mutant cancers. Nevertheless, we found that BRCA1 interacts with the specific p63 isoform ΔNp63γ along with transcription factor isoforms AP-2α and AP-2γ. BRCA1 required ΔNp63γ and AP-2γ to localize to an intronic enhancer region within the p63 gene to upregulate transcription of the ΔNp63 isoforms. In mammary stem\\/progenitor cells, siRNA-mediated knockdown of ΔNp63 expression resulted in genomic instability, increased cell proliferation, loss of DNA damage checkpoint control, and impaired growth control. Together, our findings establish that transcriptional upregulation of ΔNp63 proteins is critical for BRCA1 suppressor function and that defects in BRCA1-ΔNp63 signaling are key events in the pathogenesis of basal-like breast cancer. Cancer Res; 71(5); 1933-44. ©2011 AACR.

  10. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families

    Energy Technology Data Exchange (ETDEWEB)

    Friedman, L.S.; Szabo, C.I.; Ostermeyer, E.A. [Univ. of California, Berkeley, CA (United States)] [and others

    1995-12-01

    Thirty-seven families with four or more cases of breast cancer or breast and ovarian cancer were analyzed for mutations in BRCA1. Twelve different germ-line mutations, four novel and eight previously observed, were detected in 16 families. Five families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at eight polymorphic markers spanning {approximately}850 kb at BRCA1. Expressivity of 185delAG in these families varied, from early-onset bilateral breast cancer and ovarian cancer to late-onset breast cancer without ovarian cancer. Mutation 4184delTCAA occurred independently in two families. In one family, penetrance was complete, with females developing early-onset breast cancer or ovarian cancer and the male carrier developing prostatic cancer, whereas, in the other family, penetrance was incomplete and only breast cancer occurred, diagnosed at ages 38-81 years. Two novel nonsense mutations led to the loss of mutant BRCA1 transcript in families with 10 and 6 cases of early-onset breast cancer and ovarian cancer. A 665-nt segment of the BRCA1 3{prime}-UTR and 1.3 kb of genomic sequence including the putative promoter region were invariant by single-strand conformation analysis in 13 families without coding-sequence mutations. Overall in our series, BRCA1 mutations have been detected in 26 families: 16 with positive BRCA1 lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage. Three other families have positive lod scores for linkage to BRCA2, but 13 families without detected BRCA1 mutations have negative lod scores for both BRCA1 and BRCA2. 57 refs., 5 figs., 3 tabs.

  11. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families.

    Science.gov (United States)

    Friedman, L S; Szabo, C I; Ostermeyer, E A; Dowd, P; Butler, L; Park, T; Lee, M K; Goode, E L; Rowell, S E; King, M C

    1995-12-01

    Thirty-seven families with four or more cases of breast cancer or breast and ovarian cancer were analyzed for mutations in BRCA1. Twelve different germ-line mutations, four novel and eight previously observed, were detected in 16 families. Five families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at eight polymorphic markers spanning approximately 850 kb at BRCA1. Expressivity of 185delAG in these families varied, from early-onset breast cancer without ovarian cancer. Mutation 4184delTCAA occurred independently in two families. In one family, penetrance was complete, with females developing early-onset breast cancer or ovarian cancer and the male carrier developing prostatic cancer, whereas, in the other family, penetrance was incomplete and only breast cancer occurred, diagnosed at ages 38-81 years. Two novel nonsense mutations led to the loss of mutant BRCA1 transcript in families with 10 and 6 cases of early-onset breast cancer and ovarian cancer. A 665-nt segment of the BRCA1 3'-UTR and 1.3 kb of genomic sequence including the putative promoter region were invariant by single-strand conformation analysis in 13 families without coding-sequence mutations. Overall in our series, BRCA1 mutations have been detected in 26 families: 16 with positive BRCA1 lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage. Three other families have positive lod scores for linkage to BRCA2, but 13 families without detected BRCA1 mutations have negative lod scores for both BRCA1 and BRCA2. PMID:8533757

  12. BRCA1/BRCA2 founder mutations and cancer risks

    DEFF Research Database (Denmark)

    Roed Nielsen, Henriette; Nilbert, Mef; Petersen, Janne;

    2016-01-01

    Mutations in the BRCA1 and BRCA2 genes significantly contribute to hereditary breast cancer and ovarian cancer, but the phenotypic effect from different mutations is insufficiently recognized. We used a western Danish clinic-based cohort of 299 BRCA families to study the female cancer risk...... in mutation carriers and their untested first-degree relatives. Founder mutations were characterized and the risk of cancer was assessed in relation to the specific mutations. In BRCA1, the cumulative cancer risk at age 70 was 35 % for breast cancer and 29 % for ovarian cancer. In BRCA2, the cumulative risk...... was 44 % for breast cancer and 15 % for ovarian cancer. We identified 47 distinct BRCA1 mutations and 48 distinct mutations in BRCA2. Among these, 8 founder mutations [BRCA1 c.81-?_4986+?del, c.3319G>T (p.Glu1107*), c.3874delT and c.5213G>A (p.Gly1738Glu) and BRCA2 c.6373delA, c.7008-1G>A, c.7617+1G...

  13. BRCA1/2 genetic background-based therapeutic tailoring of human ovarian cancer: hope or reality?

    Directory of Open Access Journals (Sweden)

    Tagliaferri Pierosandro

    2009-10-01

    Full Text Available Abstract Ovarian epithelial tumors are an hallmark of hereditary cancer syndromes which are related to the germ-line inheritance of cancer predisposing mutations in BRCA1 and BRCA2 genes. Although these genes have been associated with multiple different physiologic functions, they share an important role in DNA repair mechanisms and therefore in the whole genomic integrity control. These findings have risen a variety of issues in terms of treatment and prevention of breast and ovarian tumors arising in this context. Enhanced sensitivity to platinum-based anticancer drugs has been related to BRCA1/2 functional loss. Retrospective studies disclosed differential chemosensitivity profiles of BRCA1/2-related as compared to "sporadic" ovarian cancer and led to the identification of a "BRCA-ness" phenotype of ovarian cancer, which includes inherited BRCA1/2 germ-line mutations, a serous high grade histology highly sensitive to platinum derivatives. Molecularly-based tailored treatments of human tumors are an emerging issue in the "era" of molecular targeted drugs and molecular profiling technologies. We will critically discuss if the genetic background of ovarian cancer can indeed represent a determinant issue for decision making in the treatment selection and how the provocative preclinical findings might be translated in the therapeutic scenario. The presently available preclinical and clinical evidence clearly indicates that genetic background has an emerging role in treatment individualization for ovarian cancer patients.

  14. Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Bernstein, Jonine L; Thomas, Duncan C; Shore, Roy E;

    2013-01-01

    Women with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated...... with radiation treatment was higher among women with germline BRCA1/BRCA2 mutations than among non-carriers....

  15. Expression of the stem cell marker ALDH1 in BRCA1 related breast cancer

    NARCIS (Netherlands)

    Heerma van Voss, Marise R.; van der Groep, Petra; Bart, Joost; van der Wall, Elsken; van Diest, Paul J.

    2011-01-01

    Introduction The BRCA1 protein makes mammary stem cells differentiate into mature luminal and myoepithelial cells. If a BRCA1 mutation results in a differentiation block, an enlarged stem cell component might be present in the benign tissue of BRCA1 mutation carriers, and these mammary stem cells co

  16. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

    NARCIS (Netherlands)

    Mavaddat, N.; Barrowdale, D.; Andrulis, I.L.; Domchek, S.M.; Eccles, D.; Nevanlinna, H.; Ramus, S.J.; Spurdle, A.; Robson, M.; Sherman, M.; Mulligan, A.M.; Couch, F.J.; Engel, C.; McGuffog, L.; Healey, S.; Sinilnikova, O.M.; Southey, M.C.; Terry, M.B.; Goldgar, D.; O'Malley, F.; John, E.M.; Janavicius, R.; Tihomirova, L.; Hansen, T.V.; Nielsen, F.C.; Osorio, A.; Stavropoulou, A.; Benitez, J.; Manoukian, S.; Peissel, B.; Barile, M.; Volorio, S.; Pasini, B.; Dolcetti, R.; Putignano, A.L.; Ottini, L.; Radice, P.; Hamann, U.; Rashid, M.U.; Hogervorst, F.B.L.; Kriege, M.; Luijt, R.B. van der; Peock, S.; Frost, D.; Evans, D.G.; Brewer, C.; Walker, L.; Rogers, M.T.; Side, L.E.; Houghton, C.; Weaver, J.; Godwin, A.K.; Schmutzler, R.K.; Wappenschmidt, B.; Meindl, A.; Kast, K.; Arnold, N.; Niederacher, D.; Sutter, C.; Deissler, H.; Gadzicki, D.; Preisler-Adams, S.; Varon-Mateeva, R.; Schonbuchner, I.; Gevensleben, H.; Stoppa-Lyonnet, D.; Belotti, M.; Barjhoux, L.; Isaacs, C.; Peshkin, B.N.; Caldes, T.; Hoya, M. de la; Canadas, C.; Heikkinen, T.; Heikkila, P.; Aittomaki, K.; Blanco, I.; Lazaro, C.; Brunet, J.; Agnarsson, B.A.; Arason, A.; Barkardottir, R.B.; Dumont, M.; Simard, J.; Montagna, M.; Agata, S.; D'Andrea, E.; Yan, M.; Fox, S.; Rebbeck, T.R.; Rubinstein, W.; Tung, N.; Garber, J.E.; Wang, X.; Fredericksen, Z.; Pankratz, V.S.; Lindor, N.M.; Szabo, C.; Offit, K.; Sakr, R.; Gaudet, M.M.; Singer, C.F.; Tea, M.K.; Rappaport, C.; Mai, P.L.; Greene, M.H.; Sokolenko, A.; Imyanitov, E.; Toland, A.E.; Senter, L.; Sweet, K.; Thomassen, M.; Gerdes, A.M.; Kruse, T.; Caligo, M.; Aretini, P.; Rantala, J.; Wachenfeld, A. von; Henriksson, K.; Steele, L.; Neuhausen, S.L.; Nussbaum, R.; Beattie, M.; Odunsi, K.; Sucheston, L.; Gayther, S.A.; Nathanson, K.; Gross, J.; Walsh, C.; Karlan, B.; Chenevix-Trench, G.; Easton, D.F.; Antoniou, A.C.; Ligtenberg, M.J.L.; Hoogerbrugge, N.

    2012-01-01

    BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the patholo

  17. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    NARCIS (Netherlands)

    D.G. Cox; J. Simard; D. Sinnett; Y. Hamdi; P. Soucy; M. Ouimet; L. Barjhoux; C. Verny-Pierre; L. McGuffog; S. Healey; C. Szabo; M.H. Greene; P.L. Mai; I.L. Andrulis; M. Thomassen; A.M. Gerdes; M.A. Caligo; E. Friedman; Y. Laitman; B. Kaufman; S.S. Paluch; A. Borg; P. Karlsson; M.S. Askmalm; G.B. Bustinza; K.L. Nathanson; S.M. Domchek; T.R. Rebbeck; J. Benitez; U. Hamann; M.A. Rookus; A.M.W. van den Ouweland; M.G.E.M. Ausems; C.M. Aalfs; C.J. van Asperen; P. Devilee; H.J.J.P. Gille; S. Peock; D. Frost; D.G. Evans; R. Eeles; L. Izatt; J. Adlard; J. Paterson; J. Eason; A.K. Godwin; M.A. Remon; V. Moncoutier; M. Gauthier-Villars; C. Lasset; S. Giraud; A. Hardouin; P. Berthet; H. Sobol; F. Eisinger; B.B. de Paillerets; O. Caron; C. Delnatte; D. Goldgar; A. Miron; H. Ozcelik; S. Buys; M.C. Southey; M.B. Terry; C.F. Singer; A.C. Dressler; M.K. tea; T.V.O. Hansen; O. Johannsson; M. Piedmonte; G.C. Rodriguez; J.B. Basil; S. Blank; A.E. Toland; M. Montagna; C. Isaacs; I. Blanco; S.A. Gayther; K.B. Moysich; R.K. Schmutzler; B. Wappenschmidt; C. Engel; A. Meindl; N. Ditsch; N. Arnold; D. Niederacher; C. Sutter; D. Gadzicki; B. Fiebig; T. Caldes; R. Laframboise; H. Nevanlinna; X. Chen; J. Beesley; A.B. Spurdle; S.L. Neuhausen; Y.C. Ding; F.J. Couch; X. Wang; P. Peterlongo; S. Manoukian; L. Bernard; P. Radice; D.F. Easton; G. Chenevix-Trench; A.C. Antoniou; D. Stoppa-Lyonnet; S. Mazoyer; O.M. Sinilnikova

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly in

  18. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers.

    NARCIS (Netherlands)

    Cox, D.G.; Simard, J.; Sinnett, D.; Hamdi, Y.; Soucy, P.; Ouimet, M.; Barjhoux, L.; Verny-Pierre, C.; McGuffog, L.; Healey, S.; Szabo, C.; Greene, M.H.; Mai, P.L.; Andrulis, I.L.; Thomassen, M.; Gerdes, A.M.; Caligo, M.A.; Friedman, E.; Laitman, Y.; Kaufman, B.; Paluch, S.S.; Borg, A.; Karlsson, P.; Askmalm, M.S.; Bustinza, G.B.; Nathanson, K.L.; Domchek, S.M.; Rebbeck, T.R.; Benitez, J.; Hamann, U.; Rookus, M.A.; Ouweland, A.M. van den; Ausems, M.G.; Aalfs, C.M.; Asperen, C.J. van; Devilee, P.; Gille, H.J.; Peock, S.; Frost, D.; Evans, D.G.; Eeles, R.; Izatt, L.; Adlard, J.; Paterson, J.; Eason, J.; Godwin, A.K.; Remon, M.A.; Moncoutier, V.; Gauthier-Villars, M.; Lasset, C.; Giraud, S.; Hardouin, A.; Berthet, P.; Sobol, H.; Eisinger, F.; Bressac de Paillerets, B.; Caron, O.; Delnatte, C.; Goldgar, D.; Miron, A.; Ozcelik, H.; Buys, S.; Southey, M.C.; Terry, M.B.; Singer, C.F.; Dressler, A.C.; Tea, M.K.; Hansen, T.V.; Johannsson, O.; Piedmonte, M.; Rodriguez, G.C.; Basil, J.B.; Blank, S.; Toland, A.E.; Montagna, M.; Isaacs, C.; Blanco, I.; Gayther, S.A.; Moysich, K.B.; Schmutzler, R.K.; Wappenschmidt, B.; Engel, C.; Meindl, A.; Ditsch, N.; Arnold, N.; Niederacher, D.; Sutter, C.; Gadzicki, D.; Fiebig, B.; Caldes, T.; Laframboise, R.; Nevanlinna, H.; Chen, X.; Beesley, J.; Spurdle, A.B.; Neuhausen, S.L.; Ding, Y.C.; Couch, F.J.; Wang, X.; Peterlongo, P.; Manoukian, S.; Bernard, L.; Radice, P.; Easton, D.F.; Chenevix-Trench, G.; Antoniou, A.C.; Stoppa-Lyonnet, D.; Mazoyer, S.; Sinilnikova, O.M.; Ligtenberg, M.J.L.; Hoogerbrugge, N.

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly in

  19. Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

    DEFF Research Database (Denmark)

    Mavaddat, Nasim; Barrowdale, Daniel; Andrulis, Irene L;

    2012-01-01

    BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the path...

  20. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    DEFF Research Database (Denmark)

    Cox, David G; Simard, Jacques; Sinnett, Daniel;

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly...

  1. Prolactin inhibits a major tumor-suppressive function of wild type BRCA1.

    Science.gov (United States)

    Chen, Kuan-Hui Ethan; Walker, Ameae M

    2016-06-01

    Even though mutations in the tumor suppressor, BRCA1, markedly increase the risk of breast and ovarian cancer, most breast and ovarian cancers express wild type BRCA1. An important question is therefore how the tumor-suppressive function of normal BRCA1 is overcome during development of most cancers. Because prolactin promotes these and other cancers, we investigated the hypothesis that prolactin interferes with the ability of BRCA1 to inhibit the cell cycle. Examining six different cancer cell lines with wild type BRCA1, and making use of both prolactin and the growth-inhibiting selective prolactin receptor modulator, S179D PRL, we demonstrate that prolactin activation of Stat5 results in the formation of a complex between phospho-Stat5 and BRCA1. Formation of this complex does not interfere with nuclear translocation or binding of BRCA1 to the p21 promoter, but does interfere with the ability of BRCA1 to transactivate the p21 promoter. Overexpression of a dominant-negative Stat5 in prolactin-stimulated cells resulted in increased p21 expression. We conclude that prolactin inhibits a major tumor-suppressive function of BRCA1 by interfering with BRCA1's upregulation of expression of the cell cycle inhibitor, p21.

  2. BRCA1 and its phosphorylation involved in caffeine-inhibitable event upstream of G2 checkpoint

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Caffeine,which specifically inhibits ATM/ATR kinases,efficiently abrogates the ionizing radiation(IR)-induced G2 arrest and increases the sensitivity of various tumor cells to IR.Mechanisms for the effect of caffeine remain to be elucidated.As a target of ATM/ATR kinases,BRCA1 becomes activated and phosphorylated in response to IR.Thus,in this work,we investigated the possible role of BRCA1 in the effect of caffeine on G2 checkpoint and observed how BRCA1 phosphorylation was regulated in this process.For these purposes,the BRCA1 protein level and the phosphorylation states were analyzed by Western blotting by using an antibody against BRCA1 and phospho-specific antibodies against Ser-1423 and Ser-1524 residues in cells exposed to a combination of IR and caffeine.The results showed that caffeine down-regulated IR-induced BRCA1 expression and specifically abolished BRCA1 phosphorylation of Ser-1524,which was followed by an override of G2 arrest by caffeine.In addition,the ability of BRCA1 to transactivate p21 may be required for MCF-7 but not necessary for Hela response to caffeine.These data suggest that BRCA1 may be a potential target of caffeine.BRCA1 and its phosphorylation are most likely to be involved in the caffeine-inhibitable event upstream of G2 arrest.

  3. Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells.

    Science.gov (United States)

    Busschots, Steven; O'Toole, Sharon; O'Leary, John J; Stordal, Britta

    2015-08-01

    A major risk factor for ovarian cancer is germline mutations of BRCA1/2. It has been found that (80%) of cellular models with acquired platinum or taxane resistance display an inverse resistance relationship, that is collateral sensitivity to the other agent. We used a clinically relevant comparative selection strategy to develop novel chemoresistant cell lines which aim to investigate the mechanisms of resistance that arise from different exposures of carboplatin and taxol on cells having BRCA1 function (UPN251) or dysfunction (OVCAR8). Resistance to carboplatin and taxol developed quicker and more stably in UPN251 (BRCA1-wildtype) compared to OVCAR8 (BRCA1-methylated). Alternating carboplatin and taxol treatment delayed but did not prevent resistance development when compared to single-agent administration. Interestingly, the sequence of drug exposure influenced the resistance mechanism produced. UPN251-6CALT (carboplatin first) and UPN251-6TALT (taxol first) have different profiles of cross resistance. UPN251-6CALT displays significant resistance to CuSO4 (2.3-fold, p=0.004) while UPN251-6TALT shows significant sensitivity to oxaliplatin (0.6-fold, p=0.01). P-glycoprotein is the main mechanism of taxol resistance found in the UPN251 taxane-resistant sublines. UPN251 cells increase cellular glutathione levels (3.0-fold, p=0.02) in response to carboplatin treatment. However, increased glutathione is not maintained in the carboplatin-resistant sublines. UPN251-7C and UPN251-6CALT are low-level resistant to CuSO4 suggesting alterations in copper metabolism. However, none of the UPN251 sublines have alterations in the protein expression of ATP7A or CTR1. The protein expression of BRCA1 and MRP2 is unchanged in the UPN251 sublines. The UPN251 sublines remain sensitive to parp inhibitors veliparib and CEP8983 suggesting that these agents are candidates for the treatment of platinum/taxane resistant ovarian cancer patients.

  4. Breast cancer risk in Chinese women with BRCA1 or BRCA2 mutations.

    Science.gov (United States)

    Yao, Lu; Sun, Jie; Zhang, Juan; He, Yingjian; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xie, Yuntao

    2016-04-01

    BRCA1/2 mutations represent approximately 5 % of unselected Chinese women with breast cancer. However, the breast cancer risk of Chinese women with BRCA1/2 mutations is unknown. Therefore, the aim of this study was to estimate the age-specific cumulative risk of breast cancer in Chinese women who carry a BRCA1 or BRCA2 mutation. Our study included 1816 unselected Chinese women with breast cancer and 5549 female first-degree relatives of these probands. All probands were screened for BRCA1/2 mutation. The age-specific cumulative risks of BRCA1/2 carriers were estimated using the kin-cohort study by comparing the history of breast cancer in first-degree female relatives of BRCA1/2 carriers and non-carriers. Among the 1816 probands, 125 BRCA1/2 pathogenic mutations were identified (70 in the BRCA1 gene and 55 in the BRCA2 gene). The incidence of breast cancer in the first-degree female relatives of BRCA1/2 mutation carriers was significantly higher (3.7-fold and 4.4-fold for BRCA1 and BRCA2 mutation carriers, respectively) than in non-carriers. The estimated cumulative risks of breast cancer by age 70 years were 37.9 % [95 % confidence interval (CI) 24.1-54.4 %] for BRCA1 mutation carriers and 36.5 % (95 % CI 26.7-51.8 %) for BRCA2 mutation carriers, respectively. Our study suggests that the breast cancer risk of Chinese women with BRCA1/2 mutations appears to be relatively high by the age of 70. Therefore, genetic counseling, enhanced surveillance, and individual preventive strategies should be provided for Chinese women who carry a BRCA1/2 mutation.

  5. Cross-species comparison of aCGH data from mouse and human BRCA1- and BRCA2-mutated breast cancers

    NARCIS (Netherlands)

    Holstege, H.; Van Beers, E.; Velds, A.; Liu, X.; Joosse, S.A.; Klarenbeek, S.; Schut, E.; Kerkhoven, R.; Klijn, C.N.; Wessels, L.F.A.; Nederlof, P.M.; Jonkers, J.

    2010-01-01

    Background: Genomic gains and losses are a result of genomic instability in many types of cancers. BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair. Some of these genomic aberrations may harbor g

  6. Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells

    DEFF Research Database (Denmark)

    Björkman, Andrea; Qvist, Per; Du, Likun;

    2015-01-01

    machinery. A shift to the use of microhomology-based, alternative end-joining (A-EJ) and increased frequencies of intra-S region deletions as well as insertions of inverted S sequences were observed at the recombination junctions amplified from BRCA1-deficient human B cells. Furthermore, increased use of...... underlying BRCA1’s function in maintaining genome stability and tumor suppression but may also point to a previously unrecognized role of BRCA1 in B-cell lymphomagenesis....

  7. BRCA1在胃癌中的研究进展%Progress in research of the BRCA1 gene in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    钟国栋; 余英豪

    2013-01-01

    Chemotherapy occupies an important position in the treatment of gastric cancer.Platinum drugs are commonly chemotherapy drugs for gastric cancer; however,sensitivity to these drugs varies among different patients.The breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene that is associated with sensitivity to platinum drugs.At present,the research on the BRCA1 gene is mainly focused on breast cancer,and there have been fewer studies on gastric cancer.This paper will give an overview of the structure and function of the BRCA1 gene and the relationship between BRCA1 and gastric cancer.%化疗在胃癌的治疗中占有重要地位,铂类药物是常用的胃癌化疗药物之一,不同个体对铂类药物的敏感性差异很大.乳腺癌易感基因l(breast cancer susceptibility gene 1,BRCA1)是一种抑癌基因,与铂类药物的敏感性有关.目前针对BRCA1的研究多集于乳腺癌方面,而在胃癌中的研究很少.本文就BRCA1的结构与功能,BR CA1与胃癌关系的相关研究进展进行综述.

  8. A high frequent BRCA1 founder mutation identified in the Greenlandic population

    DEFF Research Database (Denmark)

    Harboe, Theresa Larriba; Eiberg, Hans; Kern, Peder;

    2009-01-01

    Approximately 10% of all breast and ovarian cancers are dominantly inherited and mutations are mainly found in the BRCA 1 and 2 genes. The penetrance of BRCA1 mutations is reported to be between 68 and 92% and confers a 36-92% life time risk of breast cancer. Most mutations in BRCA1 are uniquely ...... carrying a BRCA1 mutation known to trigger the development of potentially lethal diseases leads us to recommend an offer of genetic counselling and test for the mutation to all females of Inuit origin, thereby hopefully preventing a number of breast and ovarian cancer deaths....

  9. Genetic instability of BRCA1 gene at locus D17S855 is related to clinicopathological behaviors of gastric cancer from Chinese population

    Institute of Scientific and Technical Information of China (English)

    Xue-Rong Chen; Wei-Zhong Zhang; Xing-Qiu Lin; Jin-Wei Wang

    2006-01-01

    AIM: To investigate genetic instability of gene BRCA1 at locus D17S855, and their relationship with clinicopathological characteristics of gastric cancer in Chinese population.METHODS: Microsatellite instability (MSI) and loss of heterozygosity (LOH) of gene BRCA1 at locus D17S855were compared between 37 samples of gastric cancer and corresponding non-cancerous gastric tissue.RESULTS: MSI at locus D17S855 was positive in 7of 37 samples of gastric cancer (18.95%). MSI had a close relationship with TNM staging but no relation with lymph node metastasis, histological type or tumor differentiation. MSI positive frequency in TNM Ⅰ + Ⅱ (31.58%, 6/19) was much higher than that in TNM Ⅲ + Ⅳ (5.56%, 1/18), (P < 0.05). LOH positive rate was 18.92% (7/37). LOH had no relationship to histological type, tumor differentiation or lymph node metastasis, but LOH positive rate in TNM Ⅲ +Ⅳ was 33.33% (6/18), much higher than that in TNM Ⅰ + Ⅱ ( 5.26%, 1/19), (P < 0.05). BRCA1 protein was expressed in 14 of 37 samples of gastric cancer. The positive rates of BRCA1 protein in TNM Ⅰ + Ⅱ and TNM Ⅲ + Ⅳ were 57.89% and 16.67%, respectively, (P <0.05). The positive rate of BRCA1 protein was 77.78% in high differentiation samples, 30.77% in middle differentiation and 12.50% in lower differentiation samples, (P <0.05).CONCLUSION: MSI of BRCA1 gene could be used as a molecular marker in early phases of sporadic gastric cancer in Chinese population. LOH occurs at later period of gastric cancer, therefore, it could be used as prognostic factor.

  10. Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability.

    Science.gov (United States)

    Trego, Kelly S; Groesser, Torsten; Davalos, Albert R; Parplys, Ann C; Zhao, Weixing; Nelson, Michael R; Hlaing, Ayesu; Shih, Brian; Rydberg, Björn; Pluth, Janice M; Tsai, Miaw-Sheue; Hoeijmakers, Jan H J; Sung, Patrick; Wiese, Claudia; Campisi, Judith; Cooper, Priscilla K

    2016-02-18

    XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. We identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability to overcome replication fork stalling, and replication stress. XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper-phosphorylation and persistent chromatin binding. These unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging. PMID:26833090

  11. BRCA1 silencing is associated with failure of DNA repairing in retinal neurocytes.

    Directory of Open Access Journals (Sweden)

    Pei Chen

    Full Text Available Retinal post-mitotic neurocytes display genomic instability after damage induced by physiological or pathological factors. The involvement of BRCA1, an important factor in development and DNA repair in mature retinal neurocytes remains unclear. Thus, we investigated the developmental expression profile of BRCA1 in the retina and defined the role of BRCA1 in DNA repair in retinal neurocytes. Our data show the expression of BRCA1 is developmentally down-regulated in the retinas of mice after birth. Similarly, BRCA1 is down-regulated after differentiation induced by TSA in retinal precursor cells. An end-joining activity assay and DNA fragmentation analysis indicated that the DNA repair capacity is significantly reduced. Moreover, DNA damage in differentiated cells or cells in which BRCA1 is silenced by siRNA interference is more extensive than that in precursor cells subjected to ionizing radiation. To further investigate non-homologous end joining (NHEJ, the major repair pathway in non-divided neurons, we utilized an NHEJ substrate (pEPI-NHEJ in which double strand breaks are generated by I-SceI. Our data showed that differentiation and the down-regulation of BRCA1 respectively result in a 2.39-fold and 1.68-fold reduction in the total NHEJ frequency compared with that in cells with normal BRCA1. Furthermore, the analysis of NHEJ repair junctions of the plasmid substrate indicated that BRCA1 is involved in the fidelity of NHEJ. In addition, as expected, the down-regulation of BRCA1 significantly inhibits the viability of retina precursor cells. Therefore, our data suggest that BRCA1 plays a critical role in retinal development and repairs DNA damage of mature retina neurocytes.

  12. Should we screen BRCA1 mutation carriers only with MRI? A multicenter study

    NARCIS (Netherlands)

    Obdeijn, I.-M.; Winter-Warnars, G.A.O.; Mann, R.M.; Hooning, M.J.; Hunink, M.G.M.; Tilanus-Linthorst, M.M.

    2014-01-01

    BRCA1 mutation carriers are offered screening with MRI and mammography. Aim of the study was to investigate the additional value of digital mammography over MRI screening. BRCA1 mutation carriers, who developed breast cancer since the introduction of digital mammography between January 2003 and Marc

  13. Should we screen BRCA1 mutation carriers only with MRI? A multicenter study

    NARCIS (Netherlands)

    A.I.M. Obdeijn (Inge-Marie); G.A.O. Winter-Warnars (Gonneke A.); R. Mann; M.J. Hooning (Maartje); M.G.M. Hunink (Myriam); M.M.A. Tilanus-Linthorst (Madeleine)

    2014-01-01

    textabstractBRCA1 mutation carriers are offered screening with MRI and mammography. Aim of the study was to investigate the additional value of digital mammography over MRI screening. BRCA1 mutation carriers, who developed breast cancer since the introduction of digital mammography between January 2

  14. Relationship between BRCA1 Expression and Efifcacy of Platinum-based Chemotherapy in Colorectal Cancer

    Institute of Scientific and Technical Information of China (English)

    Xu Guanghui; Li Yu; Liu Yi

    2014-01-01

    Objective:To explore the expression of breast cancer susceptibility gene 1 (BRCA1) in human colorectal cancer and its correlation with efifcacy of platinum-based chemotherapy. Methods:A total of 78 samples from patients with colorectal cancer and receiving platinum-based chemotherapy were selected, and meanwhile 14 cases of normal colonic mucosa samples were selected as a normal control, 12 cases of non-cancerous tissue in colorectal cancer samples were selected as a pericarcinorma control. The expression of BRCA1 in these tissues was detected using immunohistochemical S-P method, and all patients treated with drugs were followed-up for survival time. Results: The positive rate of BRCA1 expression in colorectal cancer tissue was 52.6%, signiifcantly lower than that in the control groups. BRCA1 expression was closely associated with histological differentiation degrees (χ2=14.16,P=0.001), but not with the age, gender, local inifltration, lymph node metastasis and TNM staging. Comparing with those with positive BRCA1 expression, the patients with negative BRCA1 expression after oxaliplatin-based chemotherapy had signiifcantly longer disease-free survival (DFS) (P=0.032). Conclusion:Application of oxaliplatin-based chemotherapy in the patients with negative BRCA1 expression can obtain the survival beneift, and the level of BRCA1 expression can be useful in the selection of chemotherapy regimens and evaluation of prognosis for patients with colorectal cancer after surgery.

  15. Scientists find a new function for breast cancer gene BRCA1

    Science.gov (United States)

    Scientists at the National Cancer Institute (NCI) have uncovered a new function for BRCA1, a gene most commonly associated with hereditary breast and ovarian cancer. Working on mouse cells in the lab, they discovered that BRCA1 suppresses the expression o

  16. BRCA1-Associated Triple-Negative Breast Cancer and Potential Treatment for Ruthenium-Based Compounds.

    Science.gov (United States)

    Hongthong, Khwanjira; Ratanaphan, Adisorn

    2016-01-01

    Triple-negative breast cancer (TNBC) is defined by the absence of expression of estrogen receptor (ER), progesterone receptor (PR), and a lack of overexpression or amplification of human epidermal growth factor receptor 2 (HER2). The clinicopathological characteristics of TNBC include a high grading, a high rate of cell proliferation and a greater degree of chromosomal rearrangement. Patients with triple-negative breast cancer are more likely to be drug resistant and more difficult to treat, and are also frequently BRCA1 mutants. Methylation of the BRCA1 promoter region is associated with a reduction of the BRCA1 mRNA level. TNBC patients with a methylated BRCA1 had a better disease-free survival compared with those with non-methylated BRCA1. From a therapeutic perspective, the expression level of BRCA1 has been a major determinant of the responses to different classes of chemotherapy. BRCA1-dysfunctional tumors are hypersensitive to DNA damaging chemotherapeutic agents like platinum drugs. Although platinum based drugs are currently widely used as conventional chemotherapeutic drugs in breast cancer chemotherapy, their use has several disadvantages. It is therefore of interest to seek out alternative therapeutic metal-based compounds that could overcome the limitations of these platinum based drugs. Ruthenium-based compounds could be the most promising alternative to the platinum drugs. This review highlights the use of BRCA1 as a predictive marker as well as for a potential drug target for anticancer ruthenium compounds.

  17. Missense polymorphisms in BRCA1 and BRCA2 and risk of breast and ovarian cancer

    DEFF Research Database (Denmark)

    Dombernowsky, Sarah Louise; Weischer, Maren; Freiberg, Jacob Johannes;

    2009-01-01

    PURPOSE: BRCA1 and BRCA2 are key tumor suppressors with a role in cellular DNA repair, genomic stability, and checkpoint control. Mutations in BRCA1 and BRCA2 often cause hereditary breast and ovarian cancer; however, missense polymorphisms in these genes pose a problem in genetic counseling....... Therefore, genetic counseling of such families safely can disregard findings of these missense polymorphisms....

  18. BRCA1 and BRCA2 heterozygosity and repair of X-ray-induced DNA damage

    NARCIS (Netherlands)

    Van Assen-Bolt, AJ; Van Waarde-Verhagen, MAWH; Sijmonds, RH; Van der Hout, AH; Bauch, T; Streffer, C; Kampinga, HH

    2002-01-01

    Purpose: Up to 90% of hereditary breast cancer cases are linked to germ-line mutations in one of the two copies of the BRCA1 or BRCA2 genes. Brca1 and Brca2 proteins are both involved in the cellular defence against DNA damage, although the precise function of the proteins is still not known. Some s

  19. Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Phillips, Kelly-Anne; Milne, Roger L; Rookus, Matti A;

    2013-01-01

    To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.......To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers....

  20. EGFR Expression Predicts BRCA1 Status in Patients with Breast Cancer

    NARCIS (Netherlands)

    Diest, P.J. van; Groep, P. van der; Wall, E. van der

    2006-01-01

    In their article, Lakhani et al. (1) report on the value of basal phenotype markers for the prediction of BRCA1 status. One of the useful features pointing to ‘‘BRCA1-ness’’ appeared to be high expression of the epidermal growth factor receptor (EGFR). No rationale is given by the authors for includ

  1. Common genetic variation at BARD1 is not associated with breast cancer risk in BRCA1 or BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Marquart, Louise; McGuffog, Lesley;

    2011-01-01

    Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies....

  2. Molecular biology in radiation oncology. Radiation oncology perspective of BRCA1 and BRCA2

    International Nuclear Information System (INIS)

    The breast cancer susceptibility genes, BRCA1 and BRCA2, are used to illustrate the application of molecular biology to clinical radiation oncology. Identified by linkage analysis and cloned, the structure of the genes and the numerous mutations are determined by molecular biology techniques that examine the structure of the DNA and the proteins made by the normal and mutant alleles. Mutations in the non-transcribed portion of the gene will not be found in protein structure assays and may be important in gene function. In addition to potential deleterious mutations, normal polymorphisms of the gene will also be detected, therefore not all differences in gene sequence may represent important mutations, a finding that complicates genetic screening and counseling. The localization of the protein in the nucleus, the expression in relation to cell cycle and the association with RAD51 led to the discovery that the two BRCA genes may be involved in transcriptional regulation and DNA repair. The defect in DNA repair can increase radiosensitivity which might improve local control using breast-conserving treatment in a tumor which is homozygous for the loss of the gene (i.e., BRCA1 and BRCA2 are tumor suppressor genes). This is supported by the early reports of a high rate of local control with breast-conserving therapy. Nonetheless, this radiosensitivity theoretically may also lead to increased susceptibility to carcinogenic effects in surviving cells, a finding that might not be observed for decades. The susceptibility to radiation-induced DNA damage appears also to make the cells more sensitive to chemotherapy. Understanding the role of the normal BRCA genes in DNA repair might help define a novel mechanism for radiation sensitization by interfering with the normal gene function using a variety of molecular or biochemical therapies

  3. Molecular biology in radiation oncology. Radiation oncology perspective of BRCA1 and BRCA2

    Energy Technology Data Exchange (ETDEWEB)

    Coleman, C.N. [Harvard Medical School (United States). Joint Center for Radiation Therapy

    1999-07-01

    The breast cancer susceptibility genes, BRCA1 and BRCA2, are used to illustrate the application of molecular biology to clinical radiation oncology. Identified by linkage analysis and cloned, the structure of the genes and the numerous mutations are determined by molecular biology techniques that examine the structure of the DNA and the proteins made by the normal and mutant alleles. Mutations in the non-transcribed portion of the gene will not be found in protein structure assays and may be important in gene function. In addition to potential deleterious mutations, normal polymorphisms of the gene will also be detected, therefore not all differences in gene sequence may represent important mutations, a finding that complicates genetic screening and counseling. The localization of the protein in the nucleus, the expression in relation to cell cycle and the association with RAD51 led to the discovery that the two BRCA genes may be involved in transcriptional regulation and DNA repair. The defect in DNA repair can increase radiosensitivity which might improve local control using breast-conserving treatment in a tumor which is homozygous for the loss of the gene (i.e., BRCA1 and BRCA2 are tumor suppressor genes). This is supported by the early reports of a high rate of local control with breast-conserving therapy. Nonetheless, this radiosensitivity theoretically may also lead to increased susceptibility to carcinogenic effects in surviving cells, a finding that might not be observed for decades. The susceptibility to radiation-induced DNA damage appears also to make the cells more sensitive to chemotherapy. Understanding the role of the normal BRCA genes in DNA repair might help define a novel mechanism for radiation sensitization by interfering with the normal gene function using a variety of molecular or biochemical therapies.

  4. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

    NARCIS (Netherlands)

    R. Rebbeck (Timothy); N. Mitra (Nandita); F. Wan (Fei); O. Sinilnikova (Olga); S. Healey (Sue); L. McGuffog (Lesley); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas); A.C. Antoniou (Antonis C.); K.L. Nathanson (Katherine); Y. Laitman (Yael); A. Kushnir (Anya); S. Paluch-Shimon (Shani); R. Berger (Raanan); J. Zidan (Jamal); E. Friedman (Eitan); H. Ehrencrona (Hans); M. Stenmark-Askmalm (Marie); Z. Einbeigi (Zakaria); N. Loman (Niklas); K. Harbst (Katja); J. Rantala (Johanna); B. Melin (Beatrice); D. Huo (Dezheng); O.I. Olopade (Olofunmilayo); J.L. Seldon (Joyce); P.A. Ganz (Patricia); R.L. Nussbaum (Robert L.); S. Chan (Salina); K. Odunsi (Kunle); S.A. Gayther (Simon); S.M. Domchek (Susan); B.K. Arun (Banu); K.H. Lu (Karen); G. Mitchell (Gillian); B. Karlan; C.S. Walsh (Christine); K.J. Lester (Kathryn); A.K. Godwin (Andrew); S.S. Pathak; E.B. Ross (Eric); M.J. Daly (Mark); A.S. Whittemore (Alice); E.M. John (Esther); A. Miron (Alexander); M.B. Terry (Mary Beth); W.K. Chung (Wendy K.); D. Goldgar (David); S.S. Buys (Saundra); R. Janavicius (Ramunas); L. Tihomirova (Laima); N. Tung (Nadine); C.M. Dorfling (Cecilia); E.J. van Rensburg (Elizabeth); L. Steele (Linda); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); B. Ejlertsen (Bent); A-M. Gerdes (Anne-Marie); T.V.O. Hansen (Thomas); T. Ramon Y Cajal; A. Osorio (Ana); J. Benítez (Javier); J. Godino (Javier); M.I. Tejada; M. Duran (Mercedes); J.N. Weitzel (Jeffrey); K.A. Bobolis (Kristie A.); S.R. Sand (Sharon); A. Fontaine (Annette); A. Savarese (Antonella); B. Pasini (Barbara); B. Peissel (Bernard); B. Bonnani (Bernardo); D. Zaffaroni (Daniela); F. Vignolo-Lutati (Francesca); G. Scuvera (Giulietta); G. Giannini (Giuseppe); L. Bernard (Loris); M. Genuardi (Maurizio); P. Radice (Paolo); R. Dolcetti (Riccardo); S. Manoukian (Siranoush); V. Pensotti (Valeria); V. Gismondi (Viviana); D. Yannoukakos (Drakoulis); F. Fostira (Florentia); J. Garber (Judy); D. Torres (Diana); M.U. Rashid (Muhammad); U. Hamann (Ute); S. Peock (Susan); D. Frost (Debra); R. Platte (Radka); D.G. Evans (Gareth); R. Eeles (Rosalind); R. Davidson (Rosemarie); D. Eccles (Diana); T. Cole (Trevor); J. Cook (Jackie); C. Brewer (Carole); S. Hodgson (Shirley); P.J. Morrison (Patrick); L.J. Walker (Lisa); M.E. Porteous (Mary); M.J. Kennedy (John); L. Izatt (Louise); L. Adlard; A. Donaldson (Alan); S.D. Ellis (Steve); P. Sharma (Priyanka); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); A. Becker (Alexandra); K. Rhiem (Kerstin); E. Hahnen (Eric); C. Engel (Christoph); A. Meindl (Alfons); S. Engert (Stefanie); N. Ditsch (Nina); N. Arnold (Norbert); H. Plendl (Hansjoerg); C. Mundhenke (Christoph); D. Niederacher (Dieter); M.C. Fleisch (Markus); C. Sutter (Christian); C.R. Bartram; N. Dikow (Nicola); S. Wang-Gohrke (Shan); D. Gadzicki (Dorothea); D. Steinemann (Doris); K. Kast (Karin); M. Beer (Marit); R. Varon-Mateeva (Raymonda); P.A. Gehrig (Paola A.); B.H.F. Weber (Bernhard); D. Stoppa-Lyonnet (Dominique); M. Belotti (Muriel); M. Gauthier-Villars (Marion); F. Damiola (Francesca); N. Boutry-Kryza (N.); C. Lasset (Christine); H. Sobol (Hagay); J.-P. Peyrat; D.W. Muller (Danièle); J.P. Fricker (Jean Pierre); M.-A. Collonge-Rame; I. Mortemousque (Isabelle); C. Nogues (Catherine); E. Rouleau (Etienne); C. Isaacs (Claudine); A. de Paepe (Anne); B. Poppe (Bruce); K. Claes (Kathleen); K. De Leeneer (Kim); M. Piedmonte (Marion); G. Rodriguez (Gustavo); K. Wakely (Katie); J.F. Boggess (John); S.V. Blank (Stephanie); J. Basil (Jack); M. Azodi (Masoud); K.-A. Phillips (Kelly-Anne); T. Caldes (Trinidad); M. de La Hoya (Miguel); A. Romero (Atocha); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); A.H. van der Hout (Annemarie); F.B.L. Hogervorst (Frans); S. Verhoef; J.M. Collee (Margriet); C.M. Seynaeve (Caroline); J.C. Oosterwijk (Jan); J.J. Gille (Johan); J.T. Wijnen (Juul); E.B. Gómez García (Encarna); C.M. Kets; M.G.E.M. Ausems (Margreet); C.M. Aalfs (Cora); P. Devilee (Peter); A.R. Mensenkamp (Arjen); A. Kwong (Ava); E. Olah; J. Papp (Janos); O. Díez (Orland); C. Lazaro (Conxi); E. Darder (Esther); I. Blanco (Ignacio); M. Salinas; A. Jakubowska (Anna); J. Lubinski (Jan); J. Gronwald (Jacek); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); G. Sukiennicki (Grzegorz); T. Huzarski (Tomasz); T. Byrski (Tomasz); C. Cybulski (Cezary); A. Toloczko-Grabarek (Aleksandra); E. Złowocka-Perłowska (Elzbieta); J. Menkiszak (Janusz); A. Arason (Adalgeir); R.B. Barkardottir (Rosa); J. Simard (Jacques); R. Laframboise (Rachel)

    2015-01-01

    textabstractImportance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2. Design, Setting, and Participants: Observational study ofwomen whowere asce

  5. BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Whiley, Phillip J; Thompson, Bryony;

    2012-01-01

    Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p.Arg1699Gln in the BRCA1 transcriptiona...

  6. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

    DEFF Research Database (Denmark)

    Rebbeck, Timothy R; Mitra, Nandita; Wan, Fei;

    2015-01-01

    IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained...

  7. Age at menarche and menopause and breast cancer risk in the International BRCA1/2 Carrier Cohort Study.

    NARCIS (Netherlands)

    Chang-Claude, J.; Andrieu, N.; Rookus, M.A.; Brohet, R.M.; Antoniou, A.C.; Peock, S.; Davidson, R.; Izatt, L.; Cole, T.; Nogues, C.; Luporsi, E.; Huiart, L.; Hoogerbrugge, N.; Leeuwen, F.E. van; Osorio, A.; Eyfjord, J.; Radice, P.; Goldgar, D.E.; Easton, D.F.

    2007-01-01

    BACKGROUND: Early menarche and late menopause are important risk factors for breast cancer, but their effects on breast cancer risk in BRCA1 and BRCA2 carriers are unknown. METHODS: We assessed breast cancer risk in a large series of 1,187 BRCA1 and 414 BRCA2 carriers from the International BRCA1/2

  8. Evolutionary constraint helps unmask a splicing regulatory region in BRCA1 exon 11.

    Directory of Open Access Journals (Sweden)

    Michela Raponi

    Full Text Available BACKGROUND: Alternative splicing across exon 11 produces several BRCA1 isoforms. Their proportion varies during the cell cycle, between tissues and in cancer suggesting functional importance of BRCA1 splicing regulation around this exon. Although the regulatory elements driving exon 11 splicing have never been identified, a selective constraint against synonymous substitutions (silent nucleotide variations that do not alter the amino acid residue sequence in a critical region of BRCA1 exon 11 has been reported to be associated with the necessity to maintain regulatory sequences. METHODOLOGY/PRINCIPAL FINDINGS: Here we have designed a specific minigene to investigate the possibility that this bias in synonymous codon usage reflects the need to preserve the BRCA1 alternative splicing program. We report that in-frame deletions and translationally silent nucleotide substitutions in the critical region affect splicing regulation of BRCA1 exon 11. CONCLUSIONS/SIGNIFICANCE: Using a hybrid minigene approach, we have experimentally validated the hypothesis that the need to maintain correct alternative splicing is a selective pressure against translationally silent sequence variations in the critical region of BRCA1 exon 11. Identification of the trans-acting factors involved in regulating exon 11 alternative splicing will be important in understanding BRCA1-associated tumorigenesis.

  9. RANKL/RANK control Brca1 mutation-driven mammary tumors.

    Science.gov (United States)

    Sigl, Verena; Owusu-Boaitey, Kwadwo; Joshi, Purna A; Kavirayani, Anoop; Wirnsberger, Gerald; Novatchkova, Maria; Kozieradzki, Ivona; Schramek, Daniel; Edokobi, Nnamdi; Hersl, Jerome; Sampson, Aishia; Odai-Afotey, Ashley; Lazaro, Conxi; Gonzalez-Suarez, Eva; Pujana, Miguel A; Cimba, For; Heyn, Holger; Vidal, Enrique; Cruickshank, Jennifer; Berman, Hal; Sarao, Renu; Ticevic, Melita; Uribesalgo, Iris; Tortola, Luigi; Rao, Shuan; Tan, Yen; Pfeiler, Georg; Lee, Eva Yhp; Bago-Horvath, Zsuzsanna; Kenner, Lukas; Popper, Helmuth; Singer, Christian; Khokha, Rama; Jones, Laundette P; Penninger, Josef M

    2016-07-01

    Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients.

  10. RANKL/RANK control Brca1 mutation-driven mammary tumors.

    Science.gov (United States)

    Sigl, Verena; Owusu-Boaitey, Kwadwo; Joshi, Purna A; Kavirayani, Anoop; Wirnsberger, Gerald; Novatchkova, Maria; Kozieradzki, Ivona; Schramek, Daniel; Edokobi, Nnamdi; Hersl, Jerome; Sampson, Aishia; Odai-Afotey, Ashley; Lazaro, Conxi; Gonzalez-Suarez, Eva; Pujana, Miguel A; Cimba, For; Heyn, Holger; Vidal, Enrique; Cruickshank, Jennifer; Berman, Hal; Sarao, Renu; Ticevic, Melita; Uribesalgo, Iris; Tortola, Luigi; Rao, Shuan; Tan, Yen; Pfeiler, Georg; Lee, Eva Yhp; Bago-Horvath, Zsuzsanna; Kenner, Lukas; Popper, Helmuth; Singer, Christian; Khokha, Rama; Jones, Laundette P; Penninger, Josef M

    2016-07-01

    Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients. PMID:27241552

  11. Mechanisms of increased risk of tumorigenesis in Atm and Brca1 double heterozygosity

    Directory of Open Access Journals (Sweden)

    Wang Jufang

    2011-08-01

    Full Text Available Abstract Background Both epidemiological and experimental studies suggest that heterozygosity for a single gene is linked with tumorigenesis and heterozygosity for two genes increases the risk of tumor incidence. Our previous work has demonstrated that Atm/Brca1 double heterozygosity leads to higher cell transformation rate than single heterozygosity. However, the underlying mechanisms have not been fully understood yet. In the present study, a series of pathways were investigated to clarify the possible mechanisms of increased risk of tumorigenesis in Atm and Brca1 heterozygosity. Methods Wild type cells, Atm or Brca1 single heterozygous cells, and Atm/Brca1 double heterozygous cells were used to investigate DNA damage and repair, cell cycle, micronuclei, and cell transformation after photon irradiation. Results Remarkable high transformation frequency was confirmed in Atm/Brca1 double heterozygous cells compared to wild type cells. It was observed that delayed DNA damage recognition, disturbed cell cycle checkpoint, incomplete DNA repair, and increased genomic instability were involved in the biological networks. Haploinsufficiency of either ATM or BRCA1 negatively impacts these pathways. Conclusions The quantity of critical proteins such as ATM and BRCA1 plays an important role in determination of the fate of cells exposed to ionizing radiation and double heterozygosity increases the risk of tumorigenesis. These findings also benefit understanding of the individual susceptibility to tumor initiation.

  12. Are we ready for BRCA-1 screening? The medical, ethical, and legal implications

    International Nuclear Information System (INIS)

    Inherited breast cancers account for approximately 5 to 10% of all breast malignancies. One gene, BRCA-1, is believed to account for 40-45% of hereditary breast cancers. Women who carry a BRCA-1 mutation has a 85-90% life-time risk of developing breast cancer and a 45-50% risk of developing ovarian cancer. Using linkage analyses of families with early onset breast cancer, bilateral breast cancer, and/or ovarian cancer, BRCA-1 was localized to chromosome 17q21. BRCA-1 has now been isolated and cloned. With the discovery of this inherited mutation, issues of genetic screening are facing women and their health care providers. Currently, testing for the presence of a BRCA-1 mutation is confined to members of high-risk families participating in research protocols, however, commercially available diagnostic assays are being developed for wide-spread screening. Screening for BRCA-1 is likely an inevitable reality. Therefore, panel members will discuss the implications of genetic screening specifically as they relate to the BRCA-1 gene. In particular, we will focus upon the genetic counseling that should be offered prior to the decision to proceed with testing, as well as the clinical and social implications of a positive test for a BRCA-1 mutation. Privacy issues for patients who pursue testing such s what should and should not be written in the medical records will be discussed, and the status of legislative measures designed to minimize insurance discrimination for those who test positive will be presented. Finally, options for management of women who have inherited a BRCA-1 mutation will be discussed, including the controversial role of radiotherapy for women diagnosed with breast cancer

  13. The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers

    OpenAIRE

    Friedenson Bernard

    2007-01-01

    Abstract Background The present study was designed to test the hypothesis that inactivation of virtually any component within the pathway containing the BRCA1 and BRCA2 proteins would increase the risks for lymphomas and leukemias. In people who do not have BRCA1 or BRCA2 gene mutations, the encoded proteins prevent breast/ovarian cancer. However BRCA1 and BRCA2 proteins have multiple functions including participating in a pathway that mediates repair of DNA double strand breaks by error-free...

  14. BRCA1 Expression is an Important Biomarker for Chemosensitivity: Suppression of BRCA1 Increases the Apoptosis via Up-regulation of p53 and p21 During Cisplatin Treatment in Ovarian Cancer Cells

    Directory of Open Access Journals (Sweden)

    Ikuo Konishi

    2006-01-01

    Full Text Available BRCA1 is a tumor suppressor which plays a crucial role in the repair of DNA double-strand breaks, and its abnormality is responsible for hereditary ovarian cancer syndrome. It has recently been reported that reduced expression of BRCA1 is also common in sporadic ovarian carcinoma via its promoter hypermethylation, and that ovarian carcinoma patients negative for BRCA1 expression showed favorable prognosis. To address if BRCA1 expression plays a role in the chemotherapeutic response, we analyzed the effect of BRCA1 suppression on the sensitivity to cisplatin and paclitaxel in ovarian cancer cells. Specific siRNA for BRCA1 gene was transfected into 3 ovarian cancer cell lines with various p53 status. Reduced expression of BRCA1 by transfection of BRCA1-siRNA resulted in a 5.3-fold increase in sensitivity to cisplatin in p53-wild A2780 cells, but not in p53-mutated A2780/CDDP and p53-deleted SKOV3 cells. Regarding the sensitivity to paclitaxel, BRCA1 suppression caused no significant changes in all the 3 cell lines. For ionizing radiation sensitivity, BRCA1 suppression also showed a significant higher sensitivity in A2780 cells. Growth curve and cell cycle analyses showed no signifi cant differences between BRCA1-siRNA-transfected A2780 cells and control cells. However, cisplatin treatment under suppression of BRCA1 showed a significantly increased apoptosis along with up-regulation of p53 and p21 in A2780 cells. Accordingly, reduced expression of BRCA1 enhances the cisplatin sensitivity and apoptosis via up-regulation of p53 and p21, but does not affect the paclitaxel sensitivity. Expression of BRCA1 might be an important biomarker for cisplatin resistance in ovarian carcinoma.

  15. Color bar coding the BRCA1 gene on combed DNA: a useful strategy for detecting large gene rearrangements.

    Science.gov (United States)

    Gad, S; Aurias, A; Puget, N; Mairal, A; Schurra, C; Montagna, M; Pages, S; Caux, V; Mazoyer, S; Bensimon, A; Stoppa-Lyonnet, D

    2001-05-01

    Genetic linkage data have shown that alterations of the BRCA1 gene are responsible for the majority of hereditary breast and ovarian cancers. BRCA1 germline mutations, however, are found less frequently than expected. Mutation detection strategies, which are generally based on the polymerase chain reaction, therefore focus on point and small gene alterations. These approaches do not allow for the detection of large gene rearrangements, which also can be involved in BRCA1 alterations. Indeed, a few of them, spread over the entire BRCA1 gene, have been detected recently by Southern blotting or transcript analysis. We have developed an alternative strategy allowing a panoramic view of the BRCA1 gene, based on dynamic molecular combing and the design of a full four-color bar code of the BRCA1 region. The strategy was tested with the study of four large BRCA1 rearrangements previously reported. In addition, when screening a series of 10 breast and ovarian cancer families negatively tested for point mutation in BRCA1/2, we found an unreported 17-kb BRCA1 duplication encompassing exons 3 to 8. The detection of rearrangements as small as 2 to 6 kb with respect to the normal size of the studied fragment is achieved when the BRCA1 region is divided into 10 fragments. In addition, as the BRCA1 bar code is a morphologic approach, the direct observation of complex and likely underreported rearrangements, such as inversions and insertions, becomes possible. PMID:11284038

  16. Mutation Analysis in the BRCA1 Gene in Chinese Breast Cancer Families

    Institute of Scientific and Technical Information of China (English)

    WUZhengyan; ZHENLinlin; FANPing

    2003-01-01

    Objective: To study the mutation of BRCA1 gene in Chinese breast cancer families. Methods:Fifteen families were selected, involving 41 members, consisting of 23 breast cancer patients. Using poly-merase chain reaction and single stranded conformation polymorphism (PCR-SSCP), and subsequent DNA sequencing, the mutation of BRCA1 genes were analyzed. Results: Four mutations were found in all fam-ilies, and the proportion of mutation was 26.7% (4/15) in breast cancer families. One of the 4 mutations was 2228 insC, resulting in chain termination at codon 711. The remaining 3 mutations were 1884A→T and 3232A→G, resulting in single amino acid change respectively. Conclusion: BRCA1 is a breast cancer susceptibility gene. The relatively low proportion and frequency of BRCA1 mutations in our study hints additional BRCA genes existed.

  17. High SINE RNA Expression Correlates with Post-Transcriptional Downregulation of BRCA1

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    Giovanni Bosco

    2013-04-01

    Full Text Available Short Interspersed Nuclear Elements (SINEs are non-autonomous retrotransposons that comprise a large fraction of the human genome. SINEs are demethylated in human disease, but whether SINEs become transcriptionally induced and how the resulting transcripts may affect the expression of protein coding genes is unknown. Here, we show that downregulation of the mRNA of the tumor suppressor gene BRCA1 is associated with increased transcription of SINEs and production of sense and antisense SINE small RNAs. We find that BRCA1 mRNA is post-transcriptionally down-regulated in a Dicer and Drosha dependent manner and that expression of a SINE inverted repeat with sequence identity to a BRCA1 intron is sufficient for downregulation of BRCA1 mRNA. These observations suggest that transcriptional activation of SINEs could contribute to a novel mechanism of RNA mediated post-transcriptional silencing of human genes.

  18. A guide for functional analysis of BRCA1 variants of uncertain significance

    DEFF Research Database (Denmark)

    Millot, Gaël A; Carvalho, Marcelo A; Caputo, Sandrine M;

    2012-01-01

    Germline mutations in the tumor suppressor gene BRCA1 confer an estimated lifetime risk of 56-80% for breast cancer and 15-60% for ovarian cancer. Since the mid 1990s when BRCA1 was identified, genetic testing has revealed over 1,500 unique germline variants. However, for a significant number of...... these variants, the effect on protein function is unknown making it difficult to infer the consequences on risks of breast and ovarian cancers. Thus, many individuals undergoing genetic testing for BRCA1 mutations receive test results reporting a variant of uncertain clinical significance (VUS), leading...... to issues in risk assessment, counseling, and preventive care. Here, we describe functional assays for BRCA1 to directly or indirectly assess the impact of a variant on protein conformation or function and how these results can be used to complement genetic data to classify a VUS as to its clinical...

  19. Screening of BRCA1 sequence variants within exon 11 by heteroduplex analysis

    Directory of Open Access Journals (Sweden)

    Lucian Negura

    2013-03-01

    Full Text Available Germ-line mutations of either BRCA1 or BRCA2 represents the major hereditary risk to breast and ovariancancer. Screening for mutations in these genes is now standard practice in molecular diagnosis, opening the way tooncogenetic counselling and follow-up. Because mutations in both BRCA1 and BRCA2 are distributed throughout theloci, accepted clinical protocols involve screening their entire coding regions. Systematic Sanger sequencing is time andmoney consuming. Therefore, a lot of pre-screening techniques evolved over time in order to identify anomalousamplicons prior to sequencing. Because BRCA mutations are always heterozygous, heteroduplex analysis proved to be asuitable pre-screening step. We previously implemented mismatch specific endonuclease heteroduplex analysis forBRCA1 exon7. Here we show the utility of the same method for mutations and SNPs found in BRCA1 exon 11

  20. Inhibition of E2-induced expression of BRCA1 by persistent organochlorines

    DEFF Research Database (Denmark)

    Rattenborg, Thomas; Gjermandsen, Irene; Bonefeld-Jørgensen, Eva Cecilie

    2002-01-01

    the expression of BRCA1. METHODS: Using human breast cancer cell lines MCF-7 and MDA-MB-231, the effect on BRCA1 expression of chemicals belonging to different classes of organochlorine chemicals (the pesticide toxaphene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and three polychlorinated biphenyls [PCB#138, PCB#153...... biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin reduced 17beta-estradiol (E2)-induced expression as well as basal reporter gene expression in both cell lines, whereas northern blot analysis only revealed a downregulation of E2-induced BRCA1 mRNA expression in MCF-7 cells. Toxaphene, like E2, induced BRCA1...

  1. Risk modeling and screening for BRCA1 mutations among Filipino breast cancer patients

    CERN Document Server

    Nato, A Q J

    2003-01-01

    Breast cancer susceptibility gene, type 1(BRCA1) has been thought to be responsible for approx 45% of families with multiple breast carcinomas and for approx 80% of breast and ovarian cancer families. In this study, we investigated 34 familial Filipino breast cancer (BC) patients to: (a) estimate breast cancer risks and BRCA1/2 mutation carrier probabilities using risk assessment and prior probability models, respectively; (b) screen for putative polymorphisms at selected smaller exons of BRCA1 by single-strand conformation polymorphism (SSCP) analysis; (c) screen for truncated mutations at BRCA1 exon 11 by radioactive protein truncation test (PTT); and (d) estimate posterior probabilities upon incorporation of screening results. SSCP analysis revealed 8 unique putative polymorphisms. Low prevalence of unique putative polymorphisms at exon 2, 5, 17, and 22 may indicate probable mutations. Contrastingly, high prevalence of unique putative polymorphisms at exons 13, 15, and 16 may suggest true polymorphisms whi...

  2. Recurrent BRCA1 and BRCA2 mutations in breast cancer patients of African ancestry.

    Science.gov (United States)

    Zhang, Jing; Fackenthal, James D; Zheng, Yonglan; Huo, Dezheng; Hou, Ningqi; Niu, Qun; Zvosec, Cecilia; Ogundiran, Temidayo O; Hennis, Anselm J; Leske, Maria Cristina; Nemesure, Barbara; Wu, Suh-Yuh; Olopade, Olufunmilayo I

    2012-07-01

    Recurrent mutations constituted nearly three quarters of all BRCA1 mutations and almost half of all BRCA2 mutations identified in the first cohort of the Nigerian Breast Cancer Study. To further characterize breast/ovarian cancer risks associated with BRCA1/BRCA2 mutations in the African diaspora, we genotyped recurrent mutations among Nigerian, African American, and Barbadian breast cancer patients. A replication cohort of 356 Nigerian breast cancer patients was genotyped for 12 recurrent BRCA1/2 mutant alleles (Y101X, 1742insG, 4241delTG, M1775R, 4359insC, C64Y, 1623delTTAAA, Q1090X, and 943ins10 from BRCA1, and 1538delAAGA, 2630del11, and 9045delGAAA from BRCA2) by means of SNaPshot followed by direct sequencing or by direct sequencing alone. In addition, 260 African Americans and 118 Barbadians were genotyped for six of the recurrent BRCA1 mutations by SNaPshot assay. Of all the BRCA1/2 recurrent mutations we identified in the first cohort, six were identified in 11 patients in the replication study. These mutation carriers constitute 3.1 % [95 % Confidence Interval (CI) 1.6-5.5 %] of the replication cohort. By comparison, 6.9 % (95 % CI 4.7-9.7 %) of the discovery cohort carried BRCA1/2 recurrent mutations. For the subset of recurrent mutations we tested in breast cancer cases from Barbados or the United States, only two 943ins10 carriers were identified in African Americans. Nigerian breast cancer patients from Ibadan carry a broad and unique spectrum of BRCA1/2 mutations. Our data suggest that BRCA1/2 mutation testing limited to recurrent mutations is not sufficient to understand the BRCA1/2-associated breast cancer risk in African populations in the diaspora. As the cost of Sanger sequencing is considerably reduced, deploying innovative technologies such as high throughput DNA sequencing of BRCA1/2 and other cancer susceptibility genes will be essential for identifying high-risk individuals and families to reduce the burden of aggressive early onset breast

  3. A germline mutation in the BRCA1 3’UTR predicts Stage IV breast cancer

    International Nuclear Information System (INIS)

    A germline, variant in the BRCA1 3’UTR (rs8176318) was previously shown to predict breast and ovarian cancer risk in women from high-risk families, as well as increased risk of triple negative breast cancer. Here, we tested the hypothesis that this variant predicts tumor biology, like other 3’UTR mutations in cancer. The impact of the BRCA1-3’UTR-variant on BRCA1 gene expression, and altered response to external stimuli was tested in vitro using a luciferase reporter assay. Gene expression was further tested in vivo by immunoflourescence staining on breast tumor tissue, comparing triple negative patient samples with the variant (TG or TT) or non-variant (GG) BRCA1 3’UTR. To determine the significance of the variant on clinically relevant endpoints, a comprehensive collection of West-Irish breast cancer patients were tested for the variant. Finally, an association of the variant with breast screening clinical phenotypes was evaluated using a cohort of women from the High Risk Breast Program at the University of Vermont. Luciferase reporters with the BRCA1-3’UTR-variant (T allele) displayed significantly lower gene expression, as well as altered response to external hormonal stimuli, compared to the non-variant 3’UTR (G allele) in breast cancer cell lines. This was confirmed clinically by the finding of reduced BRCA1 gene expression in triple negative samples from patients carrying the homozygous TT variant, compared to non-variant patients. The BRCA1-3’UTR-variant (TG or TT) also associated with a modest increased risk for developing breast cancer in the West-Irish cohort (OR = 1.4, 95% CI 1.1-1.8, p = 0.033). More importantly, patients with the BRCA1-3’UTR-variant had a 4-fold increased risk of presenting with Stage IV disease (p = 0.018, OR = 3.37, 95% CI 1.3-11.0). Supporting that this finding is due to tumor biology, and not difficulty screening, obese women with the BRCA1-3’UTR-variant had significantly less dense breasts (p = 0.0398) in the

  4. BRCA1 function in T lymphocytes: a cellular specificity of a different kind

    OpenAIRE

    Gardner, Kevin; Liu, Edison T

    2000-01-01

    Recent work by Mak et al demonstrates that mice carrying a T-cell-specific disruption of the brca1 gene display markedly impaired T-lymphocyte development and proliferation in the absence of any increased tendency for the formation of tumors. Interestingly, the extent of these defects was found to be highly dependent on cellular context. Contrasting the rather broad tissue expression pattern of brca1 against its exquisitely selective etiologic role in cancers of the breast and ovary, many of ...

  5. Role of BRCA1 and BRCA2 mutations in pancreatic cancer

    OpenAIRE

    Greer, Julia B; David C. Whitcomb

    2006-01-01

    Germline mutations in the tumour suppressor genes breast cancer antigen gene (BRCA)1 and BRCA2 have been proven to portend a drastically increased lifetime risk of breast and ovarian cancers in the individuals who carry them. A number of studies have shown that the third most common cancer associated with these mutations is pancreatic cancer. BRCA1/2 mutations are characterised by “allelic” or “phenotypic” heterogeneity, in that they demonstrate differing cancer expressivity between and withi...

  6. BRCA1 and miRNAs: An Emerging Therapeutic Target and Intervention Tool in Breast Cancer

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    Mintu Pal*

    2013-01-01

    Full Text Available Reduced BRCA1 activity, either by germ-line mutations in inherited breast cancer or by epigenetic down-regulation in sporadic cancers,represents a key pathway in tumour development and progression. Although best known for its role in the maintenance of chromosome integrity, BRCA1 has recently been found to play a role in chromatin remodelling and transcriptional regulation, as well as in mammary epithelial stem cell differentiation or mammary stem cell fate decision. While BRCA1 potentially plays a significant role in both mammary tumour development and malignant progression, its function connection to tumor development is poorly understood. Recent studies have uncovered a new role of BRCA1 in the regulation of small (~19-25 nucleotides non-coding microRNA (miRNA expression in breast cancer cells. Several studies have also shown that aggressive breast cancers and breast cancer stem cells exhibit distinctive profiles of miRNA expression, suggesting that BRCA1 associated differential expression of miRNAs can regulate important cellular functions facilitating the maintenance of breast cancer stem cells and/or promoting breast cancer aggression. In this context, we will review recent progress in the understanding of the BRCA1 function, with emphasis on the implication of the development and progression of breast cancer via differential expression of miRNAs and discuss how these studies can improve our understanding of breast cancer pathogenesis. We will also discuss the perspectives of BRCA1 function through miRNAs and the role of miRNAs in regulating BRCA1 in breast cancer, more specifically tumor suppressor, miR-125 and oncogene, mir-155 as diagnostic and prognostic tools in clinical practice, and as new avenues for therapeutic interventions.

  7. Haploinsufficiency for BRCA1 is associated with normal levels of DNA nucleotide excision repair in breast tissue and blood lymphocytes

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    Johnson Jennifer M

    2005-06-01

    Full Text Available Abstract Background Screening mammography has had a positive impact on breast cancer mortality but cannot detect all breast tumors. In a small study, we confirmed that low power magnetic resonance imaging (MRI could identify mammographically undetectable tumors by applying it to a high risk population. Tumors detected by this new technology could have unique etiologies and/or presentations, and may represent an increasing proportion of clinical practice as new screening methods are validated and applied. A very important aspect of this etiology is genomic instability, which is associated with the loss of activity of the breast cancer-predisposing genes BRCA1 and BRCA2. In sporadic breast cancer, however, there is evidence for the involvement of a different pathway of DNA repair, nucleotide excision repair (NER, which remediates lesions that cause a distortion of the DNA helix, including DNA cross-links. Case presentation We describe a breast cancer patient with a mammographically undetectable stage I tumor identified in our MRI screening study. She was originally considered to be at high risk due to the familial occurrence of breast and other types of cancer, and after diagnosis was confirmed as a carrier of a Q1200X mutation in the BRCA1 gene. In vitro analysis of her normal breast tissue showed no differences in growth rate or differentiation potential from disease-free controls. Analysis of cultured blood lymphocyte and breast epithelial cell samples with the unscheduled DNA synthesis (UDS assay revealed no deficiency in NER. Conclusion As new breast cancer screening methods become available and cost effective, patients such as this one will constitute an increasing proportion of the incident population, so it is important to determine whether they differ from current patients in any clinically important ways. Despite her status as a BRCA1 mutation carrier, and her mammographically dense breast tissue, we did not find increased cell

  8. High penetrances of BRCA1 and BRCA2 mutations confirmed in a prospective series

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    Møller Pål

    2010-01-01

    Full Text Available Abstract Penetrances of BRCA1 and BRCA2 mutations have been derived from retrospective studies, implying the possibility of ascertainment biases to influence the results. We have followed women at risk for breast and/or ovarian cancer for two decades, and report the prospectively observed age-related annual incidence rates to contract breast or ovarian cancer for women with deleterious BRCA1 or BRCA2 mutations based on 4830 observation years. Patients were grouped according to mutation, age and having/not having had previous cancer. In women not having had previous cancer and aged 40-59 years, the annual incidence rate to contract breast or ovarian cancer in those having the most frequent BRCA1 founder mutations was 4.0%, for women in this age group and with less frequent BRCA1 mutations annual incidence rate was 5.9%, and for women with BRCA2 mutations 3.5%. The observed figures may be used for genetic counseling of healthy mutation carriers in the respective age groups. The results may indicate that less frequent BRCA1 mutations have higher penetrances than BRCA1 founder mutations.

  9. 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.

  10. Monozygotic twins discordant for constitutive BRCA1 promoter methylation, childhood cancer and secondary cancer.

    Science.gov (United States)

    Galetzka, Danuta; Hansmann, Tamara; El Hajj, Nady; Weis, Eva; Irmscher, Benjamin; Ludwig, Marco; Schneider-Rätzke, Brigitte; Kohlschmidt, Nicolai; Beyer, Vera; Bartsch, Oliver; Zechner, Ulrich; Spix, Claudia; Haaf, Thomas

    2012-01-01

    We describe monozygotic twins discordant for childhood leukemia and secondary thyroid carcinoma. We used bisulfite pyrosequencing to compare the constitutive promoter methylation of BRCA1 and several other tumor suppressor genes in primary fibroblasts. The affected twin displayed an increased BRCA1 methylation (12%), compared with her sister (3%). Subsequent bisulfite plasmid sequencing demonstrated that 13% (6 of 47) BRCA1 alleles were fully methylated in the affected twin, whereas her sister displayed only single CpG errors without functional implications. This between-twin methylation difference was also found in irradiated fibroblasts and untreated saliva cells. The BRCA1 epimutation may have originated by an early somatic event in the affected twin: approximately 25% of her body cells derived from different embryonic cell lineages carry one epigenetically inactivated BRCA1 allele. This epimutation was associated with reduced basal protein levels and a higher induction of BRCA1 after DNA damage. In addition, we performed a genome-wide microarray analysis of both sisters and found several copy number variations, i.e., heterozygous deletion and reduced expression of the RSPO3 gene in the affected twin. This monozygotic twin pair represents an impressive example of epigenetic somatic mosaicism, suggesting a role for constitutive epimutations, maybe along with de novo genetic alterations in recurrent tumor development. PMID:22207351

  11. Genome instability in blood cells of a BRCA1+ breast cancer family

    International Nuclear Information System (INIS)

    BRCA1 plays an essential role in maintaining genome stability. Inherited BRCA1 germline mutation (BRCA1+) is a determined genetic predisposition leading to high risk of breast cancer. While BRCA1+ induces breast cancer by causing genome instability, most of the knowledge is known about somatic genome instability in breast cancer cells but not germline genome instability. Using the exome-sequencing method, we analyzed the genomes of blood cells in a typical BRCA1+ breast cancer family with an exon 13-duplicated founder mutation, including six breast cancer-affected and two breast cancer unaffected members. We identified 23 deleterious mutations in the breast cancer-affected family members, which are absent in the unaffected members. Multiple mutations damaged functionally important and breast cancer-related genes, including transcriptional factor BPTF and FOXP1, ubiquitin ligase CUL4B, phosphorylase kinase PHKG2, and nuclear receptor activator SRA1. Analysis of the mutations between the mothers and daughters shows that most mutations were germline mutation inherited from the ancestor(s) while only a few were somatic mutation generated de novo. Our study indicates that BRCA1+ can cause genome instability with both germline and somatic mutations in non-breast cells

  12. Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg is a pathogenic mutation.

    Directory of Open Access Journals (Sweden)

    Phillip J Whiley

    Full Text Available Rare exonic, non-truncating variants in known cancer susceptibility genes such as BRCA1 and BRCA2 are problematic for genetic counseling and clinical management of relevant families. This study used multifactorial likelihood analysis and/or bioinformatically-directed mRNA assays to assess pathogenicity of 19 BRCA1 or BRCA2 variants identified following patient referral to clinical genetic services. Two variants were considered to be pathogenic (Class 5. BRCA1:c.4484G> C(p.Arg1495Thr was shown to result in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>G(p.His41Arg RING-domain variant was found from multifactorial likelihood analysis to have a posterior probability of pathogenicity of 0.995, a result consistent with existing protein functional assay data indicating lost BARD1 binding and ubiquitin ligase activity. Of the remaining variants, seven were determined to be not clinically significant (Class 1, nine were likely not pathogenic (Class 2, and one was uncertain (Class 3.These results have implications for genetic counseling and medical management of families carrying these specific variants. They also provide additional multifactorial likelihood variant classifications as reference to evaluate the sensitivity and specificity of bioinformatic prediction tools and/or functional assay data in future studies.

  13. BRCA1 and BRCA2 mutations in central and southern Italian patients

    International Nuclear Information System (INIS)

    Protein truncation test (PTT) and single-strand conformation polymorphism (SSCP) assay were used to scan the BRCA1 and BRCA2 genes in 136 unrelated Italian breast/ovarian cancer patients. In the sample tested, BRCA1 and BRCA2 equally contributed to site-specific breast cancer patients who reported one to two breast cancer-affected first-/ second-degree relative(s) or who were diagnosed before age 40 years in the absence of a family history of breast/ovarian cancer. BRCA1 and BRCA2 mutations were mostly found in patients with disease diagnosis before and after age 50 years, respectively. Moreover, in cases with familial clustering of site-specific breast cancer, BRCA1 mostly accounted for tumours diagnosed before age 40 years and BRCA2 for tumours diagnosed after age 50 years. The BRCA1 and BRCA2 mutation spectrum was consistent with a lack of significant founder effects in the sample of patients studied. Germline BRCA1 and BRCA2 mutations account for most hereditary breast/ovarian cancers and are associated with male breast cancer. Furthermore, constitutional mutations in these genes may occur in breast/ovarian cancer patients that do not meet stringent criteria of autosomal-dominant predisposition. The relevance of BRCA1 and BRCA2 mutations in such patients is still debated. We sought to determine the impact of BRCA1 and BRCA2 mutations in a population of patients from central and southern Italy. We analyzed the BRCA1 and BRCA2 coding regions in 136 unrelated probands: 117 females with breast/ovarian cancer and 19 males with breast cancer. This population of patients was mostly representative of cases who are at risk for hereditary susceptibility, but who do not meet stringent criteria of autosomal-dominant predisposition. Probands, subclassified as follows, were consecutively recruited depending on informed consent from patients attending breast cancer clinics in Rome and Naples. Selection criteria for females were as follows: breast cancer with breast cancer

  14. Cross-species comparison of aCGH data from mouse and human BRCA1- and BRCA2-mutated breast cancers

    International Nuclear Information System (INIS)

    Genomic gains and losses are a result of genomic instability in many types of cancers. BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair. Some of these genomic aberrations may harbor genes whose absence or overexpression may give rise to cellular growth advantage. So far, it has not been easy to identify the driver genes underlying gains and losses. A powerful approach to identify these driver genes could be a cross-species comparison of array comparative genomic hybridization (aCGH) data from cognate mouse and human tumors. Orthologous regions of mouse and human tumors that are commonly gained or lost might represent essential genomic regions selected for gain or loss during tumor development. To identify genomic regions that are associated with BRCA1- and BRCA2-mutated breast cancers we compared aCGH data from 130 mouse Brca1Δ/Δ;p53Δ/Δ, Brca2Δ/Δ;p53Δ/Δ and p53Δ/Δ mammary tumor groups with 103 human BRCA1-mutated, BRCA2-mutated and non-hereditary breast cancers. Our genome-wide cross-species analysis yielded a complete collection of loci and genes that are commonly gained or lost in mouse and human breast cancer. Principal common CNAs were the well known MYC-associated gain and RB1/INTS6-associated loss that occurred in all mouse and human tumor groups, and the AURKA-associated gain occurred in BRCA2-related tumors from both species. However, there were also important differences between tumor profiles of both species, such as the prominent gain on chromosome 10 in mouse Brca2Δ/Δ;p53Δ/Δ tumors and the PIK3CA associated 3q gain in human BRCA1-mutated tumors, which occurred in tumors from one species but not in tumors from the other species. This disparity in recurrent aberrations in mouse and human tumors might be due to differences in tumor cell type or genomic organization between both species. The selection of the oncogenome during mouse and

  15. A Novel Frequent BRCA1 Allele in Chinese Patients with Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    ZHOU Dongxian; XIONG Wen; XU Hongxan; SHAO Chaopeng

    2006-01-01

    The whole length of exon 11 of BRCA1 was sequenced (total 3427 bp) in 59 patients and 10 healthy female blood donors. To allow a rapid determination of the different BRCA1 alleles, a sequence-specific primer PCR method (PCR-SSP) was established and was applied to 57 additional female donors. Finally, the full-length coding region of BRCA1 was analyzed through reversed-transcriptase PCR (RT-PCR) and cDNA sequencing (total 5554 bp) in one donor with wild-type allele and 2 patients with one or two mutated alleles. By genomic DNA sequencing, 5 homozygous polymorphisms were observed in 18 patients: 2201C>T, 2430T>C, 2731C>T, 3232A>G and 3667A>G. All of them were previously observed in Caucasians, Malay and Chinese, but for the first time the mutations were found in one allele (GenBank AY304547). Twenty-six patients and 4donors were heterozygous at these 5 nucleotide positions. The remaining 15 patients and 6 donors showed a sequence identical with the standard BRCA1 gene. Combined the PCR-SSP results and in a summary, 6 of 67 (9.0 %) healthy individuals were homozygous for the mutated allele, whereas 18 of 59 (30.5 %) breast cancer patients were homozygous. A Chi-square test showed a significant correlation between homozygous mutated BRCA1 allele and breast cancer. The cDNA sequencing showed that 2 additional mutations, 4427T>C in exon 13 and 4956A>G in exon 16, were found. A new BRCA1 allele, which is BRCA1-2201T/2430C/2731T/3232G/3667G/4427C/4956G (GenBank AY751490), was found in Chinese. And the homozygote of this mutated allele may implicate a disease-association in Chinese.

  16. BRCA1 and BRCA2 Gene Mutations Screening In Sporadic Breast Cancer Patients In Kazakhstan.

    Directory of Open Access Journals (Sweden)

    Ainur R. Akilzhanova

    2013-05-01

    Full Text Available Background: A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but little is known regarding the role of these inherited susceptibility genes in breast cancer risk among Kazakhstan women. Aim: To evaluate the role of BRCA1/2 mutations in Kazakhstan women presenting with sporadic breast cancer. Methods: We investigated the distribution and nature of polymorphisms in BRCA1 and BRCA2 entire coding regions in 156 Kazakhstan sporadic breast cancer cases and 112 age-matched controls using automatic direct sequencing. Results: We identified 22 distinct variants, including 16 missense mutations and 6 polymorphisms in BRCA1/2 genes. In BRCA1, 9 missense mutations and 3 synonymous polymorphisms were observed. In BRCA2, 7 missense mutations and 3 polymorphisms were detected. There was a higher prevalence of observed mutations in Caucasian breast cancer cases compared to Asian cases (p<0.05; higher frequencies of sequence variants were observed in Asian controls. No recurrent or founder mutations were observed in BRCA1/2 genes. There were no statistically significant differences in age at diagnosis, tumor histology, size of tumor, and lymph node involvement between women with breast cancer with or without the BRCA sequence alterations. Conclusions: Considering the majority of breast cancer cases are sporadic, the present study will be helpful in the evaluation of the need for the genetic screening of BRCA1/2 mutations and reliable genetic counseling for Kazakhstan sporadic breast cancer patients. Evaluation of common polymorphisms and mutations and breast cancer risk in families with genetic predisposition to breast cancer is ongoing in another current investigation. 

  17. BRCA1 mutations in Algerian breast cancer patients: high frequency in young, sporadic cases

    Directory of Open Access Journals (Sweden)

    Nancy Uhrhammer, Amina Abdelouahab, Laurence Lafarge, Viviane Feillel, Ahmed Ben Dib, Yves-Jean Bignon

    2008-01-01

    Full Text Available Breast cancer rates and median age of onset differ between Western Europe and North Africa. In Western populations, 5 to 10 % of breast cancer cases can be attributed to major genetic factors such as BRCA1 and BRCA2, while this attribution is not yet well defined among Africans. To help determine the contribution of BRCA1 mutations to breast cancer in a North African population, we analysed genomic DNA from breast cancer cases ascertained in Algiers. Both familial cases (at least three breast cancers in the same familial branch, or two with one bilateral or diagnosed before age 40 and sporadic cases less than 38 years of age were studied. Complete sequencing plus quantitative analysis of the BRCA1 gene was performed. 9.8 % (5/51 of early-onset sporadic and 36.4 % (4/11 of familial cases were found to be associated with BRCA1 mutations. This is in contrast 10.3 % of French HBOC families exhibiting a BRCA1 mutation. One mutation, c.798_799delTT, was observed in two Algerian families and in two families from Tunisia, suggesting a North African founder allele. Algerian non-BRCA1 tumors were of significantly higher grade than French non-BRCA tumors, and the age at diagnosis for Algerian familial cases was much younger than that for French non-BRCA familial cases. In conclusion, we observed a much higher frequency of BRCA1 mutations among young breast cancer patients than observed in Europe, suggesting biological differences and that the inclusion criterea for analysis in Western Europe may not be applicable for the Northern African population.

  18. Detection of somatic BRCA1/2 mutations in ovarian cancer - next-generation sequencing analysis of 100 cases.

    Science.gov (United States)

    Koczkowska, Magdalena; Zuk, Monika; Gorczynski, Adam; Ratajska, Magdalena; Lewandowska, Marzena; Biernat, Wojciech; Limon, Janusz; Wasag, Bartosz

    2016-07-01

    The overall prevalence of germline BRCA1/2 mutations is estimated between 11% and 15% of all ovarian cancers. Individuals with germline BRCA1/2 alterations treated with the PARP1 inhibitors (iPARP1) tend to respond better than patients with wild-type BRCA1/2. Additionally, also somatic BRCA1/2 alterations induce the sensitivity to iPARP1. Therefore, the detection of both germline and somatic BRCA1/2 mutations is required for effective iPARP1 treatment. The aim of this study was to identify the frequency and spectrum of germline and somatic BRCA1/2 alterations in a group of Polish patients with ovarian serous carcinoma. In total, 100 formalin-fixed paraffin-embedded (FFPE) ovarian serous carcinoma tissues were enrolled to the study. Mutational analysis of BRCA1/2 genes was performed by using next-generation sequencing. The presence of pathogenic variants was confirmed by Sanger sequencing. In addition, to confirm the germline or somatic status of the mutation, the nonneoplastic tissue was analyzed by bidirectional Sanger sequencing. In total, 27 (28% of patient samples) mutations (20 in BRCA1 and 7 in BRCA2) were identified. For 22 of 27 patients, nonneoplastic cells were available and sequencing revealed the somatic character of two BRCA1 (2/16; 12.5%) and two BRCA2 (2/6; 33%) mutations. Notably, we identified six novel frameshift or nonsense BRCA1/2 mutations. The heterogeneity of the detected mutations confirms the necessity of simultaneous analysis of BRCA1/2 genes in all patients diagnosed with serous ovarian carcinoma. Moreover, the use of tumor tissue for mutational analysis allowed the detection of both somatic and germline BRCA1/2 mutations. PMID:27167707

  19. Mutational analysis of the BRCA1 gene in 30 Czech ovarian cancer patients

    Indian Academy of Sciences (India)

    M. Zikan; P. Pohlreich; J. Stribrna

    2005-04-01

    Ovarian cancer is one of the most severe of oncological diseases. Inherited mutations in cancer susceptibility genes play a causal role in 5–10% of newly diagnosed tumours. BRCA1 and BRCA2 gene alterations are found in the majority of these cases. The aim of this study was to analyse the BRCA1 gene in the ovarian cancer risk group to characterize the spectrum of its mutations in the Czech Republic. Five overlapping fragments amplified on both genomic DNA and cDNA were used to screen for the whole protein-coding sequence of the BRCA1 gene. These fragments were analysed by the protein truncation test (PTT) and direct sequencing. Three inactivating mutations were identified in the group of 30 Czech ovarian cancer patients: the 5382insC mutation in two unrelated patients and a deletion of exons 21 and 22 in another patient. In addition, we have found an alternatively spliced product lacking exon 5 in two other unrelated patients. The 5382insC is the most frequent alteration of the BRCA1 gene in Central and Eastern Europe. The deletion of exons 21 and 22 affects the BRCT functional domain of the BRCA1 protein. Although large genomic rearragements are known to be relatively frequent in Western European populations, no analyses have been performed in our region yet.

  20. Functional and structural analysis of C-terminal BRCA1 missense variants.

    Directory of Open Access Journals (Sweden)

    Francisco Quiles

    Full Text Available Germline inactivating mutations in BRCA1 and BRCA2 genes are responsible for Hereditary Breast and Ovarian Cancer Syndrome (HBOCS. Genetic testing of these genes is available, although approximately 15% of tests identify variants of uncertain significance (VUS. Classification of these variants into pathogenic or non-pathogenic type is an important challenge in genetic diagnosis and counseling. The aim of the present study is to functionally assess a set of 7 missense VUS (Q1409L, S1473P, E1586G, R1589H, Y1703S, W1718L and G1770V located in the C-terminal region of BRCA1 by combining in silico prediction tools and structural analysis with a transcription activation (TA assay. The in silico prediction programs gave discrepant results making its interpretation difficult. Structural analysis of the three variants located in the BRCT domains (Y1703S, W1718L and G1770V reveals significant alterations of BRCT structure. The TA assay shows that variants Y1703S, W1718L and G1770V dramatically compromise the transcriptional activity of BRCA1, while variants Q1409L, S1473P, E1586G and R1589H behave like wild-type BRCA1. In conclusion, our results suggest that variants Y1703S, W1718L and G1770V can be classified as likely pathogenic BRCA1 mutations.

  1. BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex.

    Science.gov (United States)

    Kawai, Shinji; Amano, Atsuo

    2012-04-16

    MicroRNAs (miRNAs) are noncoding RNAs that function as key posttranscriptional regulators of gene expression. miRNA maturation is controlled by the DROSHA microprocessor complex. However, the detailed mechanism of miRNA biogenesis remains unclear. We show that the tumor suppressor breast cancer 1 (BRCA1) accelerates the processing of miRNA primary transcripts. BRCA1 increased the expressions of both precursor and mature forms of let-7a-1, miR-16-1, miR-145, and miR-34a. In addition, this tumor suppressor was shown to be directly associated with DROSHA and DDX5 of the DROSHA microprocessor complex, and it interacted with Smad3, p53, and DHX9 RNA helicase. We also found that BRCA1 recognizes the RNA secondary structure and directly binds with primary transcripts of miRNAs via a DNA-binding domain. Together, these results suggest that BRCA1 regulates miRNA biogenesis via the DROSHA microprocessor complex and Smad3/p53/DHX9. Our findings also indicate novel functions of BRCA1 in miRNA biogenesis, which may be linked to its tumor suppressor mechanism and maintenance of genomic stability.

  2. Contribution of BRCA1 and BRCA2 Germline Mutations to Early Algerian Breast Cancer.

    Science.gov (United States)

    Henouda, Sarra; Bensalem, Assia; Reggad, Rym; Serrar, Nedda; Rouabah, Leila; Pujol, Pascal

    2016-01-01

    Breast cancer is the most common female malignancy and the leading cancer mortality cause among Algerian women. Germline mutations in the BRCA1 and BRCA2 genes in patients with early-onset breast cancer have not been clearly identified within the Algerian population. It is necessary to study the BRCA1/2 genes involvement in the Algerian breast cancer occurrence. We performed this study to define germline mutations in BRCA1/2 and their implication in breast cancer among young women from eastern Algeria diagnosed or treated with primary invasive breast cancer at the age of 40 or less who were referred to Anti-Cancer Center of Setif, Algeria. Case series were unselected for family history. Eight distinct pathogenic mutations were identified in eight unrelated families. Three deleterious mutations and one large genomic rearrangement involving deletion of exon 2 were found in BRCA1 gene. In addition, four mutations within the BRCA2 gene and one large genomic rearrangement were identified. Novel mutation was found among Algerian population. Moreover, five variants of uncertain clinical significance and favor polymorphisms were identified. Our data suggest that BRCA1/2 mutations are responsible for a significant proportion of breast cancer in Algerian young women. PMID:26997744

  3. Telomere length shows no association with BRCA1 and BRCA2 mutation status.

    Directory of Open Access Journals (Sweden)

    Emma Killick

    Full Text Available This study aimed to determine whether telomere length (TL is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years, all healthy at time of enrollment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years, half of whom had been diagnosed with breast cancer prior to enrollment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL.

  4. Cell biology of cancer: BRCA1 and sister chromatid pairing reactions?

    Science.gov (United States)

    Skibbens, Robert V

    2008-02-15

    A significant portion of familial breast/ovarian cancer patients harbors a mutation in Breast Cancer Associated gene 1 (BRCA1). Cells deficient for BRCA1 exhibit chromosome aberrations such as whole chromosome duplications, translocations, inter-sister gaps and gene mis-regulation. Here, new evidence is reviewed that defects in sister chromatid cohesion may contribute directly to cancer cell phenotypes-especially those of BRCA1 mutant cells. Linking cohesion to BRCA1-dependent tumorigenesis are reports that BRCA1-associated components (DNA helicase, RFC, PCNA and genome surveillance factors) are required for efficient sister chromatid cohesion. Other cohesion factors (WAPL, EFO2/ESCO2 and hSecurin) are tightly correlated with various cell-type specific carcinogenesis, in support of a generalized model for cohesion in cancer. Recent findings further reveal that a reciprocal relationship exists in that DNA damage induces new Ctf7/Eco1-dependent sister chromatid pairing reactions that, in turn, are required for efficient DNA repair. Future research into sister chromatid pairing mechanisms are likely to provide critical new insights into the underlying causes of cancer.

  5. Molecular classification of familial non-BRCA1/BRCA2 breast cancer.

    Science.gov (United States)

    Hedenfalk, Ingrid; Ringner, Markus; Ben-Dor, Amir; Yakhini, Zohar; Chen, Yidong; Chebil, Gunilla; Ach, Robert; Loman, Niklas; Olsson, Håkan; Meltzer, Paul; Borg, Ake; Trent, Jeffrey

    2003-03-01

    In the decade since their discovery, the two major breast cancer susceptibility genes BRCA1 and BRCA2, have been shown conclusively to be involved in a significant fraction of families segregating breast and ovarian cancer. However, it has become equally clear that a large proportion of families segregating breast cancer alone are not caused by mutations in BRCA1 or BRCA2. Unfortunately, despite intensive effort, the identification of additional breast cancer predisposition genes has so far been unsuccessful, presumably because of genetic heterogeneity, low penetrance, or recessive/polygenic mechanisms. These non-BRCA1/2 breast cancer families (termed BRCAx families) comprise a histopathologically heterogeneous group, further supporting their origin from multiple genetic events. Accordingly, the identification of a method to successfully subdivide BRCAx families into recognizable groups could be of considerable value to further genetic analysis. We have previously shown that global gene expression analysis can identify unique and distinct expression profiles in breast tumors from BRCA1 and BRCA2 mutation carriers. Here we show that gene expression profiling can discover novel classes among BRCAx tumors, and differentiate them from BRCA1 and BRCA2 tumors. Moreover, microarray-based comparative genomic hybridization (CGH) to cDNA arrays revealed specific somatic genetic alterations within the BRCAx subgroups. These findings illustrate that, when gene expression-based classifications are used, BRCAx families can be grouped into homogeneous subsets, thereby potentially increasing the power of conventional genetic analysis.

  6. A BRCA1-mutation associated DNA methylation signature in blood cells predicts sporadic breast cancer incidence and survival.

    OpenAIRE

    Anjum, S; Fourkala, E O; Zikan, M.; Wong, A.; Gentry-Maharaj, A.; Jones, A.; HARDY, R.; Cibula, D.; Kuh, D.; Jacobs, I. J.; Teschendorff, A.E.; Menon, U; Widschwendter, M

    2014-01-01

    Background BRCA1 mutation carriers have an 85% risk of developing breast cancer but the risk of developing non-hereditary breast cancer is difficult to assess. Our objective is to test whether a DNA methylation (DNAme) signature derived from BRCA1 mutation carriers is able to predict non-hereditary breast cancer. Methods In a case/control setting (72 BRCA1 mutation carriers and 72 BRCA1/2 wild type controls) blood cell DNA samples were profiled on the Illumina 27 k methylation array. Using th...

  7. Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling

    DEFF Research Database (Denmark)

    Larsen, Martin J; Kruse, Torben A; Tan, Qihua;

    2013-01-01

    Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants...... tumors by RNA profiling to investigate the classification potential of RNA profiles to predict BRCA1/2 mutation status. We found that breast tumors from BRCA1 and BRCA2 mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority...

  8. Combinatory effect of BRCA1 and HERC2 expression on outcome in advanced non-small-cell lung cancer

    OpenAIRE

    Bonanno, Laura; Costa, Carlota; Majem, Margarita; Sanchez, Jose-Javier; Rodriguez, Ignacio; Gimenez-Capitan, Ana; Molina-Vila, Miquel Angel; Vergnenegre, Alain; Massuti, Bartomeu; Favaretto, Adolfo; Rugge, Massimo; Pallares, Cinta; Taron, Miquel; Rosell, Rafael

    2016-01-01

    Background BRCA1 is a main component of homologous recombination and induces resistance to platinum in preclinical models. It has been studied as a potential predictive marker in lung cancer. Several proteins modulate the function of BRCA1. The E3 ubiquitin ligase HERC2 facilitates the assembly of the RNF8-UBC13 complex to recruit BRCA1 to DNA damage sites. The combined analysis of multiple components of the pathway leading to the recruitment of BRCA1 at DNA damage sites has the potentiality ...

  9. BRCA1 Exon 11, a CERES (Composite Regulatory Element of Splicing Element Involved in Splice Regulation

    Directory of Open Access Journals (Sweden)

    Claudia Tammaro

    2014-07-01

    Full Text Available Unclassified variants (UV of BRCA1 can affect normal pre-mRNA splicing. Here, we investigate the UV c.693G>A, a “silent” change in BRCA1 exon 11, which we have found induces aberrant splicing in patient carriers and in vitro. Using a minigene assay, we show that the UV c.693G>A has a strong effect on the splicing isoform ratio of BRCA1. Systematic site-directed mutagenesis of the area surrounding the nucleotide position c.693G>A induced variable changes in the level of exon 11 inclusion/exclusion in the mRNA, pointing to the presence of a complex regulatory element with overlapping enhancer and silencer functions. Accordingly, protein binding analysis in the region detected several splicing regulatory factors involved, including SRSF1, SRSF6 and SRSF9, suggesting that this sequence represents a composite regulatory element of splicing (CERES.

  10. BRCA1的泛素连接酶活性与肿瘤%E3 Ligase Activity of BRCA1 and Tumor

    Institute of Scientific and Technical Information of China (English)

    汪洋; 詹启敏

    2006-01-01

    乳腺癌易感基因1(BRCA1)是一种抑癌基因表达产物,参与许多重要的细胞生命过程如细胞周期调控、中心体复制、DNA损伤修复等.近来研究表明,BRCA1基因表达产物具有E3泛素连接酶活性,催化底物蛋白FANCD2、NPM、γ-Tubulin、RNAPⅡ等及其自身的泛素化,从而调控众多生命过程的顺利进行,并且与肿瘤的发生发展密切相关.

  11. The prevalence of BRCA1 mutations among young women with triple-negative breast cancer

    International Nuclear Information System (INIS)

    Molecular screening for BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer. Features of hereditary breast cancer include an early age-of-onset and over-representation of the 'triple-negative' phenotype (negative for estrogen-receptor, progesterone-receptor and HER2). The decision to offer genetic testing to a breast cancer patient is usually based on her family history, but in the absence of a family history of cancer, some women may qualify for testing based on the age-of-onset and/or the pathologic features of the breast cancer. We studied 54 women who were diagnosed with high-grade, triple-negative invasive breast cancer at or before age 40. These women were selected for study because they had little or no family history of breast or ovarian cancer and they did not qualify for genetic testing using conventional family history criteria. BRCA1 screening was performed using a combination of fluorescent multiplexed-PCR analysis, BRCA1 exon-13 6 kb duplication screening, the protein truncation test (PTT) and fluorescent multiplexed denaturing gradient gel electrophoresis (DGGE). All coding exons of BRCA1 were screened. The two large exons of BRCA2 were also screened using PTT. All mutations were confirmed with direct sequencing. Five deleterious BRCA1 mutations and one deleterious BRCA2 mutation were identified in the 54 patients with early-onset, triple-negative breast cancer (11%). Women with early-onset triple-negative breast cancer are candidates for genetic testing for BRCA1, even in the absence of a family history of breast or ovarian cancer

  12. Selenium supplementation reduced oxidative DNA damage in adnexectomized BRCA1 mutations carriers.

    Science.gov (United States)

    Dziaman, Tomasz; Huzarski, Tomasz; Gackowski, Daniel; Rozalski, Rafal; Siomek, Agnieszka; Szpila, Anna; Guz, Jolanta; Lubinski, Jan; Wasowicz, Wojciech; Roszkowski, Krzysztof; Olinski, Ryszard

    2009-11-01

    Some experimental evidence suggests that BRCA1 plays a role in repair of oxidative DNA damage. Selenium has anticancer properties that are linked with protection against oxidative stress. To assess whether supplementation of BRCA1 mutation carriers with selenium have a beneficial effect concerning oxidative stress/DNA damage in the present double-blinded placebo control study, we determined 8-oxodG level in cellular DNA and urinary excretion of 8-oxodG and 8-oxoGua in the mutation carriers. We found that 8-oxodG level in leukocytes DNA is significantly higher in BRCA1 mutation carriers. In the distinct subpopulation of BRCA1 mutation carriers without symptoms of cancer who underwent adnexectomy and were supplemented with selenium, the level of 8-oxodG in DNA decreased significantly in comparison with the subgroup without supplementation. Simultaneously in the same group, an increase of urinary 8-oxoGua, the product of base excision repair (hOGG1 glycosylase), was observed. Therefore, it is likely that the selenium supplementation of the patients is responsible for the increase of BER enzymes activities, which in turn may result in reduction of oxidative DNA damage. Importantly, in a double-blinded placebo control prospective study, it was shown that in the same patient groups, reduction in cancer incidents was observed. Altogether, these results suggest that BRCA1 deficiency contributes to 8-oxodG accumulation in cellular DNA, which in turn may be a factor responsible for cancer development in women with mutations, and that the risk to developed breast cancer in BRCA1 mutation carriers may be reduced in selenium-supplemented patients who underwent adnexectomy. PMID:19843683

  13. Nucleolar exit of RNF8 and BRCA1 in response to DNA damage

    Energy Technology Data Exchange (ETDEWEB)

    Guerra-Rebollo, Marta; Mateo, Francesca; Franke, Kristin [Department of Cell Biology, Molecular Biology Institute of Barcelona (IBMB), CSIC, Barcelona Science Park, Helix Building, Baldiri Reixac 15-21, 08028 Barcelona (Spain); Huen, Michael S.Y. [Department of Anatomy, Centre for Cancer Research, The University of Hong Kong, L1, Laboratory Block, 21 Sassoon Road, Hong Kong Special Administrative Region (Hong Kong); Lopitz-Otsoa, Fernando; Rodriguez, Manuel S. [Proteomics Unit, CIC bioGUNE CIBERehd, ProteoRed, Technology Park of Bizkaia, Building 801A, 48160 Derio (Spain); Plans, Vanessa [Department of Cell Biology, Molecular Biology Institute of Barcelona (IBMB), CSIC, Barcelona Science Park, Helix Building, Baldiri Reixac 15-21, 08028 Barcelona (Spain); Thomson, Timothy M., E-mail: titbmc@ibmb.csic.es [Department of Cell Biology, Molecular Biology Institute of Barcelona (IBMB), CSIC, Barcelona Science Park, Helix Building, Baldiri Reixac 15-21, 08028 Barcelona (Spain)

    2012-11-01

    The induction of DNA double-strand breaks (DSBs) elicits a plethora of responses that redirect many cellular functions to the vital task of repairing the injury, collectively known as the DNA damage response (DDR). We have found that, in the absence of DNA damage, the DSB repair factors RNF8 and BRCA1 are associated with the nucleolus. Shortly after exposure of cells to {gamma}-radiation, RNF8 and BRCA1 translocated from the nucleolus to damage foci, a traffic that was reverted several hours after the damage. RNF8 interacted through its FHA domain with the ribosomal protein RPSA, and knockdown of RPSA caused a depletion of nucleolar RNF8 and BRCA1, suggesting that the interaction of RNF8 with RPSA is critical for the nucleolar localization of these DDR factors. Knockdown of RPSA or RNF8 impaired bulk protein translation, as did {gamma}-irradiation, the latter being partially countered by overexpression of exogenous RNF8. Our results suggest that RNF8 and BRCA1 are anchored to the nucleolus through reversible interactions with RPSA and that, in addition to its known functions in DDR, RNF8 may play a role in protein synthesis, possibly linking the nucleolar exit of this factor to the attenuation of protein synthesis in response to DNA damage. -- Highlights: Black-Right-Pointing-Pointer RNF8 and BRCA1 are associated with the nucleolus of undamaged cells. Black-Right-Pointing-Pointer Upon {gamma}-radiation, RNF8 and BRCA1 are translocated from the nucleolus to damage foci. Black-Right-Pointing-Pointer The ribosomal protein RPSA anchors RNF8 to the nucleolus. Black-Right-Pointing-Pointer RNF8 may play previously unsuspected roles in protein synthesis.

  14. Nucleolar exit of RNF8 and BRCA1 in response to DNA damage

    International Nuclear Information System (INIS)

    The induction of DNA double-strand breaks (DSBs) elicits a plethora of responses that redirect many cellular functions to the vital task of repairing the injury, collectively known as the DNA damage response (DDR). We have found that, in the absence of DNA damage, the DSB repair factors RNF8 and BRCA1 are associated with the nucleolus. Shortly after exposure of cells to γ-radiation, RNF8 and BRCA1 translocated from the nucleolus to damage foci, a traffic that was reverted several hours after the damage. RNF8 interacted through its FHA domain with the ribosomal protein RPSA, and knockdown of RPSA caused a depletion of nucleolar RNF8 and BRCA1, suggesting that the interaction of RNF8 with RPSA is critical for the nucleolar localization of these DDR factors. Knockdown of RPSA or RNF8 impaired bulk protein translation, as did γ-irradiation, the latter being partially countered by overexpression of exogenous RNF8. Our results suggest that RNF8 and BRCA1 are anchored to the nucleolus through reversible interactions with RPSA and that, in addition to its known functions in DDR, RNF8 may play a role in protein synthesis, possibly linking the nucleolar exit of this factor to the attenuation of protein synthesis in response to DNA damage. -- Highlights: ► RNF8 and BRCA1 are associated with the nucleolus of undamaged cells. ► Upon γ-radiation, RNF8 and BRCA1 are translocated from the nucleolus to damage foci. ► The ribosomal protein RPSA anchors RNF8 to the nucleolus. ► RNF8 may play previously unsuspected roles in protein synthesis.

  15. The prevalence of BRCA1 mutations among young women with triple-negative breast cancer

    Directory of Open Access Journals (Sweden)

    DeSai Damini

    2009-03-01

    Full Text Available Abstract Background Molecular screening for BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer. Features of hereditary breast cancer include an early age-of-onset and over-representation of the 'triple-negative' phenotype (negative for estrogen-receptor, progesterone-receptor and HER2. The decision to offer genetic testing to a breast cancer patient is usually based on her family history, but in the absence of a family history of cancer, some women may qualify for testing based on the age-of-onset and/or the pathologic features of the breast cancer. Methods We studied 54 women who were diagnosed with high-grade, triple-negative invasive breast cancer at or before age 40. These women were selected for study because they had little or no family history of breast or ovarian cancer and they did not qualify for genetic testing using conventional family history criteria. BRCA1 screening was performed using a combination of fluorescent multiplexed-PCR analysis, BRCA1 exon-13 6 kb duplication screening, the protein truncation test (PTT and fluorescent multiplexed denaturing gradient gel electrophoresis (DGGE. All coding exons of BRCA1 were screened. The two large exons of BRCA2 were also screened using PTT. All mutations were confirmed with direct sequencing. Results Five deleterious BRCA1 mutations and one deleterious BRCA2 mutation were identified in the 54 patients with early-onset, triple-negative breast cancer (11%. Conclusion Women with early-onset triple-negative breast cancer are candidates for genetic testing for BRCA1, even in the absence of a family history of breast or ovarian cancer.

  16. Yeast screens identify the RNA polymerase II CTD and SPT5 as relevant targets of BRCA1 interaction.

    Directory of Open Access Journals (Sweden)

    Craig B Bennett

    Full Text Available BRCA1 has been implicated in numerous DNA repair pathways that maintain genome integrity, however the function responsible for its tumor suppressor activity in breast cancer remains obscure. To identify the most highly conserved of the many BRCA1 functions, we screened the evolutionarily distant eukaryote Saccharomyces cerevisiae for mutants that suppressed the G1 checkpoint arrest and lethality induced following heterologous BRCA1 expression. A genome-wide screen in the diploid deletion collection combined with a screen of ionizing radiation sensitive gene deletions identified mutants that permit growth in the presence of BRCA1. These genes delineate a metabolic mRNA pathway that temporally links transcription elongation (SPT4, SPT5, CTK1, DEF1 to nucleopore-mediated mRNA export (ASM4, MLP1, MLP2, NUP2, NUP53, NUP120, NUP133, NUP170, NUP188, POM34 and cytoplasmic mRNA decay at P-bodies (CCR4, DHH1. Strikingly, BRCA1 interacted with the phosphorylated RNA polymerase II (RNAPII carboxy terminal domain (P-CTD, phosphorylated in the pattern specified by the CTDK-I kinase, to induce DEF1-dependent cleavage and accumulation of a RNAPII fragment containing the P-CTD. Significantly, breast cancer associated BRCT domain defects in BRCA1 that suppressed P-CTD cleavage and lethality in yeast also suppressed the physical interaction of BRCA1 with human SPT5 in breast epithelial cells, thus confirming SPT5 as a relevant target of BRCA1 interaction. Furthermore, enhanced P-CTD cleavage was observed in both yeast and human breast cells following UV-irradiation indicating a conserved eukaryotic damage response. Moreover, P-CTD cleavage in breast epithelial cells was BRCA1-dependent since damage-induced P-CTD cleavage was only observed in the mutant BRCA1 cell line HCC1937 following ectopic expression of wild type BRCA1. Finally, BRCA1, SPT5 and hyperphosphorylated RPB1 form a complex that was rapidly degraded following MMS treatment in wild type but not BRCA1

  17. Breast cancer 1 (BrCa1 may be behind decreased lipogenesis in adipose tissue from obese subjects.

    Directory of Open Access Journals (Sweden)

    Francisco J Ortega

    Full Text Available CONTEXT: Expression and activity of the main lipogenic enzymes is paradoxically decreased in obesity, but the mechanisms behind these findings are poorly known. Breast Cancer 1 (BrCa1 interacts with acetyl-CoA carboxylase (ACC reducing the rate of fatty acid biosynthesis. In this study, we aimed to evaluate BrCa1 in human adipose tissue according to obesity and insulin resistance, and in vitro cultured adipocytes. RESEARCH DESIGN AND METHODS: BrCa1 gene expression, total and phosphorylated (P- BrCa1, and ACC were analyzed in adipose tissue samples obtained from a total sample of 133 subjects. BrCa1 expression was also evaluated during in vitro differentiation of human adipocytes and 3T3-L1 cells. RESULTS: BrCa1 gene expression was significantly up-regulated in both omental (OM; 1.36-fold, p = 0.002 and subcutaneous (SC; 1.49-fold, p = 0.001 adipose tissue from obese subjects. In parallel with increased BrCa1 mRNA, P-ACC was also up-regulated in SC (p = 0.007 as well as in OM (p = 0.010 fat from obese subjects. Consistent with its role limiting fatty acid biosynthesis, both BrCa1 mRNA (3.5-fold, p<0.0001 and protein (1.2-fold, p = 0.001 were increased in pre-adipocytes, and decreased during in vitro adipogenesis, while P-ACC decreased during differentiation of human adipocytes (p = 0.005 allowing lipid biosynthesis. Interestingly, BrCa1 gene expression in mature adipocytes was restored by inflammatory stimuli (macrophage conditioned medium, whereas lipogenic genes significantly decreased. CONCLUSIONS: The specular findings of BrCa1 and lipogenic enzymes in adipose tissue and adipocytes reported here suggest that BrCa1 might help to control fatty acid biosynthesis in adipocytes and adipose tissue from obese subjects.

  18. Histopathological features of breast tumours in BRCA1, BRCA2 and mutation-negative breast cancer families

    International Nuclear Information System (INIS)

    Histopathological features of BRCA1 and BRCA2 tumours have previously been characterised and compared with unselected breast tumours; however, familial non-BRCA1/2 tumours are less well known. The aim of this study was to characterise familial non-BRCA1/2 tumours and to evaluate routine immunohistochemical and pathological markers that could help us to further distinguish families carrying BRCA1/2 mutations from other breast cancer families. Breast cancer tissue specimens (n = 262) from 25 BRCA1, 20 BRCA2 and 74 non-BRCA1/2 families were studied on a tumour tissue microarray. Immunohistochemical staining of oestrogen receptor (ER), progesterone receptor (PgR) and p53 as well as the histology and grade of these three groups were compared with each other and with the respective information on 862 unselected control patients from the archives of the Pathology Department of Helsinki University Central Hospital. Immunohistochemical staining of erbB2 was also performed among familial cases. BRCA1-associated cancers were diagnosed younger and were more ER-negative and PgR-negative, p53-positive and of higher grade than the other tumours. However, in multivariate analysis the independent factors compared with non-BRCA1/2 tumours were age, grade and PgR negativity. BRCA2 cases did not have such distinctive features compared with non-BRCA1/2 tumours or with unselected control tumours. Familial cases without BRCA1/2 mutations had tumours of lower grade than the other groups. BRCA1 families differed from mutation-negative families by age, grade and PgR status, whereas ER status was not an independent marker

  19. AURKA F31I Polymorphism and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: A CIMBA study

    Science.gov (United States)

    Couch, Fergus J.; Sinilnikova, Olga; Vierkant, Robert A; Pankratz, V. Shane; Fredericksen, Zachary S.; Stoppa-Lyonnet, Dominique; Coupier, Isabelle; Hughes, David; Hardouin, Agnès; Berthet, Pascaline; Peock, Susan; Cook, Margaret; Baynes, Caroline; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary E.; Jakubowska, Anna; Lubinski, Jan; Gronwald, Jacek; Spurdle, Amanda B.; Schmutzler, Rita; Versmold, Beatrix; Engel, Christoph; Meindl, Alfons; Sutter, Christian; Horst, Jurgen; Schaefer, Dieter; Offit, Kenneth; Kirchhoff, Tomas; Andrulis, Irene L.; Ilyushik, Eduard; Glendon, Gordon; Devilee, Peter; Vreeswijk, Maaike P.G.; Vasen, Hans F.A.; Borg, Ake; Backenhorn, Katja; Struewing, Jeffery P.; Greene, Mark H.; Neuhausen, Susan L.; Rebbeck, Timothy R.; Nathanson, Katherine; Domchek, Susan; Wagner, Theresa; Garber, Judy E.; Szabo, Csilla; Zikan, Michal; Foretova, Lenka; Olson, Janet E.; Sellers, Thomas A.; Lindor, Noralane; Nevanlinna, Heli; Tommiska, Johanna; Aittomaki, Kristiina; Hamann, Ute; Rashid, Muhammad U.; Torres, Diana; Simard, Jacques; Durocher, Francine; Guenard, Frederic; Lynch, Henry T.; Isaacs, Claudine; Weitzel, Jeffrey; Olopade, Olufunmilayo I.; Narod, Steven; Daly, Mary B.; Godwin, Andrew K.; Tomlinson, Gail; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniouon, Antonis C.

    2009-01-01

    The AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 co-operate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). CIMBA was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4935 BRCA1 and 2241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations were genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined (HR = 0.91; 95% CI 0.77-1.06). Similarly, no significant association was seen in BRCA1 (HR = 0.90; 95% CI 0.75-1.08) or BRCA2 carriers (HR = 0.93; 95% CI 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers. PMID:17627006

  20. BRCA1 and MicroRNAs: Emerging Networks and Potential Therapeutic Targets

    OpenAIRE

    Chang, Suhwan; Sharan, Shyam K.

    2012-01-01

    BRCA1 is a well-known tumor suppressor implicated in familial breast and ovarian cancer. Since its cloning in 1994, numerous studies have established BRCA1’s role in diverse cellular and biochemical processes, such as DNA damage repair, cell cycle control, and transcriptional regulation as well as ubiquitination. In addition, a number of recent studies have functionally linked this tumor suppressor to another important cellular regulator, microRNAs, which are short (19–22 nt) RNAs that were d...

  1. Risk modeling and screening for BRCA1 mutations among Filipino breast cancer patients

    International Nuclear Information System (INIS)

    Breast cancer susceptibility gene, type 1(BRCA1) has been thought to be responsible for ∼45% of families with multiple breast carcinomas and for ∼80% of breast and ovarian cancer families. In this study, we investigated 34 familial Filipino breast cancer (BC) patients to: (a) estimate breast cancer risks and BRCA1/2 mutation carrier probabilities using risk assessment and prior probability models, respectively; (b) screen for putative polymorphisms at selected smaller exons of BRCA1 by single-strand conformation polymorphism (SSCP) analysis; (c) screen for truncated mutations at BRCA1 exon 11 by radioactive protein truncation test (PTT); and (d) estimate posterior probabilities upon incorporation of screening results. SSCP analysis revealed 8 unique putative polymorphisms. Low prevalence of unique putative polymorphisms at exon 2, 5, 17, and 22 may indicate probable mutations. Contrastingly, high prevalence of unique putative polymorphisms at exons 13, 15, and 16 may suggest true polymorphisms which are biologically insignificant. PTT, DHPLC, and sequence analyses revealed a novel mutation in exon 11 involving GT insertion that resulted to a stop codon which generated a 29.7 kDa truncated protein product. This is the second documented mutation in BRCA1 exon 11 in a Filipino BC patient since 1998. Initial genotype-phenotype correlations in Filipino BC patients may be elucidated based on screening tests performed. Our results corroborate the findings of a study on unselected incident Filipino BC cases where the reported prevalence of BRCA1 mutation is low. The higher prevalence of putative polypmorphisms may be attributed to the increased stringency in patient prospecting. The Gail, Claus, and BRCAPRO models can be utilized to estimate BC risk in unaffected high-risk individuals but validation is needed. Most of the BRCAPRO and Myriad.com prior probability estimates coincide with the presence of BRCA1 mutation and/or putative polymorphisms. This pioneering

  2. Telomere length shows no association with BRCA1 and BRCA2 mutation status

    DEFF Research Database (Denmark)

    Killick, Emma; Tymrakiewicz, Malgorzata; Cieza-Borrella, Clara;

    2014-01-01

    This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy...... mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL....

  3. Rare BRCA1 haplotypes including 3′UTR SNPs associated with breast cancer risk

    OpenAIRE

    Pelletier, Cory; Speed, William C; Paranjape, Trupti; Keane, Katie; Blitzblau, Rachel; Hollestelle, Antoinette; Safavi, Kyan; Van Den Ouweland, Ans; Zelterman, Daniel; Slack, Frank J; Kidd, Kenneth K.; Weidhaas, Joanne B

    2011-01-01

    Genetic markers identifying women at an increased risk of developing breast cancer exist, yet the majority of inherited risk remains elusive. While numerous BRCA1 coding sequence mutations are associated with breast cancer risk, BRCA1 mutations account for less then 5% of breast cancer risk. Since 3′ untranslated region (3′UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we tested the hypothesis that such polymorphisms in ...

  4. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers : results from the Consortium of Investigators of Modifiers of BRCA1/2

    NARCIS (Netherlands)

    Mulligan, Anna Marie; Couch, Fergus J.; Barrowdale, Daniel; Domchek, Susan M.; Eccles, Diana; Nevanlinna, Heli; Ramus, Susan J.; Robson, Mark; Sherman, Mark; Spurdle, Amanda B.; Wappenschmidt, Barbara; Lee, Andrew; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga M.; Janavicius, Ramunas; Hansen, Thomas V. O.; Nielsen, Finn C.; Ejlertsen, Bent; Osorio, Ana; Munoz-Repeto, Ivan; Duran, Mercedes; Godino, Javier; Pertesi, Maroulio; Benitez, Javier; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Bonanni, Bernardo; Viel, Alessandra; Pasini, Barbara; Papi, Laura; Ottini, Laura; Savarese, Antonella; Bernard, Loris; Radice, Paolo; Hamann, Ute; Verheus, Martijn; Meijers-Heijboer, Hanne E. J.; Wijnen, Juul; Garcia, Encarna B. Gomez; Nelen, Marcel R.; Kets, C. Marleen; Seynaeve, Caroline; Tilanus-Linthorst, Madeleine M. A.; van der Luijt, Rob B.; van Os, Theo; Rookus, Matti; Frost, Debra; Jones, J. Louise; Evans, D. Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Adlard, Julian; Davidson, Rosemarie; Cook, Jackie; Donaldson, Alan; Dorkins, Huw; Gregory, Helen; Eason, Jacqueline; Houghton, Catherine; Barwell, Julian; Side, Lucy E.; McCann, Emma; Murray, Alex; Peock, Susan; Godwin, Andrew K.; Schmutzler, Rita K.; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ruehl, Ina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Kast, Karin; Preisler-Adams, Sabine; Varon-Mateeva, Raymonda; Schoenbuchner, Ines; Fiebig, Britta; Heinritz, Wolfram; Schaefer, Dieter; Gevensleben, Heidrun; Caux-Moncoutier, Virginie; Fassy-Colcombet, Marion; Cornelis, Francois; Mazoyer, Sylvie; Leone, Melanie; Boutry-Kryza, Nadia; Hardouin, Agnes; Berthet, Pascaline; Muller, Daniele; Fricker, Jean-Pierre; Mortemousque, Isabelle; Pujol, Pascal; Coupier, Isabelle; Lebrun, Marine; Kientz, Caroline; Longy, Michel; Sevenet, Nicolas; Stoppa-Lyonnet, Dominique; Isaacs, Claudine; Caldes, Trinidad; de la Hoya, Miguel; Heikkinen, Tuomas; Aittomaki, Kristiina; Blanco, Ignacio; Lazaro, Conxi; Barkardottir, Rosa B.; Soucy, Penny; Dumont, Martine; Simard, Jacques; Montagna, Marco; Tognazzo, Silvia; D'Andrea, Emma; Fox, Stephen; Yan, Max; Rebbeck, Tim; Olopade, Olufunmilayo I.; Weitzel, Jeffrey N.; Lynch, Henry T.; Ganz, Patricia A.; Tomlinson, Gail E.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, Noralane M.; Szabo, Csilla; Offit, Kenneth; Sakr, Rita; Gaudet, Mia; Bhatia, Jasmine; Kauff, Noah; Singer, Christian F.; Tea, Muy-Kheng; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Mai, Phuong L.; Greene, Mark H.; Imyanitov, Evgeny; O'Malley, Frances P.; Ozcelik, Hilmi; Glendon, Gordon; Toland, Amanda E.; Gerdes, Anne-Marie; Thomassen, Mads; Kruse, Torben A.; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Soller, Maria; Henriksson, Karin; Wachenfeldt, von Anna; Arver, Brita; Stenmark-Askmalm, Marie; Karlsson, Per; Ding, Yuan Chun; Neuhausen, Susan L.; Beattie, Mary; Pharoah, Paul D. P.; Moysich, Kirsten B.; Nathanson, Katherine L.; Karlan, Beth Y.; Gross, Jenny; John, Esther M.; Daly, Mary B.; Buys, Saundra M.; Southey, Melissa C.; Hopper, John L.; Terry, Mary Beth; Chung, Wendy; Miron, Alexander F.; Goldgar, David; Chenevix-Trench, Georgia; Easton, Douglas F.; Andrulis, Irene L.; Antoniou, Antonis C.

    2011-01-01

    Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 an

  5. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

    NARCIS (Netherlands)

    Couch, Fergus J.; Wang, Xianshu; McGuffog, Lesley; Lee, Andrew; Olswold, Curtis; Kuchenbaecker, Karoline B.; Soucy, Penny; Fredericksen, Zachary; Barrowdale, Daniel; Dennis, Joe; Gaudet, Mia M.; Dicks, Ed; Kosel, Matthew; Healey, Sue; Sinilnikova, Olga M.; Lee, Adam; Bacot, Francois; Vincent, Daniel; Hogervorst, Frans B. L.; Peock, Susan; Stoppa-Lyonnet, Dominique; Jakubowska, Anna; Radice, Paolo; Schmutzler, Rita Katharina; Domchek, Susan M.; Piedmonte, Marion; Singer, Christian F.; Friedman, Eitan; Thomassen, Mads; Hansen, Thomas V. O.; Neuhausen, Susan L.; Szabo, Csilla I.; Blanco, Ignacio; Greene, Mark H.; Karlan, Beth Y.; Garber, Judy; Phelan, Catherine M.; Weitzel, Jeffrey N.; Montagna, Marco; Olah, Edith; Andrulis, Irene L.; Godwin, Andrew K.; Yannoukakos, Drakoulis; Goldgar, David E.; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; Terry, Mary Beth; Daly, Mary B.; van Rensburg, Elizabeth J.; Hamann, Ute; Ramus, Susan J.; Toland, Amanda Ewart; Caligo, Maria A.; Olopade, Olufunmilayo I.; Tung, Nadine; Claes, Kathleen; Beattie, Mary S.; Southey, Melissa C.; Imyanitov, Evgeny N.; Tischkowitz, Marc; Janavicius, Ramunas; John, Esther M.; Kwong, Ava; Diez, Orland; Balmana, Judith; Barkardottir, Rosa B.; Arun, Banu K.; Rennert, Gad; Teo, Soo-Hwang; Ganz, Patricia A.; Campbell, Ian; van der Hout, Annemarie H.; van Deurzen, Carolien H. M.; Seynaeve, Caroline; Garcia, Encarna B. Gomez; van Leeuwen, Flora E.; Meijers-Heijboer, Hanne E. J.; Gille, Johannes J. P.; Ausems, Margreet G. E. M.; Blok, Marinus J.; Ligtenberg, Marjolijn J. L.; Rookus, Matti A.; Devilee, Peter; Verhoef, Senno; van Os, Theo A. M.; Wijnen, Juul T.; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Evans, D. Gareth; Izatt, Louise; Eeles, Rosalind A.; Adlard, Julian; Eccles, Diana M.; Cook, Jackie; Brewer, Carole; Douglas, Fiona; Hodgson, Shirley; Morrison, Patrick J.; Side, Lucy E.; Donaldson, Alan; Houghton, Catherine; Rogers, Mark T.; Dorkins, Huw; Eason, Jacqueline; Gregory, Helen; McCann, Emma; Murray, Alex; Calender, Alain; Hardouin, Agnes; Berthet, Pascaline; Delnatte, Capucine; Nogues, Catherine; Lasset, Christine; Houdayer, Claude; Leroux, Dominique; Rouleau, Etienne; Prieur, Fabienne; Damiola, Francesca; Sobol, Hagay; Coupier, Isabelle; Venat-Bouvet, Laurence; Castera, Laurent; Gauthier-Villars, Marion; Leone, Melanie; Pujol, Pascal; Mazoyer, Sylvie; Bignon, Yves-Jean; Zlowocka-Perlowska, Elzbieta; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska, Katarzyna; Huzarski, Tomasz; Spurdle, Amanda B.; Viel, Alessandra; Peissel, Bernard; Bonanni, Bernardo; Melloni, Giulia; Ottini, Laura; Papi, Laura; Varesco, Liliana; Tibiletti, Maria Grazia; Peterlongo, Paolo; Volorio, Sara; Manoukian, Siranoush; Pensotti, Valeria; Arnold, Norbert; Engel, Christoph; Deissler, Helmut; Gadzicki, Dorothea; Gehrig, Andrea; Kast, Karin; Rhiem, Kerstin; Meindl, Alfons; Niederacher, Dieter; Ditsch, Nina; Plendl, Hansjoerg; Preisler-Adams, Sabine; Engert, Stefanie; Sutter, Christian; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Weber, Bernhard H. F.; Arver, Brita; Stenmark-Askmalm, Marie; Loman, Niklas; Rosenquist, Richard; Einbeigi, Zakaria; Nathanson, Katherine L.; Rebbeck, Timothy R.; Blank, Stephanie V.; Cohn, David E.; Rodriguez, Gustavo C.; Small, Laurie; Friedlander, Michael; Bae-Jump, Victoria L.; Fink-Retter, Anneliese; Rappaport, Christine; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Tea, Muy-Kheng; Lindor, Noralane M.; Kaufman, Bella; Paluch, Shani Shimon; Laitman, Yael; Skytte, Anne-Bine; Gerdes, Anne-Marie; Pedersen, Inge Sokilde; Moeller, Sanne Traasdahl; Kruse, Torben A.; Jensen, Uffe Birk; Vijai, Joseph; Sarrel, Kara; Robson, Mark; Kauff, Noah; Mulligan, Anna Marie; Glendon, Gord; Ozcelik, Hilmi; Ejlertsen, Bent; Nielsen, Finn C.; Jonson, Lars; Andersen, Mette K.; Ding, Yuan Chun; Steele, Linda; Foretova, Lenka; Teule, Alex; Lazaro, Conxi; Brunet, Joan; Angel Pujana, Miquel; Mai, Phuong L.; Loud, Jennifer T.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Narod, Steven A.; Herzog, Josef; Sand, Sharon R.; Tognazzo, Silvia; Agata, Simona; Vaszko, Tibor; Weaver, Joellen; Stavropoulou, Alexandra V.; Buys, Saundra S.; Romero, Atocha; de la Hoya, Miguel; Aittomaki, Kristiina; Muranen, Taru A.; Duran, Mercedes; Chung, Wendy K.; Lasa, Adriana; Dorfling, Cecilia M.; Miron, Alexander; Benitez, Javier; Senter, Leigha; Huo, Dezheng; Chan, Salina B.; Sokolenko, Anna P.; Chiquette, Jocelyne; Tihomirova, Laima; Friebel, Tara M.; Agnarsson, Bjarni A.; Lu, Karen H.; Lejbkowicz, Flavio; James, Paul A.; Hall, Per; Dunning, Alison M.

    2013-01-01

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a furthe

  6. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

    NARCIS (Netherlands)

    F.J. Couch (Fergus); X. Wang (Xing); L. McGuffog (Lesley); A. Lee; C. Olswold (Curtis); K.B. Kuchenbaecker (Karoline); P. Soucy (Penny); Z. Fredericksen (Zachary); D. Barrowdale (Daniel); J. Dennis (Joe); M.M. Gaudet (Mia); E. Dicks (Ed); M. Kosel (Matthew); S. Healey (Sue); O. Sinilnikova (Olga); F. Bacot (Francois); D. Vincent (Daniel); F.B.L. Hogervorst (Frans); S. Peock (Susan); D. Stoppa-Lyonnet (Dominique); A. Jakubowska (Anna); P. Radice (Paolo); R.K. Schmutzler (Rita); S.M. Domchek (Susan); M. Piedmonte (Marion); C.F. Singer (Christian); E. Friedman (Eitan); M. Thomassen (Mads); T.V.O. Hansen (Thomas); S.L. Neuhausen (Susan); C. Szabo (Csilla); I. Blanco (Ignacio); M.H. Greene (Mark); B. Karlan; J. Garber; C. Phelan (Catherine); J.N. Weitzel (Jeffrey); M. Montagna (Marco); E. Olah; I.L. Andrulis (Irene); A.K. Godwin (Andrew); D. Yannoukakos (Drakoulis); D. Goldgar (David); T. Caldes (Trinidad); H. Nevanlinna (Heli); A. Osorio (Ana); M.-B. Terry (Mary-Beth); M.B. Daly (Mary); E.J. van Rensburg (Elizabeth); U. Hamann (Ute); S.J. Ramus (Susan); A. Ewart-Toland (Amanda); M.A. Caligo (Maria); O.I. Olopade (Olofunmilayo); N. Tung (Nadine); K. Claes (Kathleen); M.S. Beattie (Mary); M.C. Southey (Melissa); E.N. Imyanitov (Evgeny); M. Tischkowitz (Marc); R. Janavicius (Ramunas); E.M. John (Esther); A. Kwong (Ava); O. Diez (Orland); J. Balmana (Judith); R.B. Barkardottir (Rosa); B.K. Arun (Banu); G. Rennert (Gad); S.-H. Teo; P.A. Ganz (Patricia); I. Campbell (Ian); A.H. van der Hout (Annemarie); C.H.M. van Deurzen (Carolien); C.M. Seynaeve (Caroline); E.B. Gómez García (Encarna); F.E. van Leeuwen (F.); H.E.J. Meijers-Heijboer (Hanne E.); J.J. Gille (Johan); M.G.E.M. Ausems (Margreet); M.J. Blok (Marinus); M.J. Ligtenberg (Marjolijn); M.A. Rookus (Matti); P. Devilee (Peter); S. Verhoef; T.A.M. van Os (Theo); J.T. Wijnen (Juul); D. Frost (Debra); S. Ellis (Steve); E. Fineberg (Elena); R. Platte (Radka); D.G. Evans (Gareth); L. Izatt (Louise); R. Eeles (Rosalind); J.W. Adlard (Julian); D. Eccles (Diana); J. Cook (Jackie); C. Brewer (C.); F. Douglas (Fiona); S.V. Hodgson (Shirley); P.J. Morrison (Patrick); L. Side (Lucy); A. Donaldson (Alan); C. Houghton (Catherine); M.T. Rogers (Mark); H. Dorkins (Huw); J. Eason (Jacqueline); H. Gregory (Helen); E. McCann (Emma); A. Murray (Alexandra); A. Calender (Alain); A. Hardouin (Agnès); P. Berthet (Pascaline); C.D. Delnatte (Capucine); C. Nogues (Catherine); C. Lasset (Christine); C. Houdayer (Claude); D. Leroux (Dominique); E. Rouleau (Etienne); F. Prieur (Fabienne); F. Damiola (Francesca); H. Sobol (Hagay); I. Coupier (Isabelle); L. Vénat-Bouvet (Laurence); L. Castera (Laurent); M. Gauthier-Villars (Marion); M. Léone (Mélanie); P. Pujol (Pascal); S. Mazoyer (Sylvie); Y.-J. Bignon (Yves-Jean); E. Złowocka-Perłowska (Elzbieta); J. Gronwald (Jacek); J. Lubinski (Jan); K. Durda (Katarzyna); K. Jaworska (Katarzyna); T. Huzarski (Tomasz); A.B. Spurdle (Amanda); A. Viel (Alessandra); B. Peissel (Bernard); B. Bonnani (Bernardo); G. Melloni (Giulia); L. Ottini (Laura); L. Papi (Laura); L. Varesco (Liliana); M.G. Tibiletti (Maria Grazia); P. Peterlongo (Paolo); S. Volorio (Sara); S. Manoukian (Siranoush); V. Pensotti (Valeria); N. Arnold (Norbert); C. Engel (Christoph); H. Deissler (Helmut); D. Gadzicki (Dorothea); P.A. Gehrig (Paola A.); K. Kast (Karin); K. Rhiem (Kerstin); A. Meindl (Alfons); D. Niederacher (Dieter); N. Ditsch (Nina); H. Plendl (Hansjoerg); S. Preisler-Adams (Sabine); S. Engert (Stefanie); C. Sutter (Christian); R. Varon-Mateeva (Raymonda); B. Wapenschmidt (Barbara); B.H.F. Weber (Bernhard); B. Arver (Brita Wasteson); M. Stenmark-Askmalm (M.); N. Loman (Niklas); R. Rosenquist (R.); Z. Einbeigi (Zakaria); K.L. Nathanson (Katherine); R. Rebbeck (Timothy); S.V. Blank (Stephanie); D.E. Cohn (David); G.C. Rodriguez (Gustavo); L. Small (Laurie); M. Friedlander (Michael); V.L. Bae-Jump (Victoria L.); A. Fink-Retter (Anneliese); C. Rappaport (Christine); D. Gschwantler-Kaulich (Daphne); G. Pfeiler (Georg); M.-K. Tea; N.M. Lindor (Noralane); B. Kaufman (Bella); S. Shimon Paluch (Shani); Y. Laitman (Yael); A.-B. Skytte (Anne-Bine); A-M. Gerdes (Anne-Marie); I.S. Pedersen (Inge Sokilde); S.T. Moeller (Sanne Traasdahl); T.A. Kruse (Torben); U.B. Jensen; J. Vijai (Joseph); K. Sarrel (Kara); M. Robson (Mark); N. Kauff (Noah); A.M. Mulligan (Anna Marie); G. Glendon (Gord); H. Ozcelik (Hilmi); B. Ejlertsen (Bent); F.C. Nielsen (Finn); L. Jønson (Lars); M.K. Andersen (Mette); Y.C. Ding (Yuan); L. Steele (Linda); L. Foretova (Lenka); A. Teulé (A.); C. Lazaro (Conxi); J. Brunet (Joan); M.A. Pujana (Miguel); P.L. Mai (Phuong); J.T. Loud (Jennifer); C.S. Walsh (Christine); K.J. Lester (Kathryn); S. Orsulic (Sandra); S. Narod (Steven); J. Herzog (Josef); S.R. Sand (Sharon); S. Tognazzo (Silvia); S. Agata (Simona); T. Vaszko (Tibor); J. Weaver (JoEllen); A. Stavropoulou (Alexandra); S.S. Buys (Saundra); A. Romero (Alfonso); M. de La Hoya (Miguel); K. Aittomäki (Kristiina); T.A. Muranen (Taru); M. Duran; W.K. Chung (Wendy); A. Lasa (Adriana); C.M. Dorfling (Cecelia); A. Miron (Alexander); J. Benítez (Javier); L. Senter (Leigha); D. Huo (Dezheng); S. Chan (Salina); A. Sokolenko (Anna); J. Chiquette (Jocelyne); L. Tihomirova (Laima); M.O.W. Friebel (Mark ); B.A. Agnarsson (Bjarni); K.H. Lu (Karen); F. Lejbkowicz (Flavio); P.A. James (Paul ); A.S. Hall (Alistair); A.M. Dunning (Alison); Y. Tessier (Yann); J. Cunningham (Jane); S. Slager (Susan); C. Wang (Chen); S. Hart (Stewart); K. Stevens (Kristen); J. Simard (Jacques); T. Pastinen (Tomi); V.S. Pankratz (Shane); K. Offit (Kenneth); D.F. Easton (Douglas); G. Chenevix-Trench (Georgia); A.C. Antoniou (Antonis); H. Thorne (Heather); E. Niedermayr (Eveline); Å. Borg (Åke); H. Olsson; H. Jernström (H.); K. Henriksson (Karin); K. Harbst (Katja); M. Soller (Maria); U. Kristoffersson (Ulf); A. Öfverholm (Anna); M. Nordling (Margareta); P. Karlsson (Per); A. von Wachenfeldt (Anna); A. Liljegren (Annelie); A. Lindblom (Annika); G.B. Bustinza; J. Rantala (Johanna); B. Melin (Beatrice); C.E. Ardnor (Christina Edwinsdotter); M. Emanuelsson (Monica); H. Ehrencrona (Hans); M.H. Pigg (Maritta ); S. Liedgren (Sigrun); M.A. Rookus (M.); S. Verhoef (S.); F.E. van Leeuwen (F.); M.K. Schmidt (Marjanka); J.L. de Lange (J.); J.M. Collee (Margriet); A.M.W. van den Ouweland (Ans); M.J. Hooning (Maartje); C.J. van Asperen (Christi); J.T. Wijnen (Juul); R.A.E.M. Tollenaar (Rob); P. Devilee (Peter); T.C.T.E.F. van Cronenburg; C.M. Kets; A.R. Mensenkamp (Arjen); R.B. van der Luijt (Rob); C.M. Aalfs (Cora); T.A.M. van Os (Theo); Q. Waisfisz (Quinten); E.J. Meijers-Heijboer (Hanne); E.B. Gomez Garcia (Encarna); J.C. Oosterwijk (Jan); M.J. Mourits; G.H. de Bock (Geertruida); S.D. Ellis (Steve); E. Fineberg (Elena); Z. Miedzybrodzka (Zosia); L. Jeffers (Lisa); T.J. Cole (Trevor); K.-R. Ong (Kai-Ren); J. Hoffman (Jonathan); M. James (Margaret); J. Paterson (Joan); A. Taylor (Amy); A. Murray (Anna); M.J. Kennedy (John); D.E. Barton (David); M.E. Porteous (Mary); S. Drummond (Sarah); C. Brewer (Carole); E. Kivuva (Emma); A. Searle (Anne); S. Goodman (Selina); R. Davidson (Rosemarie); V. Murday (Victoria); N. Bradshaw (Nicola); L. Snadden (Lesley); M. Longmuir (Mark); C. Watt (Catherine); S. Gibson (Sarah); E. Haque (Eshika); E. Tobias (Ed); A. Duncan (Alexis); L. Izatt (Louise); C. Jacobs (Chris); C. Langman (Caroline); A.F. Brady (Angela); S.A. Melville (Scott); K. Randhawa (Kashmir); J. Barwell (Julian); G. Serra-Feliu (Gemma); I.O. Ellis (Ian); F. Lalloo (Fiona); J. Taylor (James); A. Male (Alison); C. Berlin (Cheryl); R. Collier (Rebecca); F. Douglas (Fiona); O. Claber (Oonagh); I. Jobson (Irene); L.J. Walker (Lisa); D. McLeod (Diane); D. Halliday (Dorothy); S. Durell (Sarah); B. Stayner (Barbara); S. Shanley (Susan); N. Rahman (Nazneen); R. Houlston (Richard); A. Stormorken (Astrid); E. Bancroft (Elizabeth); E. Page (Elizabeth); A. Ardern-Jones (Audrey); K. Kohut (Kelly); J. Wiggins (Jennifer); E. Castro (Elena); S.R. Killick; S. Martin (Sue); D. Rea (Dan); A. Kulkarni (Anjana); O. Quarrell (Oliver); C. Bardsley (Cathryn); S. Goff (Sheila); G. Brice (Glen); L. Winchester (Lizzie); C. Eddy (Charlotte); V. Tripathi (Vishakha); V. Attard (Virginia); A. Lehmann (Anna); A. Lucassen (Anneke); G. Crawford (Gabe); D. McBride (Donna); S. Smalley (Sarah); S. Mazoyer (Sylvie); F. Damiola (Francesca); L. Barjhoux (Laure); C. Verny-Pierre (Carole); S. Giraud (Sophie); D. Stoppa-Lyonnet (Dominique); B. Buecher (Bruno); V. Moncoutier (Virginie); M. Belotti (Muriel); C. Tirapo (Carole); A. de Pauw (Antoine); B. Bressac-de Paillerets (Brigitte); O. Caron (Olivier); Y.-J. Bignon (Yves-Jean); N. Uhrhammer (Nancy); V. Bonadona (Valérie); S. Handallou (Sandrine); A. hardouin (Agnès); H. Sobol (Hagay); V. Bourdon (Violaine); T. Noguchi (Tetsuro); A. Remenieras (Audrey); F. Eisinger (François); J.-P. Peyrat; J. Fournier (Joëlle); F. Révillion (Françoise); P. Vennin (Philippe); C. Adenis (Claude); R. Lidereau (Rosette); L. Demange (Liliane); D.W. Muller (Danièle); J.P. Fricker (Jean Pierre); E. Barouk-Simonet (Emmanuelle); F. Bonnet (Françoise); V. Bubien (Virginie); N. Sevenet (Nicolas); M. Longy (Michel); C. Toulas (Christine); R. Guimbaud (Rosine); L. Gladieff (Laurence); V. Feillel (Viviane); H. Dreyfus (Hélène); C. Rebischung (Christine); M. Peysselon (Magalie); F. Coron (Fanny); L. Faivre (Laurence); M. Lebrun (Marine); C. Kientz (Caroline); S.F. Ferrer; M. Frenay (Marc); I. Mortemousque (Isabelle); F. Coulet (Florence); C. Colas (Chrystelle); F. Soubrier; J. Sokolowska (Johanna); M. Bronner (Myriam); H. Lynch (Henry); C.L. Snyder (Carrie); M. Angelakos (Maggie); J. Maskiell (Judi); G.S. Dite (Gillian)

    2013-01-01

    textabstractBRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), w

  7. Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families

    DEFF Research Database (Denmark)

    Hansen, Thomas v O; Jønson, Lars; Albrechtsen, Anders;

    2009-01-01

    BRCA1 and BRCA2 germ-line mutations predispose to breast and ovarian cancer. Large genomic rearrangements of BRCA1 account for 0-36% of all disease causing mutations in various populations, while large genomic rearrangements in BRCA2 are more rare. We examined 642 East Danish breast and/or ovarian...

  8. BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer

    DEFF Research Database (Denmark)

    Thomassen, Mads; Hansen, Thomas V O; Borg, Ake;

    2008-01-01

    A national study of BRCA1 and BRCA2 mutations in Danish HBOC (Hereditary Breast Ovarian Cancer) families revealed a total number of 322 mutation positive families, 206 (64%) BRCA1 and 116 (36%) BRCA2 positive families from a population of 5.5 million inhabitants. Seven hundred and twenty six muta...

  9. Potentiality of phosphorylation of BRCA1 at Ser 1524 to activate p21 in response to X-ray irradiation

    Institute of Scientific and Technical Information of China (English)

    LI Ning; ZHANG Hong; WANG Yanling; WANG Xiaohu; HAO Jifang; ZHAO Weiping

    2008-01-01

    The breast and ovarian cancer susceptibility gene BRCA1 encodes a nuclear phosphoprotein, which functions as a tumor suppressor gene. Many studies suggested that multiple functions of BRCA1 may contribute to its tumor suppressor activity, including roles in cell cycle checkpoints, apoptosis and transcription. It is postulated that phosphorylation of BRCA1 is an important means by which its cellular functions are regulated. In this study, we employed phospho-Ser-specific antibody recognizing Ser-1524 to study BRCA1 phosphorylation under conditions of DNA damage and the effects of phosphorylation on BRCA1 functions. The results showed that 10 Gy X-ray treatment significantly induced phosphorylation of Ser-1524 but not total BRCA1 protein levels. The expression both of p53 andp21 increased after irradiation, but ionizing radiation (IR)-induced activation of p21 was prior to that of p53. The percentages of G0/G1 phase remarkably increased after IR. In addition, no detectable levels of 89 kDa fragment of PARP, a marker of apoptotic cells, were observed. Data implied that IR-induced phosphorylation of BRCA1 at Ser-1524 might activate p21 protein, by which BRCA1 regulated cell cycle, but play no role in apoptosis.

  10. Validation study suggested no differential misclassification of self-reported mammography history in BRCA1/2 mutation carriers

    NARCIS (Netherlands)

    Pijpe, Anouk; Mulder, Renee L.; Manders, Peggy; van Leeuwen, Flora E.; Rookus, Matti A.

    2011-01-01

    Objectives: We assessed accuracy of self-reported lifetime mammography history by BRCA1/2 mutation carriers with and without breast cancer. Study Design and Setting: Within the framework of the HEBON study (The Netherlands Collaborative Group on Hereditary Breast Cancer), 218 Dutch BRCA1/2 mutation

  11. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Bolton, Kelly L; Chenevix-Trench, Georgia; Goh, Cindy;

    2012-01-01

    Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear....

  12. JMJD1C demethylates MDC1 to regulate the RNF8 and BRCA1-mediated chromatin response to DNA breaks

    DEFF Research Database (Denmark)

    Watanabe, Sugiko; Watanabe, Kenji; Akimov, Vyacheslav;

    2013-01-01

    Chromatin ubiquitylation flanking DNA double-strand breaks (DSBs), mediated by RNF8 and RNF168 ubiquitin ligases, orchestrates a two-branch pathway, recruiting repair factors 53BP1 or the RAP80-BRCA1 complex. We report that human demethylase JMJD1C regulates the RAP80-BRCA1 branch of this DNA...

  13. Post-mortem testing; germline BRCA1/2 variant detection using archival FFPE non-tumor tissue

    DEFF Research Database (Denmark)

    Petersen, Annabeth Høgh; Jørgensen, Mads Malik Aagaard; Nielsen, Henriette Roed;

    2016-01-01

    Accurate estimation of cancer risk in HBOC families often requires BRCA1/2 testing, but this may be impossible in deceased family members. Previous, testing archival formalin-fixed, paraffin-embedded (FFPE) tissue for germline BRCA1/2 variants was unsuccessful, except for the Jewish founder...... mutations. A high-throughput method to systematically test for variants in all coding regions of BRCA1/2 in archival FFPE samples of non-tumor tissue is described, using HaloPlex target enrichment and next-generation sequencing. In a validation study, correct identification of variants or wild......1, six variants known to affect function and one variant likely to affect function in BRCA2, as well as four variants of unknown significance (VUS) in BRCA1 and three VUS in BRCA2 were discovered. It is now possible to test for germline BRCA1/2 variants in deceased persons, using archival FFPE...

  14. Pyrosequencing quantified methylation level of BRCA1 promoter as prognostic factor for survival in breast cancer patient.

    Science.gov (United States)

    Cai, Feng-Feng; Chen, Su; Wang, Ming-Hong; Lin, Xiao-Yan; Zhang, Lian; Zhang, Jia-Xin; Wang, Lian-Xin; Yang, Jun; Ding, Jin-Hua; Pan, Xin; Shao, Zhi-Ming; Biskup, Ewelina

    2016-05-10

    BRCA1 promoter methylation is an essential epigenetic transcriptional silencing mechanism, related to breast cancer (BC) occurrence and progression. We quantified the methylation level of BRCA1 promoter and evaluated its significance as prognostic and predictive factor. BRCA1 promoter methylation level was quantified by pyrosequencing in surgical cancerous and adjacent normal specimens from 154 BC patients. A follow up of 98 months was conducted to assess the correlation between BRCA1-methylation level vs. overall survival (OS) and disease free survival (DFS). The mean methylation level in BC tissues was significantly higher (mean 32.6%; median 31.9%) than in adjacent normal samples (mean 16.2%; median 13.0%) (P Classification of grades and molecular subtypes did not show any prognostic significance. Pyrosequencing is a precise and efficient method to quantify BRCA1 promoter methylation level, with a high potential for future clinical implication, as it identifies subgroups of patients with poorer prognosis. PMID:27027444

  15. Large genomic rearrangement of BRCA1 and BRCA2 genes in familial breast cancer patients in Korea.

    Science.gov (United States)

    Cho, Ja Young; Cho, Dae-Yeon; Ahn, Sei Hyun; Choi, Su-Youn; Shin, Inkyung; Park, Hyun Gyu; Lee, Jong Won; Kim, Hee Jeong; Yu, Jong Han; Ko, Beom Seok; Ku, Bo Kyung; Son, Byung Ho

    2014-06-01

    We screened large genomic rearrangements of the BRCA1 and BRCA2 genes in Korean, familial breast cancer patients. Multiplex ligation-dependent probe amplification assay was used to identify BRCA1 and BRCA2 genomic rearrangements in 226 Korean familial breast cancer patients with risk factors for BRCA1 and BRCA2 mutations, who previously tested negative for point mutations in the two genes. We identified only one large deletion (c.4186-1593_4676-1465del) in BRCA1. No large rearrangements were found in BRCA2. Our result indicates that large genomic rearrangement in the BRCA1 and BRCA2 genes does not seem like a major determinant of breast cancer susceptibility in the Korean population. A large-scale study needs to validate our result in Korea.

  16. Primary care providers' willingness to recommend BRCA1/2 testing to adolescents.

    Science.gov (United States)

    O'Neill, Suzanne C; Peshkin, Beth N; Luta, George; Abraham, Anisha; Walker, Leslie R; Tercyak, Kenneth P

    2010-03-01

    Clinical practice guidelines discourage pediatric genetic testing for BRCA1/2 mutations due to a lack of timely medical benefit and psychosocial risk. Yet, some high risk families approach primary care providers (PCPs) about testing adolescents, and little is known about PCPs attitudes regarding these requests. We assessed recommendations for testing to a composite patient (a healthy 13-year-old female, mother is a BRCA mutation carrier) among 161 adolescent and family PCPs attending a national medical conference. Testing recommendations were measured with a multidimensional scale that assessed perspectives on informed consent, genetic counseling, and insurance coverage. PCPs expressed moderate willingness to recommend testing; surprisingly, 31% recommended adolescent testing "unconditionally." In multivariable regression modeling, recommendation was positively associated with higher clinical practice volume (P recommend BRCA1/2 genetic testing to adolescents from high risk families. When paired with emerging data on the relative safety and efficacy of breast cancer genetic testing for high risk women and the advent of direct-to-consumer marketing of BRCA1/2 cancer genetic tests, professional societies may need to explore best practices to counsel high risk families and their PCPs about the potential risks and benefits of pediatric BRCA1/2 testing. PMID:19390990

  17. The contribution of founder mutations in BRCA1 to breast cancer in Belarus.

    Science.gov (United States)

    Uglanitsa, N; Oszurek, O; Uglanitsa, K; Savonievich, E; Lubiński, J; Cybulski, C; Debniak, T; Narod, S A; Gronwald, J

    2010-10-01

    Mutations in the BRCA1 gene increase susceptibility to both breast and ovarian cancer. In some countries, including several in Eastern Europe, founder mutations in the BRCA1 gene are responsible for a significant proportion of breast cancer cases. To estimate the hereditary proportion of breast cancer in Belarus, we sought the presence of any of three founder mutations in BRCA1 (4153delA, 5382insC and C61G) in 500 unselected cases of breast cancer. These mutations have previously been identified in breast/ovarian cancer families from Belarus and from other Slavic countries, including Poland and Russia. One of the three founder mutations in BRCA1 was present in 38 of 500 unselected cases of breast cancer (7.6%). A mutation was found in 12.6% of women diagnosed before age 50 and 5.6% of women diagnosed after age 50. A mutation was identified in 2 of 251 newborn controls (0.8%). The hereditary proportion of breast cancers in Belarus is among the highest of any countries studied to date.

  18. Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI

    NARCIS (Netherlands)

    J. Veltman; R. Mann; T. Kok (Theo); A.I.M. Obdeijn (Inge-Marie); N. Hoogerbrugge (Nicoline); J.G. Blickman; C. Boetes

    2008-01-01

    textabstractThe appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers (BRCA-MCs) on mammography and magnetic resonance imaging (MRI) was evaluated. Thus, 29 BRCA-MCs with breast cancer were retrospectively evaluated and the results compared with an age, tumor size and tumor type match

  19. Tumor Mutation Burden Forecasts Outcome in Ovarian Cancer with BRCA1 or BRCA2 Mutations

    DEFF Research Database (Denmark)

    Birkbak, Nicolai Juul; Kochupurakkal, Bose; Gonzalez-Izarzugaza, Jose Maria;

    2013-01-01

    Background: Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA ...

  20. Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI

    NARCIS (Netherlands)

    Veltman, J.; Mann, R.; Kok, T.; Obdeijn, I. M.; Hoogerbrugge, N.; Blickman, J. G.; Boetes, C.

    2008-01-01

    The appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers (BRCA-MCs) on mammography and magnetic resonance imaging (MRI) was evaluated. Thus, 29 BRCA-MCs with breast cancer were retrospectively evaluated and the results compared with an age, tumor size and tumor type matched control g

  1. Functional characterization of BRCA1 gene variants by mini-gene splicing assay

    DEFF Research Database (Denmark)

    Steffensen, Ane Y; Dandanell, Mette; Jønson, Lars;

    2014-01-01

    are pathogenic or benign. Here we validate a mini-gene splicing assay by comparing the results of 24 variants with previously published data from RT-PCR analysis on RNA from blood samples/lymphoblastoid cell lines. The analysis showed an overall concordance of 100%. In addition, we investigated 13 BRCA1 variants...... of unknown clinical significance or putative variants affecting splicing by in silico analysis and mini-gene splicing assay. Both the in silico analysis and mini-gene splicing assay classified six BRCA1 variants as pathogenic (c.80+1G>A, c.132C>T (p.=), c.213-1G>A, c.670+1delG, c.4185+1G>A, and c.5075-1G......>C), whereas six BRCA1 variants were classified as neutral (c.-19-22_-19-21dupAT, c.302-15C>G, c.547+14delG, c.4676-20A>G, c.4987-21G>T, and c.5278-14C>G) and one BRCA1 variant remained unclassified (c.670+16G>A). In conclusion, our study emphasizes that in silico analysis and mini-gene splicing assays...

  2. Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers:

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Rookus, Matti; Andrieu, Nadine;

    2009-01-01

    BACKGROUND: Several reproductive and hormonal factors are known to be associated with ovarian cancer risk in the general population, including parity and oral contraceptive (OC) use. However, their effect on ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has only been investigated in a...

  3. Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study

    DEFF Research Database (Denmark)

    Brohet, Richard M; Goldgar, David E; Easton, Douglas F;

    2007-01-01

    PURPOSE Earlier studies have shown that endogenous gonadal hormones play an important role in the etiology of breast cancer among BRCA1/2 mutation carriers. So far, little is known about the safety of exogenous hormonal use in mutation carriers. In this study, we examined the association between ...

  4. Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    Im, Kate M.; Kirchhoff, Tomas; Wang, Xianshu; Green, Todd; Chow, Clement Y.; Vijai, Joseph; Korn, Joshua; Gaudet, Mia M.; Fredericksen, Zachary; Pankratz, V. Shane; Guiducci, Candace; Crenshaw, Andrew; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M.; Mai, Phuong L.; Greene, Mark H.; Piedmonte, Marion; Rubinstein, Wendy S.; Hogervorst, Frans B.; Rookus, Matti A.; Collee, J. Margriet; Hoogerbrugge, Nicoline; van Asperen, Christi J.; Meijers-Heijboer, Hanne E. J.; van Roozendaal, Cees E.; Caldes, Trinidad; Perez-Segura, Pedro; Jakubowska, Anna; Lubinski, Jan; Huzarski, Tomasz; Blecharz, Pawel; Nevanlinna, Heli; Aittomaki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Barkardottir, Rosa B.; Montagna, Marco; D'Andrea, Emma; Devilee, Peter; Olopade, Olufunmilayo I.; Neuhausen, Susan L.; Peissel, Bernard; Bonanni, Bernardo; Peterlongo, Paolo; Singer, Christian F.; Rennert, Gad; Lejbkowicz, Flavio; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Toland, Amanda Ewart; Caligo, Maria Adelaide; Beattie, Mary S.; Chan, Salina; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Phelan, Catherine; Narod, Steven; John, Esther M.; Hopper, John L.; Buys, Saundra S.; Daly, Mary B.; Southey, Melissa C.; Terry, Mary-Beth; Tung, Nadine; Hansen, Thomas V. O.; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Weitzel, Jeffrey N.; Garber, Judy; Hamann, Ute; Peock, Susan; Cook, Margaret; Oliver, Clare T.; Frost, Debra; Platte, Radka; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Paterson, Joan; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary; Walker, Lisa; Rogers, Mark T.; Side, Lucy E.; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Laitman, Yael; Meindl, Alfons; Deissler, Helmut; Varon-Mateeva, Raymonda; Preisler-Adams, Sabine; Kast, Karin; Venat-Bouvet, Laurence; Stoppa-Lyonnet, Dominique; Chenevix-Trench, Georgia; Easton, Douglas F.; Klein, Robert J.; Daly, Mark J.; Friedman, Eitan; Dean, Michael; Clark, Andrew G.; Altshuler, David M.; Antoniou, Antonis C.; Couch, Fergus J.; Offit, Kenneth; Gold, Bert

    2011-01-01

    Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele freque

  5. Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Im, Kate M; Kirchhoff, Tomas; Wang, Xianshu;

    2011-01-01

    Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele fre...

  6. Refined histopathological predictors of BRCA1 and BRCA2 mutation status

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Couch, Fergus J; Parsons, Michael T;

    2014-01-01

    INTRODUCTION: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to asse...

  7. Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion

    International Nuclear Information System (INIS)

    Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes are associated to germline TP53 mutations, and are characterized by the development of central nervous system tumors, sarcomas, adrenocortical carcinomas, and other early-onset tumors. Due to the high frequency of breast cancer in LFS/LFL families, these syndromes clinically overlap with hereditary breast cancer (HBC). Germline point mutations in BRCA1, BRCA2, and TP53 genes are associated with high risk of breast cancer. Large rearrangements involving these genes are also implicated in the HBC phenotype. We have screened DNA copy number changes by MLPA on BRCA1, BRCA2, and TP53 genes in 23 breast cancer patients with a clinical diagnosis consistent with LFS/LFL; most of these families also met the clinical criteria for other HBC syndromes. We found no DNA copy number alterations in the BRCA2 and TP53 genes, but we detected in one patient a 36.4 Kb BRCA1 microdeletion, confirmed and further mapped by array-CGH, encompassing exons 9–19. Breakpoints sequencing analysis suggests that this rearrangement was mediated by flanking Alu sequences. This is the first description of a germline intragenic BRCA1 deletion in a breast cancer patient with a family history consistent with both LFL and HBC syndromes. Our results show that large rearrangements in these known cancer predisposition genes occur, but are not a frequent cause of cancer susceptibility

  8. Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico

    Science.gov (United States)

    Villarreal-Garza, Cynthia; Alvarez-Gómez, Rosa María; Pérez-Plasencia, Carlos; Herrera, Luis A.; Herzog, Josef; Castillo, Danielle; Mohar, Alejandro; Castro, Clementina; Gallardo, Lenny N.; Gallardo, Dolores; Santibáñez, Miguel; Blazer, Kathleen R.; Weitzel, Jeffrey N.

    2014-01-01

    Background Frequent recurrent BRCA1 and BRCA2 gene (BRCA) mutations among Hispanics, including a large rearrangement Mexican founder mutation (BRCA1 ex9-12del), suggest that an ancestry-informed BRCA-testing strategy could reduce disparities and promote cancer prevention by enabling economical screening for hereditary breast and ovarian cancer in Mexico. Methods In a multistage approach, 188 cancer cases unselected for family cancer history (92 ovarian cancer and 96 breast cancer) were screened for BRCA mutations using a Hispanic mutation panel (HISPANEL®) of 115 recurrent mutations in a multiplex assay (114 on a mass spectroscopy platform, and a PCR assay for the BRCA1 ex9-12del mutation), followed by sequencing of all BRCA exons and adjacent intronic regions, and BRCA1 multiplex ligation-dependent probe amplification assay (MLPA) for HISPANEL negative cases. BRCA mutation prevalence was calculated and correlated with histology and tumor receptor status, and HISPANEL sensitivity was estimated. Results BRCA mutations were detected in 28% (26/92) of ovarian cancer cases and 15% (14/96) of breast cancer cases overall and 27% (9/33) of triple negative breast cancer. Most breast cancer cases were diagnosed with locally advanced disease. The Mexican founder mutation (BRCA1 ex9-12del) accounted for 35% of the BRCA-associated ovarian cancer cases and 29% of the BRCA-associated breast cancer cases. At 2% of the sequencing and MLPA cost, the HISPANEL detected 68% of all BRCA mutations. Conclusion In this study, we found a remarkably high prevalence of BRCA mutations among ovarian and breast cases not selected for family history, and BRCA1 ex9-12del explained one third of the total. The remarkable frequency of BRCA1 ex9-12del in Mexico City supports a nearby origin of this Mexican founder mutation and may constitute a regional public health problem. The HISPANEL presents a translational opportunity for cost-effective genetic testing to enable breast and ovarian cancer

  9. BRCA1 status in Pakistani breast cancer patients with moderate family history

    International Nuclear Information System (INIS)

    Objective: To determine BRCA1 status in breast carcinoma patients of Pakistani origin. Study Design: Observational study. Place and Duration of Study: The Oncology Clinics of the Aga Khan University Hospital, Karachi, between May 2005 and December 2009. Methodology: Fifty three breast cancer patients based on clinical and laboratory diagnosis were recruited for this study. Moderate family history was defined as having a close relative (mother, daughter, sister) diagnosed with breast cancer under 45 years. Peripheral blood samples were collected from each patient in a 5 ml tube containing EDTA as anticoagulant. Subsequent to DNA extraction, mutational analysis of BRCA1 exons 2, 5, 6, 16, 20 and 22 was carried out using single strand conformation polymorphism (SSCP) assay while protein truncation test (PTT) was used to examine mutations in exon 11. All BRCA1 sequence variants were confirmed by DNA sequencing. Results: Twenty-three patients were diagnosed with early onset breast cancer, 30 patients had moderate family history. At the time of diagnosis, the median age of enrolled patients was 39 years (range 24-65 years). Out of 53 patients, analyzed by SSCP assay, mobility shift was detected in exon 6, 16 and 20 of three patients, whereas one patient was tested positive for mutation in exon 11 by PTT assays. All patients with BRCA1 mutations were further confirmed by DNA sequencing analysis. In exon 16 c.4837A > G was confirmed, which is a common polymorphism reported in several populations including Asians. Moreover, mutations in exon 6 (c.271T > G), exon 20 (c.5231 del G) and exon 11 (c.1123 T > G) were reported first time in the Pakistani population. Several BRCA1 mutations were observed in Pakistani breast cancer patients with moderate family history. Therefore, mutation-based genetic counselling for patients with moderate family history can facilitate management, if one first or second degree relative or early onset disease is apparent. (author)

  10. Long Term Outcomes of BRCA1/BRCA2 Testing: Risk Reduction and Surveillance

    Science.gov (United States)

    Schwartz, Marc D.; Isaacs, Claudine; Graves, Kristi D.; Poggi, Elizabeth; Peshkin, Beth N.; Gell, Christy; Finch, Clinton; Kelly, Scott; Taylor, Kathryn L.; Perley, Lauren

    2012-01-01

    Purpose For BRCA1/BRCA2 gene testing to benefit public health, mutation carriers must initiate appropriate risk management strategies. There has been little research examining the long-term use and prospective predictors of the full range of risk management behaviors among women who have undergone BRCA1/2 testing. We evaluated long-term uptake and predictors of risk reducing mastectomy (RRM), risk reducing oophorectomy (RRBSO), chemoprevention and cancer screening among women at a mean of 5.3 years post testing. Patients and Methods Participants were 465 women who underwent BRCA1/2 testing. Prior to genetic counseling, we measured family/personal cancer history, sociodemographics, perceived risk, cancer-specific and general distress. We contacted patients at a mean of 5.3-years post-testing to measure use of: RRM; RRBSO; chemoprevention; breast and ovarian cancer screening. Results Among participants with intact breasts and/or ovaries at the time of testing, BRCA1/2 carriers were significantly more likely to obtain RRM (37%) and RRBSO (65%) compared to women who received uninformative (RRM=6.8%; RRBSO=13.3%) or negative (RRM=0%; RRBSO=1.9%) results. Among carriers, pre-counseling anxiety was associated with subsequent uptake of RRM. RRO was predicted by age. Carriers were also more likely have used breast cancer chemoprevention and have obtained a screening MRI. Conclusion This prospective evaluation of the uptake and predictors of long-term management outcomes provides a clearer picture of decision making in this population. By a mean of 5.3 years post-testing, more than 80% of carriers had obtained RRM, RRBSO or both, suggesting that BRCA1/2 testing is likely to favorably impact breast and ovarian cancer outcomes. PMID:21717445

  11. An Estrogen Receptor-α/p300 Complex Activates the BRCA-1 Promoter at an AP-1 Site That Binds Jun/Fos Transcription Factors: Repressive Effects of p53 on BRCA-1 Transcription

    Directory of Open Access Journals (Sweden)

    Brandon D. Jeffy

    2005-09-01

    Full Text Available One of the puzzles in cancer predisposition is that women carrying BRCA-1 mutations preferentially develop tumors in epithelial tissues of the breast, ovary. Moreover, sporadic breast tumors contain lower levels of BRCA-1 in the absence of mutations in the BRCA-1 gene. The problem of tissue specificity requires analysis of factors that are unique to tissues of the breast. For example, the expression of estrogen receptor-α (ERα is inversely correlated with breast cancer risk, 90% of BRCA-1 tumors are negative for ERα. Here, we show that estrogen stimulates BRCA-1 promoter activity in transfected cells, the recruitment of ERα, its cofactor p300 to an AP-1 site that binds Jun/Fos transcription factors. The recruitment of ERα/dp300 coincides with accumulation in the S-phase of the cell cycle, is antagonized by the antiestrogen tamoxifen. Conversely, we document that overexpression of wild-type p53 prevents the recruitment of ERα to the AP-1 site, represses BRCA-1 promoter activity. Taken together, our findings support a model in which an ERα/AP-1 complex modulates BRCA-1 transcription under conditions of estrogen stimulation. Conversely, the formation of this transcription complex is abrogated in cells overexpressing p53.

  12. Cellular responses of BRCA1-defective and triple-negative breast cancer cells and in vitro BRCA1 interactions induced by metallo-intercalator ruthenium(II) complexes containing chloro-substituted phenylazopyridine

    International Nuclear Information System (INIS)

    Triple-negative breast cancer (TNBC) is defined by the absence of expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Breast cancers with a BRCA1 mutation are also frequently triple-negative. Currently, there is a lack of effective therapies and known specific molecular targets for this aggressive breast cancer subtype. To address this concern, we have explored the cellular responses of BRCA1-defective and triple-negative breast cancer cells, and in vitro BRCA1 interactions induced by the ruthenium(II) complexes containing the bidentate ligand, 5-chloro-2-(phenylazo)pyridine. Triple-negative MDA-MB-231, BRCA1-defective HCC1937 and BRCA1-competent MCF-7 breast cancer cell lines were treated with ruthenium(II) complexes. The cytoxoxicity of ruthenium-induced breast cancer cells was evaluated by a real time cellular analyzer (RTCA). Cellular uptake of ruthenium complexes was determined by ICP-MS. Cell cycle progression and apoptosis were assessed using propidium iodide and Annexin V flow cytometry. The N-terminal BRCA1 RING protein was used for conformational and functional studies using circular dichroism and in vitro ubiquitination. HCC1937 cells were significantly more sensitive to the ruthenium complexes than the MDA-MB-231 and MCF-7 cells. Treatment demonstrated a higher degree of cytotoxicity than cisplatin against all three cell lines. Most ruthenium atoms were retained in the nuclear compartment, particularly in HCC1937 cells, after 24 h of incubation, and produced a significant block at the G2/M phase. An increased induction of apoptotic cells as well as an upregulation of p53 mRNA was observed in all tested breast cancer cells. It was of interest that BRCA1 mRNA and replication of BRCA1-defective cells were downregulated. Changes in the conformation and binding constants of ruthenium-BRCA1 adducts were observed, causing inactivation of the RING heterodimer BRCA1/BARD1-mediated E3 ubiquitin ligase activity

  13. The BRCA1 Tumor Suppressor Binds to Inositol 1,4,5-Trisphosphate Receptors to Stimulate Apoptotic Calcium Release*

    Science.gov (United States)

    Hedgepeth, Serena C.; Garcia, M. Iveth; Wagner, Larry E.; Rodriguez, Ana M.; Chintapalli, Sree V.; Snyder, Russell R.; Hankins, Gary D. V.; Henderson, Beric R.; Brodie, Kirsty M.; Yule, David I.; van Rossum, Damian B.; Boehning, Darren

    2015-01-01

    The inositol 1,4,5-trisphosphate receptor (IP3R) is a ubiquitously expressed endoplasmic reticulum (ER)-resident calcium channel. Calcium release mediated by IP3Rs influences many signaling pathways, including those regulating apoptosis. IP3R activity is regulated by protein-protein interactions, including binding to proto-oncogenes and tumor suppressors to regulate cell death. Here we show that the IP3R binds to the tumor suppressor BRCA1. BRCA1 binding directly sensitizes the IP3R to its ligand, IP3. BRCA1 is recruited to the ER during apoptosis in an IP3R-dependent manner, and, in addition, a pool of BRCA1 protein is constitutively associated with the ER under non-apoptotic conditions. This is likely mediated by a novel lipid binding activity of the first BRCA1 C terminus domain of BRCA1. These findings provide a mechanistic explanation by which BRCA1 can act as a proapoptotic protein. PMID:25645916

  14. BRCA1-deficient breast cancer cell lines are resistant to MEK inhibitors and show distinct sensitivities to 6-thioguanine.

    Science.gov (United States)

    Gu, Yuexi; Helenius, Mikko; Väänänen, Kristiina; Bulanova, Daria; Saarela, Jani; Sokolenko, Anna; Martens, John; Imyanitov, Evgeny; Kuznetsov, Sergey

    2016-01-01

    Germ-line or somatic inactivation of BRCA1 is a defining feature for a portion of human breast cancers. Here we evaluated the anti-proliferative activity of 198 FDA-approved and experimental drugs against four BRCA1-mutant (HCC1937, MDA-MB-436, SUM1315MO2, and SUM149PT) and four BRCA1-wild-type (MDA-MB-231, SUM229PE, MCF10A, and MCF7) breast cancer cell lines. We found that all BRCA1-mutant cell lines were insensitive to inhibitors of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) Selumetinib and Pimasertib in contrast to BRCA1-wildtype control cell lines. However, unexpectedly, only two BRCA1-mutant cell lines, HCC1937 and MDA-MB-436, were hypersensitive to a nucleotide analogue 6-thioguanine (6-TG). SUM149PT cells readily formed radiation-induced RAD51-positive nuclear foci indicating a functional homologous recombination, which may explain their resistance to 6-TG. However, the reason underlying 6-TG resistance of SUM1315MO2 cells remains unclear. Our data reveal a remarkable heterogeneity among BRCA1-mutant cell lines and provide a reference for future studies. PMID:27313062

  15. Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

    Science.gov (United States)

    Henneman, Linda; van Miltenburg, Martine H.; Michalak, Ewa M.; Braumuller, Tanya M.; Jaspers, Janneke E.; Drenth, Anne Paulien; de Korte-Grimmerink, Renske; Gogola, Ewa; Szuhai, Karoly; Schlicker, Andreas; Bin Ali, Rahmen; Pritchard, Colin; Huijbers, Ivo J.; Berns, Anton; Rottenberg, Sven; Jonkers, Jos

    2015-01-01

    Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics. PMID:26100884

  16. Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling.

    Directory of Open Access Journals (Sweden)

    Martin J Larsen

    Full Text Available Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants of unclear pathogen significance are found in the families, constituting an increasing clinical challenge. New methods are therefore needed to improve the detection rate and aid the interpretation of the clinically uncertain variants. In this study we analyzed a series of 33 BRCA1, 22 BRCA2, and 128 sporadic tumors by RNA profiling to investigate the classification potential of RNA profiles to predict BRCA1/2 mutation status. We found that breast tumors from BRCA1 and BRCA2 mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority of BRCA1 tumors were basal-like while BRCA2 tumors were mainly luminal B. Using RNA profiles, we were able to distinguish BRCA1 tumors from sporadic tumors among basal-like tumors with 83% accuracy and BRCA2 from sporadic tumors among luminal B tumors with 89% accuracy. Furthermore, subtype-specific BRCA1/2 gene signatures were successfully validated in two independent data sets with high accuracies. Although additional validation studies are required, indication of BRCA1/2 involvement ("BRCAness" by RNA profiling could potentially be valuable as a tool for distinguishing pathogenic mutations from benign variants, for identification of undetected mutation carriers, and for selecting patients sensitive to new therapeutics such as PARP inhibitors.

  17. BRCA1/2 genetic testing uptake and psychosocial outcomes in men.

    Science.gov (United States)

    Graves, Kristi D; Gatammah, Rhoda; Peshkin, Beth N; Krieger, Ayelet; Gell, Christy; Valdimarsdottir, Heiddis B; Schwartz, Marc D

    2011-06-01

    Few studies have quantitatively evaluated the uptake and outcomes of BRCA1/2 genetic counseling and testing in men. We conducted a prospective longitudinal study to describe and compare uptake of and psychosocial outcomes following BRCA1/2 testing in a sample of men and women at high-risk for carrying a BRCA1/2 mutation. Men (n = 98) and women (n = 243) unaffected with cancer completed baseline assessments prior to genetic counseling and testing and then 6- and 12-months post-testing. Most men (n = 94; 95.9%) opted to have genetic testing, of whom 44 received positive BRCA1/2 genetic test results and 50 received true negative results. Among women, 93.4% had genetic testing, of whom 79 received positive results and 148 received negative results. In multivariate models, male BRCA1/2 carriers reported significantly higher genetic testing distress (6-months: Z = 4.48, P < 0.0001; 12-months: Z = 2.78, P < 0.01) than male non-carriers. After controlling for baseline levels of distress, no statistically significant differences emerged between male and female BRCA1/2 carriers in psychological distress at 12-months post-testing, although absolute differences were evident over time. Predictors of distress related to genetic testing among male carriers at 12-months included higher baseline cancer-specific distress (Z = 4.73, P < 0.0001) and being unmarried (Z = 2.18, P < 0.05). Similarly, baseline cancer-specific distress was independently associated with cancer-specific distress at 6- (Z = 3.66, P < 0.001) and 12-months (Z = 4.44, P < 0.0001) post-testing among male carriers. Clinically, our results suggest that pre-test assessment of distress and creation of educational materials specifically tailored to the needs and concerns of male carriers may be appropriate in this important but understudied high-risk group.

  18. BRCA1 and BRCA2 Unclassified Variants and Missense Polymorphisms in Algerian Breast/Ovarian Cancer Families

    Directory of Open Access Journals (Sweden)

    Farid Cherbal

    2012-01-01

    Full Text Available Background: BRCA1 and BRCA2 germline mutations predispose heterozygous carriers to hereditary breast/ovarian cancer. However, unclassified variants (UVs (variants with unknown clinical significance and missense polymorphisms in BRCA1 and BRCA2 genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is still unclear. The objective of our study was to identify UVs and missense polymorphisms in Algerian breast/ovarian cancer patients and relatives tested previously for BRCA1 and BRCA2 genes germline mutations analysis.

  19. Plasma Proteomic Profiling in Hereditary Breast Cancer Reveals a BRCA1-Specific Signature: Diagnostic and Functional Implications

    OpenAIRE

    Domenica Scumaci; Laura Tammè; Claudia Vincenza Fiumara; Giusi Pappaianni; Antonio Concolino; Emanuela Leone; Maria Concetta Faniello; Barbara Quaresima; Enrico Ricevuto; Francesco Saverio Costanzo; Giovanni Cuda

    2015-01-01

    Background Breast cancer (BC) is a leading cause of death among women. Among the major risk factors, an important role is played by familial history of BC. Germ-line mutations in BRCA1/2 genes account for most of the hereditary breast and/or ovarian cancers. Gene expression profiling studies have disclosed specific molecular signatures for BRCA1/2-related breast tumors as compared to sporadic cases, which might help diagnosis and clinical follow-up. Even though, a clear hallmark of BRCA1/2-po...

  20. Increased cell survival by inhibition of BRCA1 using an antisense approach in an estrogen responsive ovarian carcinoma cell line

    OpenAIRE

    Annab, Lois A; Hawkins, Rebecca E; Solomon, Greg; Barrett, J Carl; Afshari, Cynthia A.

    2000-01-01

    Introduction: Germline mutations in the breast and ovarian cancer susceptibility gene BRCA1, which is located on chromosome 17q21, are associated with a predisposition to the development of cancer in these organs [1,2]. No mutations in the BRCA1 gene have been detected in sporadic breast cancer cases, but mutations have been detected in sporadic cases of ovarian cancer [3,4]. Although there is debate regarding the level of cancer risk associated with mutations in BRCA1 and the significance of...

  1. High frequency of BRCA1, but not CHEK2 or NBS1 (NBN, founder mutations in Russian ovarian cancer patients

    Directory of Open Access Journals (Sweden)

    Suspitsin Evgeny N

    2009-02-01

    Full Text Available Abstract Background A significant portion of ovarian cancer (OC cases is caused by germ-line mutations in BRCA1 or BRCA2 genes. BRCA testing is cheap in populations with founder effect and therefore recommended for all patients with OC diagnosis. Recurrent mutations constitute the vast majority of BRCA defects in Russia, however their impact in OC morbidity has not been yet systematically studied. Furthermore, Russian population is characterized by a relatively high frequency of CHEK2 and NBS1 (NBN heterozygotes, but it remains unclear whether these two genes contribute to the OC risk. Methods The study included 354 OC patients from 2 distinct, geographically remote regions (290 from North-Western Russia (St.-Petersburg and 64 from the south of the country (Krasnodar. DNA samples were tested by allele-specific PCR for the presence of 8 founder mutations (BRCA1 5382insC, BRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, BRCA2 6174delT, CHEK2 1100delC, CHEK2 IVS2+1G>A, NBS1 657del5. In addition, literature data on the occurrence of BRCA1, BRCA2, CHEK2 and NBS1 mutations in non-selected ovarian cancer patients were reviewed. Results BRCA1 5382insC allele was detected in 28/290 (9.7% OC cases from the North-West and 11/64 (17.2% OC patients from the South of Russia. In addition, 4 BRCA1 185delAG, 2 BRCA1 4153delA, 1 BRCA2 6174delT, 2 CHEK2 1100delC and 1 NBS1 657del5 mutation were detected. 1 patient from Krasnodar was heterozygous for both BRCA1 5382insC and NBS1 657del5 variants. Conclusion Founder BRCA1 mutations, especially BRCA1 5382insC variant, are responsible for substantial share of OC morbidity in Russia, therefore DNA testing has to be considered for every OC patient of Russian origin. Taken together with literature data, this study does not support the contribution of CHEK2 in OC risk, while the role of NBS1 heterozygosity may require further clarification.

  2. Evaluation of the Dutch BRCA1/2 clinical genetic center referral criteria in an unselected early breast cancer population

    OpenAIRE

    van den Broek, Alexandra J.; de Ruiter, Karen; Van 't Veer, Laura J; Tollenaar, Rob A.E.M.; van Leeuwen, Flora E.; Verhoef, Senno; Schmidt, Marjanka K.

    2014-01-01

    In this study, we evaluated the diagnostic value of the Dutch Clinical Genetic Center (CGC) referral guidelines for BRCA1/2 mutation testing in 903 early breast cancer patients, unselected for family history, diagnosed in a cancer hospital before the age of 50 years in 1974–2002; most prevalent Dutch pathogenic BRCA1/2 mutations had been analyzed on coded DNA in a research setting. Forty-nine (5.4%) of the patients were proven to be BRCA1/2 mutation carriers. We found that 78% and 69% of BRCA...

  3. Sanger Sequencing for BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del Mutation Screen on Pap Smear Cytology Samples.

    Science.gov (United States)

    Lee, Sin Hang; Zhou, Shaoxia; Zhou, Tianjun; Hong, Guofan

    2016-02-08

    Three sets of polymerase chain reaction (PCR) primers were designed for heminested PCR amplification of the target DNA fragments in the human genome which include the site of BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del respectively, to prepare the templates for direct Sanger sequencing screen of these three founder mutations. With a robust PCR mixture, crude proteinase K digestate of the fixed cervicovaginal cells in the liquid-based Papanicolaou (Pap) cytology specimens can be used as the sample for target DNA amplification without pre-PCR DNA extraction, purification and quantitation. The post-PCR products can be used directly as the sequencing templates without further purification or quantitation. By simplifying the frontend procedures for template preparation, the cost for screening these three founder mutations can be reduced to about US $200 per test when performed in conjunction with human papillomavirus (HPV) assays now routinely ordered for cervical cancer prevention. With this projected price structure, selective patients in a high-risk population can be tested and each provided with a set of DNA sequencing electropherograms to document the absence or presence of these founder mutations in her genome to help assess inherited susceptibility to breast and ovarian cancer in this era of precision molecular personalized medicine.

  4. Sanger Sequencing for BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del Mutation Screen on Pap Smear Cytology Samples

    Directory of Open Access Journals (Sweden)

    Sin Hang Lee

    2016-02-01

    Full Text Available Three sets of polymerase chain reaction (PCR primers were designed for heminested PCR amplification of the target DNA fragments in the human genome which include the site of BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del respectively, to prepare the templates for direct Sanger sequencing screen of these three founder mutations. With a robust PCR mixture, crude proteinase K digestate of the fixed cervicovaginal cells in the liquid-based Papanicolaou (Pap cytology specimens can be used as the sample for target DNA amplification without pre-PCR DNA extraction, purification and quantitation. The post-PCR products can be used directly as the sequencing templates without further purification or quantitation. By simplifying the frontend procedures for template preparation, the cost for screening these three founder mutations can be reduced to about US $200 per test when performed in conjunction with human papillomavirus (HPV assays now routinely ordered for cervical cancer prevention. With this projected price structure, selective patients in a high-risk population can be tested and each provided with a set of DNA sequencing electropherograms to document the absence or presence of these founder mutations in her genome to help assess inherited susceptibility to breast and ovarian cancer in this era of precision molecular personalized medicine.

  5. Microelectronic DNA assay for the detection of BRCA1 gene mutations

    Science.gov (United States)

    Chen, Hua; Han, Jie; Li, Jun; Meyyappan, Meyya

    2004-01-01

    Mutations in BRCA1 are characterized by predisposition to breast cancer, ovarian cancer and prostate cancer as well as colon cancer. Prognosis for this cancer survival depends upon the stage at which cancer is diagnosed. Reliable and rapid mutation detection is crucial for the early diagnosis and treatment. We developed an electronic assay for the detection of a representative single nucleotide polymorphism (SNP), deletion and insertion in BRCA1 gene by the microelectronics microarray instrumentation. The assay is rapid, and it takes 30 minutes for the immobilization of target DNA samples, hybridization, washing and readout. The assay is multiplexing since it is carried out at the same temperature and buffer conditions for each step. The assay is also highly specific, as the signal-to-noise ratio is much larger than recommended value (72.86 to 321.05 vs. 5) for homozygotes genotyping, and signal ratio close to the perfect value 1 for heterozygotes genotyping (1.04).

  6. Breast cancer therapy for BRCA1 carriers: moving towards platinum standard?

    Directory of Open Access Journals (Sweden)

    Imyanitov Evgeny N

    2009-04-01

    Full Text Available Abstract Recently Byrski et al. reported the first-ever breast cancer (BC study, which specifically selected BRCA1-carriers for the neoadjuvant treatment and used monotherapy by cisplatin instead of conventional schemes. Although the TNM staging of the recruited patients was apparently more favorable than in most of published neoadjuvant trials, the results of Byrski et al. clearly outperform any historical data. Indeed, 9 of 10 BRCA1-associated BC demonstrated complete pathological response to the cisplatin treatment, i.e. these women have good chances to be ultimately cured from the cancer disease. High sensitivity of BRCA1-related tumors to platinating agents has been discussed for years, but it took almost a decade to translate convincing laboratory findings into first clinical observations. With increasing stratification of tumor disease entities for molecular subtypes and rapidly growing armamentarium of cancer drugs, it is getting technically and ethically impossible to subject all promising treatment options to the large randomized prospective clinical trials. Therefore, alternative approaches for initial drugs evaluation are highly required, and one of the choices is to extract maximum benefit from already available collections of biological material and medical charts. For example, many thousands of BC patients around the world have already been subjected to second- or third-line therapy with platinum agents, but the association between BRCA status and response to the treatment has not been systematically evaluated in these women. While potential biases of retrospective studies are widely acknowledged, it is frequently ignored that the use of archival collections may provide preliminary answers for long-standing questions within days instead of years. However, even elegantly-designed, small-sized, hypothesis-generating retrospective studies may require multicenter efforts and somewhat cumbersome logistics, that may explain the

  7. POTENTIAL OF MARINE DERIVED COMPOUNDS AGAINST BREAST CANCER (BRCA1): AN IN-SILICO DOCKING STUDY

    OpenAIRE

    Senthilraja P; Senthil Vinoth K; Sindhuraj M; Prakash M

    2012-01-01

    The present study focused on molecular computational analysis to identify the potential compounds, derived from marine organisms (algae, sponges and fungi), which can block the mutated gene (BRCA1) responsible for the breast cancer. Seven compounds were tested against the carcinogenic protein. The 3D crystal structure of the protein (ID: 2IOK) was retrieved from protein data bank (PDB) and the protein binding sites of the test compounds were identified. The results revealed that among seven c...

  8.  Poly(ADP-ribose polymerase (PARP inhibitors in BRCA1/2 cancer therapy

    Directory of Open Access Journals (Sweden)

    Katarzyna Kluzek

    2012-06-01

    Full Text Available  A majority of currently used anticancer drugs belong to a group of chemical agents that damage DNA. The efficiency of the treatment is limited by effective DNA repair systems functioning in cancer cells. Many chemotherapeutic compounds cause strong systemic toxicity. Therefore, there is still a need for new anticancer agents which are less toxic for nontransformed cells and selectively kill cancer cells. One of the most promising molecular targets in cancer therapy is poly(ADP-ribose polymerases (PARP. PARP play an essential role in repairing DNA strand breaks. Small molecule inhibitors of these enzymes have been developed and have proved to be extremely toxic for cancer cells that lack the functional BRCA1 and BRCA2 proteins that are involved in homologous recombination, a complex repair mechanism of DNA double strand breaks. Mutations in BRCA1/2 genes are associated with genetically inherited breast and ovarian cancers. Therefore PARP inhibitors may prove to be very effective and selective in the treatment of these cancer types. This review is focused on the function of BRCA1/2 proteins and poly(ADP-ribose polymerases in DNA repair systems, especially in the homologous recombination process. A short history of the studies that led to synthesis of high specificity small molecule PARP inhibitors is also presented, as well as the results of clinical trials concerning the most effective PARP inhibitors in view of their potential application in oncological treatment, particularly breast cancers.

  9. Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population

    Energy Technology Data Exchange (ETDEWEB)

    Friedman, L.S.; Gayther, S.A.; Ponder, B.A.J. [Univ. of Cambridge (United Kingdom)] [and others

    1997-02-01

    A population-based series of 54 male breast cancer cases from Southern California were analyzed for germ-line mutations in the inherited breast/ovarian cancer genes, BRCA1 and BRCA2. Nine (17%) of the patients had a family history of breast and/or ovarian cancer in at least one first-degree relative. A further seven (13%) of the patients reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. No germ-line BRCA1 mutations were found. Two male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative. The remaining eight cases (89%) of male breast cancer with a family history of breast/ovarian cancer in first-degree relatives remain unaccounted for by mutations in either the BRCA1 gene or the BRCA2 gene. 23 refs., 1 fig., 5 tabs.

  10. Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members

    DEFF Research Database (Denmark)

    Thomassen, Mads; Blanco, Ana; Montagna, Marco;

    2012-01-01

    . Splicing analysis was performed by reverse transcriptase PCR or mini gene assay, and sequencing to identify aberrant transcripts. The findings were compared to bioinformatic predictions using four programs. The posterior probability of pathogenicity was estimated using multifactorial likelihood analysis...... was initiated to evaluate and implement strategies to characterize the clinical significance of BRCA1 and BRCA2 variants. As an initial project of the ENIGMA Splicing Working Group, we report splicing and multifactorial likelihood analysis of 25 BRCA1 and BRCA2 variants from seven different laboratories......, including co-occurrence with a deleterious mutation, segregation and/or report of family history. Abnormal splicing patterns expected to lead to a non-functional protein were observed for 7 variants (BRCA1 c.441+2T>A, c.4184_4185+2del, c.4357+1G>A, c.4987-2A>G, c.5074G>C, BRCA2 c.316+5G>A, and c.8754+3G...

  11. Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic

    DEFF Research Database (Denmark)

    Ahlborn, Lise B; Dandanell, Mette; Steffensen, Ane Y;

    2015-01-01

    needed to classify whether these uncertain variants are pathogenic or benign. In this study, we investigated 14 BRCA1 variants by in silico splicing analysis and mini-gene splicing assay. All 14 alterations were missense variants located within the BRCT domain of BRCA1 and had previously been examined...... by functional analysis at the protein level. Results from a validated mini-gene splicing assay indicated that nine BRCA1 variants resulted in splicing aberrations leading to truncated transcripts and thus can be considered pathogenic (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5072C>T/p.Thr1691Ile, c...... to have no or an uncertain effect on the protein level, whereas one variant (c.5072C>T/p.Thr1691Ile) were shown to have a strong effect on the protein level as well. In conclusion, our study emphasizes that in silico splicing prediction and mini-gene splicing analysis are important for the classification...

  12. [Breast cancer genetics. BRCA1 and BRCA2: the main genes for disease predisposition].

    Science.gov (United States)

    Ruiz-Flores, P; Calderón-Garcidueñas, A L; Barrera-Saldaña, H A

    2001-01-01

    Breast cancer is among the most common world cancers. In Mexico this neoplasm has been progressively increasing since 1990 and is expected to continue. The risk factors for this disease are age, some reproductive factors, ionizing radiation, contraceptives, obesity and high fat diets, among other factors. The main risk factor for BC is a positive family history. Several families, in which clustering but no mendelian inheritance exists, the BC is due probably to mutations in low penetrance genes and/or environmental factors. In families with autosomal dominant trait, the BRCA1 and BRCA2 genes are frequently mutated. These genes are the two main BC susceptibility genes. BRCA1 predispose to BC and ovarian cancer, while BRCA2 mutations predispose to BC in men and women. Both are long genes, tumor suppressors, functioning in a cell cycle dependent manner, and it is believed that both switch on the transcription of several genes, and participate in DNA repair. The mutations profile of these genes is known in developed countries, while in Latin America their search has just began. A multidisciplinary group most be responsible of the clinical management of patients with mutations in BRCA1 and BRCA2, and the risk assignment and Genetic counseling most be done carefully.

  13. Haplotype analysis of common variants in the BRCA1 gene and risk of sporadic breast cancer

    International Nuclear Information System (INIS)

    Truncation mutations in the BRCA1 gene cause a substantial increase in risk of breast cancer. However, these mutations are rare in the general population and account for little of the overall incidence of sporadic breast cancer. We used whole-gene resequencing data to select haplotype tagging single nucleotide polymorphisms, and examined the association between common haplotypes of BRCA1 and breast cancer in a nested case-control study in the Nurses' Health Study (1323 cases and 1910 controls). One haplotype was associated with a slight increase in risk (odds ratio 1.18, 95% confidence interval 1.02–1.37). A significant interaction (P = 0.05) was seen between this haplotype, positive family history of breast cancer, and breast cancer risk. Although not statistically significant, similar interactions were observed with age at diagnosis and with menopausal status at diagnosis; risk tended to be higher among younger, pre-menopausal women. We have described a haplotype in the BRCA1 gene that was associated with an approximately 20% increase in risk of sporadic breast cancer in the general population. However, the functional variant(s) responsible for the association are unclear

  14. Germline BRCA1/2 mutation testing is indicated in every patient with epithelial ovarian cancer: A systematic review.

    Science.gov (United States)

    Arts-de Jong, Marieke; de Bock, Geertruida H; van Asperen, Christi J; Mourits, Marian J E; de Hullu, Joanne A; Kets, C Marleen

    2016-07-01

    The presence of a germline BRCA1/2 mutation improves options for tailored risk-reducing strategies and treatment in both breast and ovarian cancer patients and their relatives. Currently, referral for germline BRCA1/2 mutation testing of women with epithelial ovarian cancer (EOC) varies widely, based on different criteria, such as age of onset, family history of breast and/or ovarian cancer and histological type of EOC. The overall probability of a germline BRCA1/2 mutation in women with EOC is above 10%, and a substantial part of the germline BRCA1/2 mutation carriers is missed when applying these criteria for referral. Therefore, we strongly recommend referral of all women with EOC for genetic counselling and DNA analysis. PMID:27209246

  15. Screening of 1331 Danish breast and/or ovarian cancer families identified 40 novel BRCA1 and BRCA2 mutations

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Jønson, Lars; Steffensen, Ane Y;

    2011-01-01

    Germ-line mutations in the tumour suppressor genes BRCA1 and BRCA2 predispose to breast and ovarian cancer. Since 1999 we have performed mutational screening of breast and/or ovarian cancer patients in East Denmark. During this period we have identified 40 novel sequence variations in BRCA1...... and BRCA2 in high risk breast and/or ovarian cancer families. The mutations were detected via pre-screening using dHPLC or high-resolution melting and direct sequencing. We identified 16 variants in BRCA1, including 9 deleterious frame-shift mutations, 2 intronic variants, 4 missense mutations, and 1...... interpreted as pathogenic, 3 missense mutations were suggested to be pathogenic based on in silico analysis, 6 mutations were suggested to be benign since they were identified in patients together with a well-known disease-causing BRCA1/BRCA2 mutation, while 12 were variants of unknown significance....

  16. BRCA1 and TOP2A gene amplification and protein expression in four molecular subtypes of breast cancer

    Directory of Open Access Journals (Sweden)

    Mitrović Olivera

    2013-01-01

    Full Text Available We studied TOP2A amplification (using FISH methods, and TOP2A and BRCA1 protein overexpression (immunohistochemistry in four molecular subtypes of breast cancer. Of 53 patients, 32 showed TOP2A and 38 showed BRCA1 overexpression. The highest percentage of TOP2A amplification (47.8% and deletion (13% was detected in Luminal B subtypes. Of 11 Luminal B tumors with TOP2A amplification, 9 (81.8% overexpressed TOP2A. BRCA1 protein overexpression showed significant positive correlation with TOP2A protein expression. BRCA1 and TOP2A proteins exhibited similar patterns of expression in Luminal B and triple-negative breast cancer, suggesting the same prognosis in those patients. [Projekat Ministarstva nauke Republike Srbije, br. 175053

  17. RNA profiling reveals familial aggregation of molecular subtypes in non-BRCA1/2 breast cancer families

    DEFF Research Database (Denmark)

    Larsen, Martin J; Thomassen, Mads; Tan, Qihua;

    2014-01-01

    BACKGROUND: In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in BRCA1 or BRCA2 cannot be identified, even though hereditary factors are expected to be involved. It has been proposed that tumors with similar molecular phenotypes also share similar...... underlying pathophysiological mechanisms. In the current study, the aim was to investigate if global RNA profiling can be used to identify functional subgroups within breast tumors from families tested negative for BRCA1/2 germline mutations and how these subgroupings relate to different breast cancer...... cancer subtypes, exist among non-BRCA1/2 breast cancers. The distribution of subtypes was markedly different from the distribution found among BRCA1/2 mutation carriers. From 11 breast cancer families, breast tumor biopsies from more than one affected family member were included in the study. Notably...

  18. HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin–proteasome pathway (Biochemical and Biophysical Research Communications, v. 444 issue 3)

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xiaozhen [Department of Cell Biology, Peking University Health Science Center, Beijing 100191 (China); Institute of Systems Biology, Peking University, Beijing 100191 (China); Lu, Guang; Li, Li; Yi, Juan; Yan, Kaowen; Wang, Yaqing; Zhu, Baili; Kuang, Jingyu; Lin, Ming; Zhang, Sha [Department of Cell Biology, Peking University Health Science Center, Beijing 100191 (China); Shao, Genze, E-mail: gzshao@bjmu.edu.cn [Department of Cell Biology, Peking University Health Science Center, Beijing 100191 (China); Institute of Systems Biology, Peking University, Beijing 100191 (China)

    2014-02-14

    Highlights: • The 2000–2634 aa region of HUWE1 mediates the interaction with BRCA1 degron. • HUWE1 promotes the degradation of BRCA1 through the ubiquitin–proteasome pathway. • HUWE1 expression is inversely correlated with BRCA1 in breast cancer cells. • RNAi inhibition of HUWE1 confers increased resistance of MCF-10F cells to IR and MMC. - Abstract: The cellular BRCA1 protein level is essential for its tumor suppression activity and is tightly regulated through multiple mechanisms including ubiquitn–proteasome system. E3 ligases are involved to promote BRCA1 for ubiquitination and degradation. Here, we identified HUWE1/Mule/ARF-BP1 as a novel BRCA1-interacting protein involved in the control of BRCA1 protein level. HUWE1binds BRCA1 through its N-terminus degron domain. Depletion of HUWE1 by siRNA-mediated interference significantly increases BRCA1 protein levels and prolongs the half-life of BRCA1. Moreover, exogenous expression of HUWE1 promotes BRCA1 degradation through the ubiquitin–proteasome pathway, which could explain an inverse correlation between HUWE1 and BRCA1 levels in MCF10F, MCF7 and MDA-MB-231 breast cancer cells. Consistent with a functional role for HUWE1 in regulating BRCA1-mediated cellular response to DNA damage, depletion of HUWE1 by siRNA confers increased resistance to ionizing radiation and mitomycin. These data indicate that HUWE1 is a critical negative regulator of BRCA1 and suggest a new molecular mechanism for breast cancer pathogenesis.

  19. HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin–proteasome pathway (Biochemical and Biophysical Research Communications, v. 444, isse 4)

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xiaozhen [Department of Cell Biology, Peking University Health Science Center, Beijing 100191 (China); Institute of Systems Biology, Peking University, Beijing 100191 (China); Lu, Guang; Li, Li; Yi, Juan; Yan, Kaowen; Wang, Yaqing; Zhu, Baili; Kuang, Jingyu; Lin, Ming; Zhang, Sha [Department of Cell Biology, Peking University Health Science Center, Beijing 100191 (China); Shao, Genze, E-mail: gzshao@bjmu.edu.cn [Department of Cell Biology, Peking University Health Science Center, Beijing 100191 (China); Institute of Systems Biology, Peking University, Beijing 100191 (China)

    2014-02-21

    Highlights: • The 2000–2634aa region of HUWE1 mediates the interaction with BRCA1 degron. • HUWE1 promotes the degradation of BRCA1 through the ubiquitin–proteasome pathway. • HUWE1 expression is inversely correlated with BRCA1 in breast cancer cells. • RNAi inhibition of HUWE1 confers increased resistance of MCF-10F cells to IR and MMC. - Abstract: The cellular BRCA1 protein level is essential for its tumor suppression activity and is tightly regulated through multiple mechanisms including ubiquitn–proteasome system. E3 ligases are involved to promote BRCA1 for ubiquitination and degradation. Here, we identified HUWE1/Mule/ARF-BP1 as a novel BRCA1-interacting protein involved in the control of BRCA1 protein level. HUWE1 binds BRCA1 through its N-terminus degron domain. Depletion of HUWE1 by siRNA-mediated interference significantly increases BRCA1 protein levels and prolongs the half-life of BRCA1. Moreover, exogenous expression of HUWE1 promotes BRCA1 degradation through the ubiquitin–proteasome pathway, which could explain an inverse correlation between HUWE1 and BRCA1 levels in MCF10F, MCF7 and MDA-MB-231 breast cancer cells. Consistent with a functional role for HUWE1 in regulating BRCA1-mediated cellular response to DNA damage, depletion of HUWE1 by siRNA confers increased resistance to ionizing radiation and mitomycin. These data indicate that HUWE1 is a critical negative regulator of BRCA1 and suggest a new molecular mechanism for breast cancer pathogenesis.

  20. The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers

    Directory of Open Access Journals (Sweden)

    Friedenson Bernard

    2007-08-01

    Full Text Available Abstract Background The present study was designed to test the hypothesis that inactivation of virtually any component within the pathway containing the BRCA1 and BRCA2 proteins would increase the risks for lymphomas and leukemias. In people who do not have BRCA1 or BRCA2 gene mutations, the encoded proteins prevent breast/ovarian cancer. However BRCA1 and BRCA2 proteins have multiple functions including participating in a pathway that mediates repair of DNA double strand breaks by error-free methods. Inactivation of BRCA1, BRCA2 or any other critical protein within this "BRCA pathway" due to a gene mutation should inactivate this error-free repair process. DNA fragments produced by double strand breaks are then left to non-specific processes that rejoin them without regard for preserving normal gene regulation or function, so rearrangements of DNA segments are more likely. These kinds of rearrangements are typically associated with some lymphomas and leukemias. Methods Literature searches produced about 2500 epidemiology and basic science articles related to the BRCA pathway. These articles were reviewed and copied to a database to facilitate access. Meta-analyses of statistical information compared risks for hematologic cancers vs. mutations for the components in a model pathway containing BRCA1/2 gene products. Results Deleterious mutations of genes encoding proteins virtually anywhere within the BRCA pathway increased risks up to nearly 2000 fold for certain leukemias and lymphomas. Cancers with large increases in risk included mantle cell lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, and prolymphocytic leukemia. Mantle cell lymphoma is defined by a characteristic rearrangement of DNA fragments interchanged between chromosomes 11 and 14. DNA translocations or rearrangements also occur in significant percentages of the other cancers. Conclusion An important function of the BRCA pathway is to

  1. Increased cell survival by inhibition of BRCA1 using an antisense approach in an estrogen responsive ovarian carcinoma cell line

    International Nuclear Information System (INIS)

    We tested the hypothesis that BRCA1 may play a role in the regulation of ovarian tumor cell death as well as the inhibition of ovarian cell proliferation. Introduction of BRCA1 antisense retroviral constructs into BG-1 estrogen-dependent ovarian adenocarcinoma cells resulted in reduced BRCA1 expression. BRCA1 antisense pooled populations and derived subclones were able to proliferate in monolayer culture without estrogen, whereas control cells began to die after 10 days of estrogen deprivation. In addition, both populations and subclones of BRCA1 antisense infected cells demonstrated a growth advantage in monolayer culture in the presence of estrogen and were able to proliferate in monolayer culture without estrogen, while control cells did not. Furthermore, clonal studies demonstrated that reduced levels of BRCA1 protein correlated with growth in soft agar and greater tumor formation in nude mice in the absence of estrogen. These data suggest that reduction of BRCA1 protein in BG-1 ovarian adenocarcinoma cells may have an effect on cell survival during estrogen deprivation both in vitro and in vivo. Germline mutations in the breast and ovarian cancer susceptibility gene BRCA1, which is located on chromosome 17q21, are associated with a predisposition to the development of cancer in these organs [1,2]. No mutations in the BRCA1 gene have been detected in sporadic breast cancer cases, but mutations have been detected in sporadic cases of ovarian cancer [3,4]. Although there is debate regarding the level of cancer risk associated with mutations in BRCA1 and the significance of the lack of mutations in sporadic tumors, it is possible that alterations in the function of BRCA1 may occur by mechanisms other than mutation, leading to an underestimation of risk when it is calculated solely on the basis of mutational analysis. Such alterations cannot be identified until the function and regulation of BRCA1 are better understood. The BRCA1 gene encodes a 220-kDa nuclear

  2. Mutations in BRCA1 and BRCA2 in breast cancer families: Are there more breast cancer-susceptibility genes?

    Energy Technology Data Exchange (ETDEWEB)

    Serova, O.M.; Mazoyer, S.; Putet, N. [CNRS, Lyon (France)] [and others

    1997-03-01

    To estimate the proportion of breast cancer families due to BRCA1 or BRCA2, we performed mutation screening of the entire coding regions of both genes supplemented with linkage analysis of 31 families, 8 containing male breast cancers and 23 site-specific female breast cancer. A combination of protein-truncation test and SSCP or heteroduplex analyses was used for mutation screening complemented, where possible, by the analysis of expression level of BRCA1 and BRCA2 alleles. Six of the eight families with male breast cancer revealed frameshift mutations, two in BRCA1 and four in BRCA2. Although most families with female site-specific breast cancers were thought to be due to mutations in either BRCA1 or BRCA2, we identified only eight mutations in our series of 23 site-specific female breast cancer families (34%), four in BRCA1 and four in BRCA2. According to the posterior probabilities calculated for mutation-negative families, based on linkage data and mutation screening results, we would expect 8-10 site-specific female breast cancer families of our series to be due to neither BRCA1 nor BRCA2. Thus, our results suggest the existence of at least one more major breast cancer-susceptibility gene. 24 refs., 1 fig., 3 tabs.

  3. Selecting for BRCA1 testing using a combination of homogeneous selection criteria and immunohistochemical characteristics of breast cancers

    International Nuclear Information System (INIS)

    BRCA1 gene-related tumours are more frequently estrogen receptor (ER) and progesterone receptor (PR) negative with a lower prevalence of human epidermal growth factor receptor 2 (HER2) overexpression or amplification. We evaluated the effectiveness of a combination of homogeneously selected criteria and immunohistochemical (IHC) characteristics of Familial Breast Cancers (FBCs) in detecting BRCA1 mutation carriers. Primary breast tumours from 93 FBC patients defined by specific eligibility criteria, based on personal and familial tumour history, were evaluated by Allred's method. The BRCA1 molecular analysis, including Multiplex Ligation-dependent Probe Amplification (MLPA), was considered as the gold standard assay. A total of 10 BRCA1 pathogenetic mutations was found. With the exclusion of the tumours characterized by double positive receptorial status and/or strong HER2 positivity (3+), we identified 22 patients, 10 of whom resulted as BRCA1 mutation carriers. The sensitivity, specificity, positive and negative predictive values were 100%, 83.3%, 45.4% and 100% respectively. Our findings suggest that the IHC analysis by Allred's method improves our ability to select patients for BRCA1 testing

  4. Comparison of risk assessment models of BRCA1 and BRCA2 mutation carrier in patients with breast cancer

    Directory of Open Access Journals (Sweden)

    Rybchenko L.A.

    2013-12-01

    Full Text Available Analysis of efficiency of the algorithm BOADICEA using and Manchester scoring system to predict the carrier of BRCA1 and BRCA2 mutations in Ukranian patients with breast cancer was performed. Materials for this study were the results of clinical, imunogistological, pathogistological, genealogical, molecular genetic researches of 146 patients with breast cancer. Calculations of mutations risk were performed using BOADICEA algorithm and Manchester scoring system. In the total group of patients the area under the curve while predicting BRCA1 mutations with algorithm BOADICEA was 0.86, with Manchester scoring system - 0.84, and in calculation of the combined risk of BRCA mutations - 0.83 and 0.84, respectively. However, statistical difference between the areas of algorithms has not been established (p> 0.05, it indicates to the same discriminatory power of the test models. Better sensitivity, specificity, positive and negative predictive value of results of BOADICEA algorithm was reached in 6% of BRCA1 probability and in 8% threshold of BRCA1/2 mutations. The Manchester scoring system has showed the best operating characteristics with 6 and 13-point probability of BRCA1 and BRCA1/2 mutations respectively. Patients with probability of mutations with such thresholds may be offered molecular study of pathogenic alleles.

  5. BRCA1 and BRCA2 sequence variations detected with next-generation sequencing in patients with premature ovarian insufficiency

    Science.gov (United States)

    Yılmaz, Nafiye Karakaş; Karagin, Peren Hatice; Terzi, Yunus Kasım; Kahyaoğlu, İnci; Yılmaz, Saynur; Erkaya, Salim; Şahin, Feride İffet

    2016-01-01

    Objective Although the association between BRCA1 and BRCA2 gene mutations and breast and ovarian cancer is known, there is insufficient data about premature ovarian insufficiency (POI). However, several studies have reported that there might be a relationship between POI and BRCA1 and BRCA2 gene mutation. Therefore, in the present study, we aimed to investigate the role of BRCA1 and BRCA2 gene mutations in the etiology of POI in a Turkish population. Material and Methods The cohort was classified into two groups: a study group, consisting of 56 individuals diagnosed with premature ovarian insufficiency (and who were younger than 40 years of age, had an antral follicle count 12 IU/I), and a control group, consisting of 45 fertile individuals. A total of 101 individuals were analyzed by next-generation sequencing to detect BRCA1 and BRCA2 gene mutations. Results We detected four new variations (p.T1246N and p.R1835Q in BRCA1 and p.I3312V and IVS-7T>A in BRCA2) that had not been reported before. Conclusion We did not find an association between the BRCA1 and BRCA2 gene mutations and premature ovarian insufficiency. However, larger, functional studies are needed to clarify the association.

  6. BRCA1基因多态性与宫颈癌发生关系的研究%Study on the polymorphism of breast cancer susceptibility gene 1 (BRCA1) and risk of cervical cancer

    Institute of Scientific and Technical Information of China (English)

    李利玲

    2011-01-01

    Objective; To study the polymorphism of breast cancer susceptibility gene 1 ( BRCA1) and the correlation with cervical cancer. Methods; A population based case -control study was conducted in 68 healthy controls and 71 cervical cancer patients. The BRCA1 Pro871 Leu polymorphism was detected by PCR - restriction fragment length polymorphism ( PCR - RFLP). Results; For the BRCA1 871 C>T polymorphism, individuals with C/T, C/C, C/T + T/T genotype significantly decreased the risk of developing cervical cancer compared with those harboring CyC genotype (C/T: OR (95% CI) =0.29 (0.13-0.68), T/T: OR (95% CI) = 0.29 (0.12-0.69), C/T + T/T; OR (95%CI) =0.29 (0.14-0.61). Conclusion: This study confirms the close relationship between BRCA1 polymorphism and cervical cancer. Mutation of BRCA1 Pro871Leu is a protective factor of inhibiting generation of cervical cancer.%目的 探讨人乳腺癌易感基因1(BRCA1)基因多态性与宫颈癌发生的关系.方法 采用病例对照研究,运用多聚酶链式反应-限制性片段长度多态性(PCR-RFLP)法检测71例宫颈癌患者和68例健康人BRCA1 871 C>T单核苷酸多态性,比较上述各组基因型和等位基因频率分布有无差异.结果 BRCA1 871T/T,C/T,C/T+T/T基因型相对于C/C基因型显著降低了宫颈癌发生的风险(C/T:OR(95%CI)=0.29(0.13-0.68),T/T:OR(95%CI)=0.29(0.12-0.69),C/T+T/T:OR(95%CI)=0.29(0.14-0.61);结论BRCA1基因突变与宫颈癌密切相关,BRCA1 871C>T降低了宫颈癌发生的风险.

  7. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

    Science.gov (United States)

    Wang, Xianshu; McGuffog, Lesley; Lee, Andrew; Olswold, Curtis; Kuchenbaecker, Karoline B.; Soucy, Penny; Fredericksen, Zachary; Barrowdale, Daniel; Dennis, Joe; Gaudet, Mia M.; Dicks, Ed; Kosel, Matthew; Healey, Sue; Sinilnikova, Olga M.; Lee, Adam; Bacot, François; Vincent, Daniel; Hogervorst, Frans B. L.; Peock, Susan; Stoppa-Lyonnet, Dominique; Jakubowska, Anna; Investigators, kConFab; Radice, Paolo; Schmutzler, Rita Katharina; Domchek, Susan M.; Piedmonte, Marion; Singer, Christian F.; Friedman, Eitan; Thomassen, Mads; Hansen, Thomas V. O.; Neuhausen, Susan L.; Szabo, Csilla I.; Blanco, Ignacio; Greene, Mark H.; Karlan, Beth Y.; Garber, Judy; Phelan, Catherine M.; Weitzel, Jeffrey N.; Montagna, Marco; Olah, Edith; Andrulis, Irene L.; Godwin, Andrew K.; Yannoukakos, Drakoulis; Goldgar, David E.; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; Terry, Mary Beth; Daly, Mary B.; van Rensburg, Elizabeth J.; Hamann, Ute; Ramus, Susan J.; Ewart Toland, Amanda; Caligo, Maria A.; Olopade, Olufunmilayo I.; Tung, Nadine; Claes, Kathleen; Beattie, Mary S.; Southey, Melissa C.; Imyanitov, Evgeny N.; Tischkowitz, Marc; Janavicius, Ramunas; John, Esther M.; Kwong, Ava; Diez, Orland; Balmaña, Judith; Barkardottir, Rosa B.; Arun, Banu K.; Rennert, Gad; Teo, Soo-Hwang; Ganz, Patricia A.; Campbell, Ian; van der Hout, Annemarie H.; van Deurzen, Carolien H. M.; Seynaeve, Caroline; Gómez Garcia, Encarna B.; van Leeuwen, Flora E.; Meijers-Heijboer, Hanne E. J.; Gille, Johannes J. P.; Ausems, Margreet G. E. M.; Blok, Marinus J.; Ligtenberg, Marjolijn J. L.; Rookus, Matti A.; Devilee, Peter; Verhoef, Senno; van Os, Theo A. M.; Wijnen, Juul T.; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Evans, D. Gareth; Izatt, Louise; Eeles, Rosalind A.; Adlard, Julian; Eccles, Diana M.; Cook, Jackie; Brewer, Carole; Douglas, Fiona; Hodgson, Shirley; Morrison, Patrick J.; Side, Lucy E.; Donaldson, Alan; Houghton, Catherine; Rogers, Mark T.; Dorkins, Huw; Eason, Jacqueline; Gregory, Helen; McCann, Emma; Murray, Alex; Calender, Alain; Hardouin, Agnès; Berthet, Pascaline; Delnatte, Capucine; Nogues, Catherine; Lasset, Christine; Houdayer, Claude; Leroux, Dominique; Rouleau, Etienne; Prieur, Fabienne; Damiola, Francesca; Sobol, Hagay; Coupier, Isabelle; Venat-Bouvet, Laurence; Castera, Laurent; Gauthier-Villars, Marion; Léoné, Mélanie; Pujol, Pascal; Mazoyer, Sylvie; Bignon, Yves-Jean; Złowocka-Perłowska, Elżbieta; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska, Katarzyna; Huzarski, Tomasz; Spurdle, Amanda B.; Viel, Alessandra; Peissel, Bernard; Bonanni, Bernardo; Melloni, Giulia; Ottini, Laura; Papi, Laura; Varesco, Liliana; Tibiletti, Maria Grazia; Peterlongo, Paolo; Volorio, Sara; Manoukian, Siranoush; Pensotti, Valeria; Arnold, Norbert; Engel, Christoph; Deissler, Helmut; Gadzicki, Dorothea; Gehrig, Andrea; Kast, Karin; Rhiem, Kerstin; Meindl, Alfons; Niederacher, Dieter; Ditsch, Nina; Plendl, Hansjoerg; Preisler-Adams, Sabine; Engert, Stefanie; Sutter, Christian; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Weber, Bernhard H. F.; Arver, Brita; Stenmark-Askmalm, Marie; Loman, Niklas; Rosenquist, Richard; Einbeigi, Zakaria; Nathanson, Katherine L.; Rebbeck, Timothy R.; Blank, Stephanie V.; Cohn, David E.; Rodriguez, Gustavo C.; Small, Laurie; Friedlander, Michael; Bae-Jump, Victoria L.; Fink-Retter, Anneliese; Rappaport, Christine; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Tea, Muy-Kheng; Lindor, Noralane M.; Kaufman, Bella; Shimon Paluch, Shani; Laitman, Yael; Skytte, Anne-Bine; Gerdes, Anne-Marie; Pedersen, Inge Sokilde; Moeller, Sanne Traasdahl; Kruse, Torben A.; Jensen, Uffe Birk; Vijai, Joseph; Sarrel, Kara; Robson, Mark; Kauff, Noah; Mulligan, Anna Marie; Glendon, Gord; Ozcelik, Hilmi; Ejlertsen, Bent; Nielsen, Finn C.; Jønson, Lars; Andersen, Mette K.; Ding, Yuan Chun; Steele, Linda; Foretova, Lenka; Teulé, Alex; Lazaro, Conxi; Brunet, Joan; Pujana, Miquel Angel; Mai, Phuong L.; Loud, Jennifer T.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Narod, Steven A.; Herzog, Josef; Sand, Sharon R.; Tognazzo, Silvia; Agata, Simona; Vaszko, Tibor; Weaver, Joellen; Stavropoulou, Alexandra V.; Buys, Saundra S.; Romero, Atocha; de la Hoya, Miguel; Aittomäki, Kristiina; Muranen, Taru A.; Duran, Mercedes; Chung, Wendy K.; Lasa, Adriana; Dorfling, Cecilia M.; Miron, Alexander; Benitez, Javier; Senter, Leigha; Huo, Dezheng; Chan, Salina B.; Sokolenko, Anna P.; Chiquette, Jocelyne; Tihomirova, Laima; Friebel, Tara M.; Agnarsson, Bjarni A.; Lu, Karen H.; Lejbkowicz, Flavio; James, Paul A.; Hall, Per

    2013-01-01

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers. PMID:23544013

  8. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

    Directory of Open Access Journals (Sweden)

    Fergus J Couch

    Full Text Available BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer, with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8, HR = 1.14, 95% CI: 1.09-1.20. In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8, HR = 1.27, 95% CI: 1.17-1.38 and 4q32.3 (rs4691139, P = 3.4 × 10(-8, HR = 1.20, 95% CI: 1.17-1.38. The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4. These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

  9. A risk prediction algorithm for ovarian cancer incorporating BRCA1, BRCA2, common alleles and other familial effects

    Science.gov (United States)

    Jervis, Sarah; Song, Honglin; Lee, Andrew; Dicks, Ed; Harrington, Patricia; Baynes, Caroline; Manchanda, Ranjit; Easton, Douglas F; Jacobs, Ian; Pharoah, Paul P D; Antoniou, Antonis C

    2015-01-01

    Background Although BRCA1 and BRCA2 mutations account for only ∼27% of the familial aggregation of ovarian cancer (OvC), no OvC risk prediction model currently exists that considers the effects of BRCA1, BRCA2 and other familial factors. Therefore, a currently unresolved problem in clinical genetics is how to counsel women with family history of OvC but no identifiable BRCA1/2 mutations. Methods We used data from 1548 patients with OvC and their relatives from a population-based study, with known BRCA1/2 mutation status, to investigate OvC genetic susceptibility models, using segregation analysis methods. Results The most parsimonious model included the effects of BRCA1/2 mutations, and the residual familial aggregation was accounted for by a polygenic component (SD 1.43, 95% CI 1.10 to 1.86), reflecting the multiplicative effects of a large number of genes with small contributions to the familial risk. We estimated that 1 in 630 individuals carries a BRCA1 mutation and 1 in 195 carries a BRCA2 mutation. We extended this model to incorporate the explicit effects of 17 common alleles that are associated with OvC risk. Based on our models, assuming all of the susceptibility genes could be identified we estimate that the half of the female population at highest genetic risk will account for 92% of all OvCs. Conclusions The resulting model can be used to obtain the risk of developing OvC on the basis of BRCA1/2, explicit family history and common alleles. This is the first model that accounts for all OvC familial aggregation and would be useful in the OvC genetic counselling process. PMID:26025000

  10. Prostate screening uptake in Australian BRCA1 and BRCA2 carriers

    Directory of Open Access Journals (Sweden)

    McKinley Joanne M

    2007-09-01

    Full Text Available Abstract Men who carry mutations in BRCA1 or BRCA2 are at increased risk for prostate cancer. However the efficacy of prostate screening in this setting is uncertain and limited data exists on the uptake of prostate screening by mutation carriers. This study prospectively evaluated uptake of prostate cancer screening in a multi-institutional cohort of mutation carriers. Subjects were unaffected male BRCA1 and BRCA2 mutation carriers, aged 40–69 years, enrolled in the Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab and who had completed a mailed, self-report follow-up questionnaire 3 yearly after study entry. Of the 75 male carriers in this study, only 26 (35% had elected to receive their mutation result. Overall, 51 (68% did not recall having received a recommendation to have prostate screening because of their family history, but 41 (55% had undergone a prostate specific antigen (PSA test and 32 (43% a digital rectal examination (DRE in the previous 3 years. Those who were aware of their mutation result were more likely to have received a recommendation for prostate screening (43 vs. 6%, p = 0.0001, and to have had a PSA test (77 vs. 43%, p = 0.005 and a DRE (69 vs. 29%, p = 0.001 in the previous 3 years. The majority of unaffected males enrolled in kConFab with a BRCA1/2 mutation have not sought out their mutation result. However, of those aware of their positive mutation status, most have undergone at least one round of prostate screening in the previous 3 years.

  11. Clinical Considerations of BRCA1- and BRCA2-Mutation Carriers: A Review

    Directory of Open Access Journals (Sweden)

    O. Bougie

    2011-01-01

    Full Text Available Individuals who carry an inherited mutation in the breast cancer 1 (BRCA1 and BRCA2 genes have a significant risk of developing breast and ovarian cancer over the course of their lifetime. As a result, there are important considerations for the clinician in the counseling, followup and management of mutation carriers. This review outlines salient aspects in the approach to patients at high risk of developing breast and ovarian cancer, including criteria for genetic testing, screening guidelines, surgical prophylaxis, and chemoprevention.

  12. BRCA1-like profile predicts benefit of tandem high dose epirubicin-cyclophospamide-thiotepa in high risk breast cancer patients randomized in the WSG-AM01 trial.

    Science.gov (United States)

    Schouten, Philip C; Gluz, Oleg; Harbeck, Nadia; Mohrmann, Svjetlana; Diallo-Danebrock, Raihana; Pelz, Enrico; Kruizinga, Janneke; Velds, Arno; Nieuwland, Marja; Kerkhoven, Ron M; Liedtke, Cornelia; Frick, Markus; Kates, Ronald; Linn, Sabine C; Nitz, Ulrike; Marme, Frederik

    2016-08-15

    BRCA1 is an important protein in the repair of DNA double strand breaks (DSBs), which are induced by alkylating chemotherapy. A BRCA1-like DNA copy number signature derived from tumors with a BRCA1 mutation is indicative for impaired BRCA1 function and associated with good outcome after high dose (HD) and tandem HD DSB inducing chemotherapy. We investigated whether BRCA1-like status was a predictive biomarker in the WSG AM 01 trial. WSG AM 01 randomized high-risk breast cancer patients to induction (2× epirubicin-cyclophosphamide) followed by tandem HD chemotherapy with epirubicin, cyclophosphamide and thiotepa versus dose dense chemotherapy (4× epirubicin-cyclophospamide followed by 3× cyclophosphamide-methotrexate-5-fluorouracil). We generated copy number profiles for 143 tumors and classified them as being BRCA1-like or non-BRCA1-like. Twenty-six out of 143 patients were BRCA1-like. BRCA1-like status was associated with high grade and triple negative tumors. With regard to event-free-survival, the primary endpoint of the trial, patients with a BRCA1-like tumor had a hazard rate of 0.2, 95% confidence interval (CI): 0.07-0.63, p = 0.006. In the interaction analysis, the combination of BRCA1-like status and HD chemotherapy had a hazard rate of 0.19, 95% CI: 0.067-0.54, p = 0.003. Similar results were observed for overall survival. These findings suggest that BRCA1-like status is a predictor for benefit of tandem HD chemotherapy with epirubicin-thiotepa-cyclophosphamide. PMID:26946057

  13. Presymptomatic breast cancer in Egypt: role of BRCA1 and BRCA2 tumor suppressor genes mutations detection

    Directory of Open Access Journals (Sweden)

    Hashishe Mervat M

    2010-06-01

    Full Text Available Abstract Background Breast cancer is one of the most common diseases affecting women. Inherited susceptibility genes, BRCA1 and BRCA2, are considered in breast, ovarian and other common cancers etiology. BRCA1 and BRCA2 genes have been identified that confer a high degree of breast cancer risk. Objective Our study was performed to identify germline mutations in some exons of BRCA1 and BRCA2 genes for the early detection of presymptomatic breast cancer in females. Methods This study was applied on Egyptian healthy females who first degree relatives to those, with or without a family history, infected with breast cancer. Sixty breast cancer patients, derived from 60 families, were selected for molecular genetic testing of BRCA1 and BRCA2 genes. The study also included 120 healthy first degree female relatives of the patients, either sisters and/or daughters, for early detection of presymptomatic breast cancer mutation carriers. Genomic DNA was extracted from peripheral blood lymphocytes of all the studied subjects. Universal primers were used to amplify four regions of the BRCA1 gene (exons 2,8,13 and 22 and one region (exon 9 of BRCA2 gene using specific PCR. The polymerase chain reaction was carried out. Single strand conformation polymorphism assay and heteroduplex analysis were used to screen for mutations in the studied exons. In addition, DNA sequencing of the normal and mutated exons were performed. Results Mutations in both BRCA1 and BRCA2 genes were detected in 86.7% of the families. Current study indicates that 60% of these families were attributable to BRCA1 mutations, while 26.7% of them were attributable to BRCA2 mutations. Results showed that four mutations were detected in the BRCA1 gene, while one mutation was detected in the BRCA2 gene. Asymptomatic relatives, 80(67% out of total 120, were mutation carriers. Conclusions BRCA1 and BRCA2 genes mutations are responsible for a significant proportion of breast cancer. BRCA mutations

  14. A Study on BRCA1/2 Mutations, Hormone Status and HER-2 Status in Korean Women with Early-onset Breast Cancer

    International Nuclear Information System (INIS)

    Women with breast cancer diagnosed at an age of 40 years or younger have a greater prevalence of germline BRCA1 and BRCA2 mutations than the prevalence of women with breast cancer diagnosed at older ages. Several immunohistochemical characteristics have been identified in breast cancers from studies of Caucasian women with BRCA1/2 mutations having familial or early-onset breast cancers. The aim of this study is to determine whether early-onset breast cancer in BRCA1 or BRCA2 mutation carriers, who were not selected from a family history, could be distinguished by the use of immunohistochemical methods and could be distinguished from breast cancer in women of a similar age without a germline BRCA1 or BRCA2 mutation. We also analyzed the prognostic difference between BRCA1/2 related and BRCA1/2 non-related patients by the use of univariate and multivariate analysis. Breast cancer tissue specimens from Korean women with early-onset breast cancers were studied using a tumor tissue microarray. Immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PR) and HER-2, as well as the histology and grade of these specimens, were compared. The prognostic impact of immunohistochemical and histological factors as well as the BRCA1/2 mutation status was investigated separately. There were 14 cases and 16 deleterious BRCA1/2 mutations among 101 patients tested. A family history (4/14) and bilateral breast cancers (3/9) were high risk factors for BRCA1/2 mutations. BRCA1/2- associated cancers demonstrated more expression of ER-negative (19.4% versus 5.1%, p=0.038) and HER-2 negative than BRCA1/2 negative tumors, especially for tumors with BRCA1 tumors The BRCA1/2 mutation rate for patients with triple negative tumors (negative expression of ER, PR and HER-2) was 24.2%. Tumor size, nodal status, and HER-2 expression status were significantly associated with disease free survival, as determined by univariate and multivariate analysis, but the BRCA1/2 status was

  15. Cluster-randomised non-inferiority trial comparing DVD-assisted and traditional genetic counselling in systematic population testing for BRCA1/2 mutations

    OpenAIRE

    Manchanda, R.; Burnell, M.; Loggenberg, K.; Desai, R.; Wardle, J.; Sanderson, S.C.; Gessler, S.; Side, L.; Balogun, N.; Kumar, A.(State University of New York at Buffalo, Buffalo, USA); Dorkins, H.; Wallis, Y; Chapman, C; Tomlinson, I; Taylor, R.

    2016-01-01

    BACKGROUND: Newer approaches to genetic counselling are required for population-based testing. We compare traditional face-to-face genetic counselling with a DVD-assisted approach for population-based BRCA1/2 testing. METHODS: A cluster-randomised non-inferiority trial in the London Ashkenazi Jewish population. INCLUSION CRITERIA: Ashkenazi Jewish men/women >18 years; exclusion criteria: (a) known BRCA1/2 mutation, (b) previous BRCA1/2 testing and (c) first-degree relative of BRCA1/2 carrier....

  16. Characteristics of BRCA1/2 Mutation-Positive Breast Cancers in Korea: A Comparison Study Based on Multicenter Data and the Korean Breast Cancer Registry

    OpenAIRE

    Yu, Jong-Han; Lee, Jong Won; Son, Byung Ho; Kim, Sung-Won; Park, Sue K.; Lee, Min Hyuk; Kim, Lee Su; Noh, Woo-Chul; Kim, Eun-Kyu; Yoon, Dae Sung; Lee, Jeeyeon; Jung, Jin Hyang; Jung, Sang Seol; Gong, Gyungyup; Ahn, Sei-Hyun

    2014-01-01

    Purpose Mutations in BRCA genes are the main cause of hereditary breast cancer in Korea. The aim of this study was to investigate the characteristics of breast cancers involving BRCA1 (BRCA1 group) and BRCA2 (BRCA2 group) mutations. Methods We retrospectively reviewed the medical records of patients with BRCA1 (BRCA1 group) or BRCA2 (BRCA2 group) mutation positive breast cancer from multiple centers and compared the data to that of the Korean Breast Cancer Society registry (registry group). R...

  17. Study on mutation test of BRCA1/2 gene of hereditary breast cancer in Xinj iang%新疆遗传性乳腺癌BRCA1/2基因突变检测的研究

    Institute of Scientific and Technical Information of China (English)

    吴涛; 欧江华; 哈木拉提·吾甫尔; 许文婷; 陈玲; 倪多

    2013-01-01

    Objective Knowing the BRCA gene mutation’s locus and carrying situation of hereditary breast cancer of BRCA1/2 in Xinjiang by means of BRCA gene mutation testing for 82 cases of hereditary breast cancer of BRCA in Xinjiang.Methods 82 cases of hereditary breast cancer from Xinjiang are studied.All the coded sequences of BRCA1/2 gene were amplified by means of extracting genomic DNA from peripheral venous blood.BRCA1/2 gene mutation analysis was prescreened through DHPLC.Then,the result was verified by DNA sequencing.The situation of BRCA gene mutation was statistically analyzed. Results In the 82 cases of hereditary breast cancer in Xinjiang,there were 8 cases of gene mutation (8/82,9.76%);4 cases of BRCA mutation;4 case of BRCA 2 mutation;and 4 cases of BRCA mutation (2073delA frameshift mutation,W372X nonsense mutation,6873delCTCC frameshift mutation,9481delA frameshift mutation)have not been reported in BIC data base.The mutation rate of BRCA1 is (4/30,13. 3%)in triple negative breast cancer.Conclusion The mutation rate of BRCA gene of hereditary breast cancer is higher than sporadic breast cancer;the rate of BRCA1’s mutation of triple negative breast cancer is high;no BRCA gene mutation hot spots have been found in multi-national region in Xinjiang.%目的通过对新疆82例遗传性乳腺癌 BRCA基因突变检测,了解新疆遗传性乳腺癌 BRCA1/2基因突变位点及携带情况。方法以来自新疆地区的82例符合遗传性乳腺癌标准的患者为研究对象,通过外周静脉血提取基因组 DNA,对 BRCA1/2基因的全部编码序列进行扩增。BRCA1/2基因突变分析由变性高效液相色谱分析(DHPLC)进行预筛,结果进行DNA测序证实。统计分析 BRCA1/2基因突变情况。结果82例遗传性乳腺癌,共发现8例(9.76%)BRCA基因突变,其中 BRCA1突变4例,BRCA2突变4例;4例 BRCA突变(2073delA移码突变、W372X无义突变、6873delCTCC移码突变、9481delA移码突变)

  18. Pit-1 inhibits BRCA1 and sensitizes human breast tumors to cisplatin and vitamin D treatment

    Science.gov (United States)

    Seoane, Samuel; Arias, Efigenia; Sigueiro, Rita; Sendon-Lago, Juan; Martinez-Ordoñez, Anxo; Castelao, Esteban; Eiró, Noemí; Garcia-Caballero, Tomás; Macia, Manuel; Lopez-Lopez, Rafael; Maestro, Miguel; Vizoso, Francisco; Mouriño, Antonio; Perez-Fernandez, Roman

    2015-01-01

    The POU class 1 homeobox 1 (POU1F1, also known as Pit-1), pertaining to the Pit-Oct-Unc (POU) family of transcription factors, has been related to tumor growth and metastasis in breast. However, its role in response to breast cancer therapy is unknown. We found that Pit-1 down-regulated DNA-damage and repair genes, and specifically inhibited BRCA1 gene expression, sensitizing breast cancer cells to DNA-damage agents. Administration of 1α, 25-dihydroxy-3-epi-vitamin D3 (3-Epi, an endogenous low calcemic vitamin D metabolite) reduced Pit-1 expression, and synergized with cisplatin, thus, decreasing cell proliferation and apoptosis in vitro, and reducing tumor growth in vivo. In addition, fifteen primary cultures of human breast tumors showed significantly decreased proliferation when treated with 3-Epi+cisplatin, compared to cisplatin alone. This response positively correlated with Pit-1 levels. Our findings demonstrate that high levels of Pit-1 and reduced BRCA1 levels increase breast cancer cell susceptibility to 3-Epi+cisplatin therapy. PMID:25992773

  19. IDENTIFICATION, ISOLATION AND AMPLIFICATION OF BRCA1 GENE INVOLVED IN BREAST CANCER

    Directory of Open Access Journals (Sweden)

    Karaneh Eftekhari

    2014-02-01

    Full Text Available Cancer is a disease that begins in the cells ofthe body which is characterized by uncontrolled, uncoordinated and undesirable cell division. If a cell accumulates critical mutations in five or six of the proto-oncogenes, tumour suppressor genes and DNA repair genes are likely to result in a fully malignant cell, capable of forming a tumour. In this work we described the isolation and amplification of the BRCA1 gene. Primers were designed and synthesised later used to amplify the BRCA1 gene. The total new workflow includes all steps from purified DNA to data analysis, and includes PCR for all amplicons covering the gene, PCR cleanup, cycle sequencing, electrophoresis, and data analysis. To simplify workflows and decrease the time-to-result, we focused on the method “one sample, one assay” approach. The success of this workflow was the 24-well plate design, which contained prespotted PCR primers covering the gene and also included multiplex nontemplate controls. The workflow was developed using a Genetic Analyzer and bands were observed.

  20. Elevated expression of Ki-67 identifies aggressive prostate cancers but does not distinguish BRCA1 or BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Mitra, A V; Jameson, C; Barbachano, Y;

    2010-01-01

    Prostate cancers in men with germline BRCA1 and BRCA2 mutations are more aggressive than morphologically similar cancers in men without these mutations. This study was performed to test the hypothesis that enhanced expression of Ki-67, as a surrogate of cell proliferation, is a characteristic...... and benign tissues (p0.5). Similar results were obtained when the data were analysed using a threshold set at 3.5 and 7.1%. This study shows that elevated expression of Ki-67 is associated both with aggressive prostate cancers and with high Gleason score irrespective of whether their occurrence is...... against a background of BRCA1 or BRCA2 mutations or as sporadic disease. The data suggest that, since elevated Ki-67 does not distinguish prostate cancers occurring in BRCA1 or BRCA2 mutation carriers from sporadic prostatic malignancies, the effects of these genetic mutations are probably independent...

  1. The Quality of Genetic Counseling and Connected Factors as Evaluated by Male BRCA1/2 Mutation Carriers in Finland.

    Science.gov (United States)

    Kajula, Outi; Kääriäinen, Maria; Moilanen, Jukka S; Kyngäs, Helvi

    2016-06-01

    There is little written about the quality of genetic counseling for men with the BRCA1/2 mutation. The purpose of this study was to describe the quality of genetic counseling and connected factors according to Finnish male BRCA1/2 mutation carriers' (n = 35) perspectives and reasons for seeking genetic counseling. Data were collected from the Departments of Clinical Genetics at five Finnish university hospitals. The exploratory study design was conducted using a 51-item questionnaire based on a previously devised quality of counseling model and analyzed using non-parametric tests and principle content analysis. The satisfaction level with genetic counseling was high, especially with regard to the content of genetic counseling. The benefit of genetic counseling on the quality of life differed significantly (p education, affected the perceived quality of genetic counseling. The results of the study could be used to tailor genetic counseling for male BRCA1/2 mutation carriers. PMID:26416184

  2. Mutation screening of MIR146A/B and BRCA1/2 3'-UTRs in the GENESIS study.

    Science.gov (United States)

    Garcia, Amandine I; Buisson, Monique; Damiola, Francesca; Tessereau, Chloé; Barjhoux, Laure; Verny-Pierre, Carole; Sornin, Valérie; Dondon, Marie-Gabrielle; Eon-Marchais, Séverine; Caron, Olivier; Gautier-Villars, Marion; Coupier, Isabelle; Buecher, Bruno; Vennin, Philippe; Belotti, Muriel; Lortholary, Alain; Gesta, Paul; Dugast, Catherine; Noguès, Catherine; Fricker, Jean-Pierre; Faivre, Laurence; Stoppa-Lyonnet, Dominique; Andrieu, Nadine; Sinilnikova, Olga M; Mazoyer, Sylvie

    2016-08-01

    Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3'- untranslated regions (3'-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1- and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3'-UTR and one in BRCA2 3'-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3'-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3'-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.

  3. Relationship Between Mutations In BRCA1 And BRCA2 Genes And Breast Cancer Prevalence Among Egyptian Women

    International Nuclear Information System (INIS)

    Breast cancer represents the most common cancer of women in the world and it is a biologically heterogeneous disease influenced by complex interactions between multiple genetic and environmental risk factors. In Egypt, breast cancer is classified as the first rank cancer case among women. The present study included 55 patients with breast cancer from Upper Egypt of which 40 patients had sporadic and 15 had familial breast cancers. Mutations in DNA of exons 10 and 11 of BRCA1 and BRCA2 were detected by single strand conformation polymorphisms (SSCPs) and sequencing. Moreover, BRCA1 protein expression was detected by immunostaining technique and correlation between risk factors and incidence rate of breast cancer. The results revealed 5 mutations (unclassified variants); three mutations (60%) were recorded internationally in Breast Information Cancer (BIC), one of them was 1767 C→T(550 Asn→His) and previously recorded in the Arabic world and the other 2 novel mutations were 1663 T→ C(479 Asp→Gly) and del AG 6079. The results obtained in the present study also demonstrated that the increase of the negative immunostaining of ''BRCA1'' protein in the tumour cells of BRCA1 mutation carriers was comparable to familial and sporadic breast cancer non-carrier. Accurate estimation of the relative frequency of BRCA1 and BRCA2 mutations in Egyptian breast cancer patients could not be deduced from the results of this relatively small pilot study. More studies with larger numbers of patients are needed to clarify the relation between BRCA1 and BRCA2 gene mutations and the prediction of breast cancer in Egypt.

  4. Quality of Life and Psychological State in Chinese Breast Cancer Patients Who Received BRCA1/2 Genetic Testing.

    Directory of Open Access Journals (Sweden)

    Jiajia Qiu

    Full Text Available This study aims to understand the quality of life (QOL and psychological state (PS of Chinese breast cancer patients who received BRCA1/2 genetic testing; to examine the psychological changes between BRCA1/2 mutation carriers and non-carriers; and to further explore the psychological experience of BRCA1/2 mutation carriers.This study was combined with quantitative and qualitative designs. First, we performed a quantitative investigation using FACT-B (Chinese version and Irritability, Depression and Anxiety scale (IDA to assess the QOL and PS in breast cancer patients who received BRCA1/2 genetic testing. Then semi-structured in-depth qualitative interviews among 13 mutation carriers were conducted in hospital.Results from the quantitative study showed QOL scores were relatively high and the IDA scores were relatively low among the patients, and there was no significant difference in the QOL or IDA scores between non-carriers and carriers. Based on the qualitative analysis, four main themes emerged: (1 Finding the reason for having breast cancer; (2 Negative emotions; (3 Behavioral changes; (4 Lack of information.The present study showed that QOL and PS are good among the breast cancer patients who received genetic testing. Genetic testing itself does not cause long psychosocial effects. BRCA1/2 mutation carriers may have certain negative emotions at the first stage they knew the testing results and may initiate behavioral and lifestyle changes. The patients with a BRCA1/2 mutation desire knowledge with regard to genetic aspects in mainland China. Professional information and advice can be provided to relieve the patients' negative emotions when they were informed of gene defect.

  5. HTLV-1 Tax oncoprotein inhibits the estrogen-induced-ER α-Mediated BRCA1 expression by interaction with CBP/p300 cofactors.

    Science.gov (United States)

    Shukrun, Meital; Jabareen, Azhar; Abou-Kandil, Ammar; Chamias, Rachel; Aboud, Mordechai; Huleihel, Mahmoud

    2014-01-01

    BRCA1 is a multifunctional tumor suppressor, whose expression is activated by the estrogen (E2)-liganded ERα receptor and regulated by certain recruited transcriptional co-activators. Interference with BRCA1 expression and/or functions leads to high risk of breast or/and ovarian cancer. Another multifunctional protein, HTLV-1Tax oncoprotein, is widely regarded as crucial for developing adult T-cell leukemia and other clinical disorders. Tax profile reveals that it can antagonize BRCA1 expression and/or functionality. Therefore, we hypothesize that Tax expression in breast cells can sensitize them to malignant transformation by environmental carcinogens. Here we examined Tax effect on BRCA1 expression by testing its influence on E2-induced expression of BRCA1 promoter-driven luciferase reporter (BRCA1-Luc). We found that E2 strongly stimulated this reporter expression by liganding to ERα, which consequently associated with BRCA1 promoter, while ERα concomitantly recruited CBP/p300 to this complex for co-operative enhancement of BRCA1 expression. Introducing Tax into these cells strongly blocked this E2-ERα-mediated activation of BRCA1 expression. We noted, also, that Tax exerted this inhibition by binding to CBP/p300 without releasing them from their complex with ERα. Chip assay revealed that the binding of Tax to the CBP/p300-ERα complex, prevented its link to AP1 site. Interestingly, we noted that elevating the intracellular pool of CBP or p300 to excessive levels dramatically reduced the Tax-mediated inhibition of BRCA1 expression. Exploring the mechanism of this reduction revealed that the excessive co-factors were sufficient to bind separately the free Tax molecules, thus lowering their amount in the CBP/p300-ERα complex and relieving, thereby, the inhibition of BRCA1 expression.

  6. A non-synonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

    Science.gov (United States)

    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

  7. PARP-1 inhibitors: are they the long-sought genetically specific drugs for BRCA1/2-associated breast cancers?

    OpenAIRE

    De Soto, Joseph A.; Deng, Chu-Xia

    2006-01-01

    Recent studies demonstrated that PARP-1 [poly(ADP-ribose) polymerase-1] inhibitors kill breast cancer associated gene-1 and –2 (BRCA1/2) deficient cells with extremely high efficiency while BRCA+/- and BRCA+/+ cells are relatively non-responsive to the treatment. It was therefore proposed that PARP-1 inhibitors might be the long-sought genetically specific drugs that are both safe and effective for treating BRCA1/2-associated breast cancers. However, a report published in a recent issue of th...

  8. Evaluation of the Needs of Male Carriers of Mutations in BRCA1 or BRCA2 Who Have Undergone Genetic Counseling

    OpenAIRE

    Liede, Alexander; Metcalfe, Kelly; Hanna, Danielle; Hoodfar, Elizabeth; Snyder, Carrie; Durham, Carolyn; Lynch, Henry T.; Narod, Steven A.

    2000-01-01

    To date, the concerns of men at risk of inheriting a BRCA1 mutation or a BRCA2 mutation have received little attention. It had been anticipated that few men would be interested in predictive testing when a BRCA mutation was identified in their family. However, these men are often affected emotionally by diagnoses of breast cancer in their relatives and may themselves harbor fears that cancer will develop. Male carriers of BRCA1/2 mutations are at increased risk of development of cancers of se...

  9. BRCA1 polymorphisms and breast cancer epidemiology in the Western New York Exposures and Breast Cancer (WEB) study

    OpenAIRE

    Ricks-Santi, Luisel J.; Nie, Jing; Marian, Catalin; Ochs-Balcom, Heather M; Trevisan, Maurizio; Edge, Stephen B.; Freudenheim, Jo L.; Shields, Peter G.

    2013-01-01

    Results of studies for the association of BRCA1 genotypes and haplotypes with sporadic breast cancer have been inconsistent. Therefore, a candidate SNP approach was used in a breast cancer case-control study to explore genotypes and haplotypes that have the potential to affect protein functions or levels. In a breast cancer case-control study, genotyping of BRCA1 polymorphisms Q356R, D693N, and E1038G was performed on 1005 cases and 1765 controls. Unconditional, polytomous logistic regression...

  10. On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations

    DEFF Research Database (Denmark)

    Hamel, Nancy; Feng, Bing-Jian; Foretova, Lenka;

    2011-01-01

    The BRCA1 mutation c.5266dupC was originally described as a founder mutation in the Ashkenazi Jewish (AJ) population. However, this mutation is also present at appreciable frequency in several European countries, which raises intriguing questions about the origins of the mutation. We genotyped 245.......5266dupC originated from a single common ancestor and was a common European mutation long before becoming an AJ founder mutation and (2) the mutation is likely present in many additional European countries where genetic screening of BRCA1 may not yet be common practice.European Journal of Human...

  11. On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations

    DEFF Research Database (Denmark)

    Hamel, Nancy; Feng, Bing-Jian; Foretova, Lenka;

    2011-01-01

    The BRCA1 mutation c.5266dupC was originally described as a founder mutation in the Ashkenazi Jewish (AJ) population. However, this mutation is also present at appreciable frequency in several European countries, which raises intriguing questions about the origins of the mutation. We genotyped 245.......5266dupC originated from a single common ancestor and was a common European mutation long before becoming an AJ founder mutation and (2) the mutation is likely present in many additional European countries where genetic screening of BRCA1 may not yet be common practice....

  12. A Rapid and Reliable Test for BRCA1 and BRCA2 Founder Mutation Analysis in Paraffin Tissue Using Pyrosequencing

    OpenAIRE

    Zhang, Liying; Kirchhoff, Tomas; Yee, Cindy J; Offit, Kenneth

    2009-01-01

    The founder mutations in BRCA (BRCA1*185delAG, BRCA1*5382insC, and BRCA2*6174delT) account for 95% of the detectable BRCA mutations in breast and ovarian cancer families of Ashkenazi Jewish ancestry. Optimal clinical management of individuals from these high-risk families relies on the identification of BRCA founder mutations in the laboratory. We have therefore developed a rapid and reliable approach using pyrosequencing, which allows for the detection of these frequent frameshift mutations ...

  13. Five recurrent BRCA1/2 mutations are responsible for cancer predisposition in the majority of Slovenian breast cancer families

    Directory of Open Access Journals (Sweden)

    Novakovic Srdjan

    2008-09-01

    Full Text Available Abstract Background Both recurrent and population specific mutations have been found in different areas of the world and more specifically in ethnically defined or isolated populations. The population of Slovenia has over several centuries undergone limited mixing with surrounding populations. The current study was aimed at establishing the mutation spectrum of BRCA1/2 in the Slovenian breast/ovarian cancer families taking advantage of a complete cancer registration database. A second objective was to determine the cancer phenotype of these families. Methods The original population database was composed of cancer patients from the Institute of Oncology Ljubljana in Slovenia which also includes current follow-up status on these patients. The inclusion criteria for the BRCA1/2 screening were: (i probands with at least two first degree relatives with breast and ovarian cancer; (ii probands with only two first degree relatives of breast cancer where one must be diagnosed less than 50 years of age; and (iii individual patients with breast and ovarian cancer, bilateral breast cancer, breast cancer diagnosed before the age of 40 and male breast cancer without any other cancer in the family. Results Probands from 150 different families met the inclusion criteria for mutation analysis of which 145 consented to testing. A BRCA1/2 mutation was found in 56 (39%. Two novel large deletions covering consecutive exons of BRCA1 were found. Five highly recurrent specific mutations were identified (1806C>T, 300T>G, 300T>A, 5382insC in the BRCA1 gene and IVS16-2A>G in the BRCA2 gene. The IVS16-2A>G in the BRCA2 gene appears to be a unique founder mutation in the Slovenian population. A practical implication is that only 4 PCR fragments can be used in a first screen and reveal the cancer predisposing mutation in 67% of the BRCA1/2 positive families. We also observed an exceptionally high frequency of 4 different pathogenic missense mutations, all affecting one of

  14. Methionine synthase and methylation of BRCA1: their association with breast cancer morbidity%BRCA1基因甲基化及甲硫氨酸合成酶与乳腺癌发病的关系

    Institute of Scientific and Technical Information of China (English)

    马文慧; 侯琳; 韩琳琳

    2011-01-01

    Background and purpose: Promoter hypermethylation is an early event in tumorigenesis.Global under-methylation (hypomethylation) and site-specific over-methylation (hypermethylation) are common features of human tumors.Methionine synthase (MS) is the key enzyme involved in methyl donor-generated and provided methyl in DNA methylation.This study investigated the mRNA expression and promoter methylation status of the BRCA1 gene in breast cancer and the effects of mRNA expression in the MS gene in BRCA1 methylation as well as their association with breast cancer morbidity.Methods: RT-PCR was used to detect mRNA expressions in the BRCA1 gene and MS gene, and sensitive methylation-specific-PCR (MSP) was used to detect the promoter methylation status of the BRCA1 gene.Thirty-one samples of breast cancer and tumor adjacent tissues, as well as 9 cases of benign breast disease were detected.Results: Significant differences in the BRCA1 mRNA expression were observed among all three tissues.Methylation of the BRCA1 gene in breast cancer increased significantly in comparison with the tumor adjacent tissues and benign breast disease tissues (x2=7.631, P<0.05).The BRCA1 methylated tumors closely correlated with histologic grades and negative expression of estrogen receptor (ER) (P<0.05).The mRNA expression of MS in breast cancer tissues was significantly lower than in both benign breast disease tissues and tumor adjacent tissues (P<0.05).There was a correlation between methylation of BRCA1 and expression of MS in breast cancer tissues (r=0.419, P<0.05).Conclusion: Methylation of BRCA1 could be a contributor to the risk of breast cancer.The MS gene may be able to regulate the expression of tumor-related genes by affecting the methylation status.%背景与目的:启动子异常甲基化是肿瘤发生的早期事件,肿瘤组织中存在的DNA甲基化异常可以概括为广泛低甲基化伴局部高甲基化.甲硫氨酸合成酶(methionine synthase,MS)是参与甲基

  15. Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

    DEFF Research Database (Denmark)

    Osorio, A.; Milne, R.L.; Pita, G.;

    2009-01-01

    BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have...... for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out Udgivelsesdato: 2009/12/15...... genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk...

  16. Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

    DEFF Research Database (Denmark)

    Osorio, A; Milne, R L; Pita, G;

    2009-01-01

    Background:In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.Methods:We have...... for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P=0.5) mutation carriers.Conclusion:This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.British Journal of Cancer advance...... genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach.Results:We found no evidence of association with breast cancer risk...

  17. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    NARCIS (Netherlands)

    A.M. Mulligan (Anna Marie); F.J. Couch (Fergus); D. Barrowdale (Daniel); S.M. Domchek (Susan); D. Eccles (Diana); H. Nevanlinna (Heli); S.J. Ramus (Susan); M. Robson (Mark); M.E. Sherman (Mark); A.B. Spurdle (Amanda); B. Wapenschmidt (Barbara); A. Lee (Andrew); L. McGuffog (Lesley); S. Healey (Sue); O. Sinilnikova (Olga); R. Janavicius (Ramunas); T.V.O. Hansen (Thomas); F.C. Nielsen (Finn); B. Ejlertsen (Bent); A. Osorio (Ana); I. Muñoz-Repeto (Iván); M. Durán (Mercedes); J. Godino (Javier); M. Pertesi (Maroulio); J. Benítez (Javier); P. Peterlongo (Paolo); S. Manoukian (Siranoush); B. Peissel (Bernard); D. Zaffaroni (D.); E. Cattaneo (Elisa); B. Bonnani (Bernardo); A. Viel (Alessandra); B. Pasini (Barbara); L. Papi (Laura); L. Ottini (Laura); A. Savarese (Antonella); L. Bernard (Loris); P. Radice (Paolo); U. Hamann (Ute); M. Verheus (Martijn); E.J. Meijers-Heijboer (Hanne); J.T. Wijnen (Juul); E.B. Gómez García (Encarna); M.R. Nelen (Marcel); C.M. Kets; C.M. Seynaeve (Caroline); M.M.A. Tilanus-Linthorst (Madeleine); R.B. van der Luijt (Rob); T.V. Os (Theo); M.A. Rookus (Matti); D. Frost (Debra); J.L. Jones (J Louise); D.G. Evans (Gareth); F. Lalloo (Fiona); R. Eeles (Rosalind); L. Izatt (Louise); J.W. Adlard (Julian); R. Davidson (Rosemarie); J. Cook (Jackie); A. Donaldson (Alan); H. Dorkins (Huw); H. Gregory (Helen); J. Eason (Jacqueline); C. Houghton (Catherine); J. Barwell (Julian); L. Side (Lucy); E. McCann (Emma); A. Murray (Alexandra); S. Peock (Susan); A.K. Godwin (Andrew); R.K. Schmutzler (Rita); K. Rhiem (Kerstin); C. Engel (Christoph); A. Meindl (Alfons); I. Ruehl (Ina); N. Arnold (Norbert); D. Niederacher (Dieter); C. Sutter (Christian); H. Deissler (Helmut); D. Gadzicki (Dorothea); K. Kast (Karin); S. Preisler-Adams (Sabine); R. Varon-Mateeva (Raymonda); I. Schoenbuchner (Ines); B. Fiebig (Britta); W. Heinritz (Wolfram); D. Schäfer; H. Gevensleben (Heidrun); V. Caux-Moncoutier (Virginie); M. Fassy-Colcombet (Marion); F. Cornelis (Franco̧is); S. Mazoyer (Sylvie); M. Léone (Mélanie); N. Boutry-Kryza (N.); A. Hardouin (Agnès); P. Berthet (Pascaline); D.W. Muller (Danièle); J.P. Fricker (Jean Pierre); I. Mortemousque (Isabelle); P. Pujol (Pascal); I. Coupier (Isabelle); M. Lebrun (Marine); C. Kientz (Caroline); M. Longy (Michel); N. Sevenet (Nicolas); D. Stoppa-Lyonnet (Dominique); C. Isaacs (Claudine); T. Caldes (Trinidad); M. de La Hoya (Miguel); T. Heikinen (Tuomas); K. Aittomäki (Kristiina); I. Blanco (Ignacio); C. Lazaro (Conxi); R.B. Barkardottir (Rosa); P. Soucy (Penny); M. Dumont (Martine); J. Simard (Jacques); M. Montagna (Marco); S. Tognazzo (Silvia); E. D'Andrea (Emma); S.B. Fox (Stephen); M. Yan (Max); R. Rebbeck (Timothy); O.I. Olopade (Olofunmilayo); J.N. Weitzel (Jeffrey); H. Lynch (Henry); P.A. Ganz (Patricia); G. Tomlinson (Gail); X. Wang (Xing); Z. Fredericksen (Zachary); V.S. Pankratz (Shane); N.M. Lindor (Noralane); C. Szabo (Csilla); K. Offit (Kenneth); R. Sakr (Rita); M.M. Gaudet (Mia); K.P. Bhatia (Kailash); N. Kauff (Noah); C.F. Singer (Christian); M.-K. Tea; D. Gschwantler-Kaulich (Daphne); A. Fink-Retter (Anneliese); P.L. Mai (Phuong); M.H. Greene (Mark); E.N. Imyanitov (Evgeny); F.P. O'Malley (Frances); H. Ozcelik (Hilmi); G. Glendon (Gord); A.E. Toland (Amanda); A-M. Gerdes (Anne-Marie); M. Thomassen (Mads); T.A. Kruse (Torben); U.B. Jensen; A.-B. Skytte (Anne-Bine); M.A. Caligo (Maria); M. Soller (Maria); K. Henriksson (Karin); A. von Wachenfeldt (Anna); B. Arver (Brita Wasteson); M. Stenmark-Askmalm (M.); P. Karlsson (Per); Y.C. Ding (Yuan); S.L. Neuhausen (Susan); M.S. Beattie (Mary); P.D.P. Pharoah (Paul); K.B. Moysich (Kirsten); K.L. Nathanson (Katherine); B. Karlan; J. Gross (Jenny); E.M. John (Esther); M.B. Daly (Mary); S.S. Buys (Saundra); M.C. Southey (Melissa); J.L. Hopper (John); M.-B. Terry (Mary-Beth); W. Chung (Wendy); A. Miron (Alexander); D. Goldgar (David); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas); I.L. Andrulis (Irene); A.C. Antoniou (Antonis)

    2011-01-01

    textabstractIntroduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes

  18. Common breast cancer susceptibility alleles are associated with tumor subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    DEFF Research Database (Denmark)

    Mulligan, Anna Marie; Couch, Fergus J; Barrowdale, Daniel;

    2011-01-01

    ABSTRACT: INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtype...

  19. Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA).

    NARCIS (Netherlands)

    Osorio, A.; Milne, R.L.; Pita, G.; Peterlongo, P.; Heikkinen, T.; Simard, J.; Chenevix-Trench, G.; Spurdle, A.B.; Beesley, J.; Chen, X.; Healey, S.; Neuhausen, S.L.; Ding, Y.C.; Couch, F.J.; Wang, X.; Lindor, N.; Manoukian, S.; Barile, M.; Viel, A.; Tizzoni, L.; Szabo, C.I.; Foretova, L.; Zikan, M.; Claes, K.; Greene, M.H.; Mai, P.; Rennert, G.; Lejbkowicz, F.; Barnett-Griness, O.; Andrulis, I.L.; Ozcelik, H.; Weerasooriya, N.; Gerdes, A.M.; Thomassen, M.; Cruger, D.G.; Caligo, M.A.; Friedman, E.; Kaufman, B.; Laitman, Y.; Cohen, S.; Kontorovich, T.; Gershoni-Baruch, R.; Dagan, E.; Jernstrom, H.; Askmalm, M.S.; Arver, B.; Malmer, B.; Domchek, S.M.; Nathanson, K.L.; Brunet, J.; Ramon Y Cajal, T.; Yannoukakos, D.; Hamann, U.; Hogervorst, F.B.L.; Verhoef, S.; Gomez Garcia, E.B.; Wijnen, J.T.; Ouweland, A.M.W. van den; Easton, D.F.; Peock, S.; Cook, M.; Oliver, C.T.; Frost, D.; Luccarini, C.; Evans, D.G.; Lalloo, F.; Eeles, R.; Pichert, G.; Cook, J.; Hodgson, S.; Morrison, P.J.; Douglas, F.; Godwin, A.K.; Sinilnikova, O.M.; Barjhoux, L.; Stoppa-Lyonnet, D.; Moncoutier, V.; Giraud, S.; Cassini, C.; Olivier-Faivre, L.; Revillion, F.; Peyrat, J.P.; Muller, D.; Fricker, J.P.; Lynch, H.T.; John, E.M.; Buys, S.; Daly, M.; Hopper, J.L.; Terry, M.B.; Miron, A.; Yassin, Y.; Goldgar, D.; Singer, C.F.; Gschwantler-Kaulich, D.; Pfeiler, G.; Spiess, A.C.; Hansen, T.V.; Johannsson, O.T.

    2009-01-01

    BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have geno

  20. Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

    NARCIS (Netherlands)

    Osorio, A.; Milne, R. L.; Pita, G.; Peterlongo, P.; Heikkinen, T.; Simard, J.; Chenevix-Trench, G.; Spurdle, A. B.; Beesley, J.; Chen, X.; Healey, S.; Neuhausen, S. L.; Ding, Y. C.; Couch, F. J.; Wang, X.; Lindor, N.; Manoukian, S.; Barile, M.; Viel, A.; Tizzoni, L.; Szabo, C. I.; Foretova, L.; Zikan, M.; Claes, K.; Greene, M. H.; Mai, P.; Rennert, G.; Lejbkowicz, F.; Barnett-Griness, O.; Andrulis, I. L.; Ozcelik, H.; Weerasooriya, N.; Gerdes, A-M; Thomassen, M.; Cruger, D. G.; Caligo, M. A.; Friedman, E.; Kaufman, B.; Laitman, Y.; Cohen, S.; Kontorovich, T.; Gershoni-Baruch, R.; Dagan, E.; Jernstrom, H.; Askmalm, M. S.; Arver, B.; Malmer, B.; Domchek, S. M.; Nathanson, K. L.; Brunet, J.; Ramon y Cajal, T.; Yannoukakos, D.; Hamann, U.; Hogervorst, F. B. L.; Verhoef, S.; Gomez Garcia, E. B.; Wijnen, J. T.; van den Ouweland, A.; Easton, D. F.; Peock, S.; Cook, M.; Oliver, C. T.; Frost, D.; Luccarini, C.; Evans, D. G.; Lalloo, F.; Eeles, R.; Pichert, G.; Cook, J.; Hodgson, S.; Morrison, P. J.; Douglas, F.; Godwin, A. K.; Sinilnikova, O. M.; Barjhoux, L.; Stoppa-Lyonnet, D.; Moncoutier, V.; Giraud, S.; Cassini, C.; Olivier-Faivre, L.; Revillion, F.; Peyrat, J-P; Muller, D.; Fricker, J-P; Lynch, H. T.; John, E. M.; Buys, S.; Daly, M.; Hopper, J. L.; Terry, M. B.; Miron, A.; Yassin, Y.; Goldgar, D.; Singer, C. F.; Gschwantler-Kaulich, D.; Pfeiler, G.; Spiess, A-C; Hansen, Thomas v. O.; Johannsson, O. T.; Kirchhoff, T.; Offit, K.; Kosarin, K.; Piedmonte, M.; Rodriguez, G. C.; Wakeley, K.; Boggess, J. F.; Basil, J.; Schwartz, P. E.; Blank, S. V.; Toland, A. E.; Montagna, M.; Casella, C.; Imyanitov, E. N.; Allavena, A.; Schmutzler, R. K.; Versmold, B.; Engel, C.; Meindl, A.; Ditsch, N.; Arnold, N.; Niederacher, D.; Deissler, H.; Fiebig, B.; Varon-Mateeva, R.; Schaefer, D.; Froster, U. G.; Caldes, T.; de la Hoya, M.; McGuffog, L.; Antoniou, A. C.; Nevanlinna, H.; Radice, P.; Benitez, J.

    2009-01-01

    BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron I of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have geno

  1. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    NARCIS (Netherlands)

    Mulligan, A.M.; Couch, F.J.; Barrowdale, D.; Domchek, S.M.; Eccles, D.; Nevanlinna, H.; Ramus, S.J.; Robson, M.; Sherman, M.; Spurdle, A.B.; Wappenschmidt, B.; Lee, A.; McGuffog, L.; Healey, S.; Sinilnikova, O.M.; Janavicius, R.; Hansen, T.V.; Nielsen, F.C.; Ejlertsen, B.; Osorio, A.; Munoz-Repeto, I.; Duran, M.; Godino, J.; Pertesi, M.; Benitez, J.; Peterlongo, P.; Manoukian, S.; Peissel, B.; Zaffaroni, D.; Cattaneo, E.; Bonanni, B.; Viel, A.; Pasini, B.; Papi, L.; Ottini, L.; Savarese, A.; Bernard, L.; Radice, P.; Hamann, U.; Verheus, M.; Meijers-Heijboer, H.E.; Wijnen, J.; Gomez Garcia, E.B.; Nelen, M.R.; Kets, C.M.; Seynaeve, C.; Tilanus-Linthorst, M.M.; Luijt, R.B. van der; Os, T.V.; Rookus, M.; Frost, D.; Jones, J.L.; Evans, D.G.; Lalloo, F.; Eeles, R.; Izatt, L.; Adlard, J.; Davidson, R.; Cook, J.; Donaldson, A.; Dorkins, H.; Gregory, H.; Eason, J.; Houghton, C.; Barwell, J.; Side, L.E.; McCann, E.; Murray, A.; Peock, S.; Godwin, A.K.; Schmutzler, R.K.; Rhiem, K.; Engel, C.; Meindl, A.; Ruehl, I.; Arnold, N.; Niederacher, D.; Sutter, C.; Deissler, H.; Gadzicki, D.; Kast, K.; Preisler-Adams, S.; Varon-Mateeva, R.; Schoenbuchner, I.; Fiebig, B.; Heinritz, W.; Schafer, D.; Gevensleben, H.; Caux-Moncoutier, V.; Fassy-Colcombet, M.; Cornelis, F.; Mazoyer, S.; Leone, M.; Boutry-Kryza, N.; Hardouin, A.; Berthet, P.; Muller, D.; Fricker, J.P.; Mortemousque, I.; Pujol, P.

    2011-01-01

    ABSTRACT: INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes i

  2. Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2 (CIMBA)

    NARCIS (Netherlands)

    A. Osorio (Ana); R.L. Milne (Roger); G. Pita (G.); P. Peterlongo (Paolo); T. Heikinen (Tuomas); J. Simard (Jacques); G. Chenevix-Trench (Georgia); A.B. Spurdle (Amanda); J. Beesley (Jonathan); X.C. Chen (X. C.); S. Healey (Sue); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); F.J. Couch (Fergus); X. Wang (Xing); N.M. Lindor (Noralane); S. Manoukian (Siranoush); M. Barile (Monica); A. Viel (Alessandra); L. Tizzoni (Laura); C. Szabo (Csilla); L. Foretova (Lenka); M. Zikan (Michal); K. Claes (Kathleen); M.H. Greene (Mark); P.L. Mai (Phuong); G. Rennert (Gad); F. Lejbkowicz (Flavio); O. Barnett-Griness (Ofra); I.L. Andrulis (Irene); H. Ozcelik (Hilmi); N. Weerasooriya (Nayana); A-M. Gerdes (Anne-Marie); M. Thomassen (Mads); D. Cruger (Dorthe); M.A. Caligo (Maria); E. Friedman (Eitan); B. Kaufman (Bella); Y. Laitman (Yael); S. Cohen (Shimrit); T. Kontorovich (Tair); R. Gershoni-Baruch; E. Dagan (Efrat); H. Jernström (H.); M.S. Askmalm (Marie); B. Arver (Brita Wasteson); B. Malmer (Beatrice); S.M. Domchek (Susan); K.L. Nathanson (Katherine); J. Brunet (Joan); T. Ramon Y Cajal; D. Yannoukakos (Drakoulis); U. Hamann (Ute); F.B.L. Hogervorst (Frans); S. Verhoef; E.B.G. Garcíla (E.B. Gómez); J.T. Wijnen (Juul); A.M.W. van den Ouweland (Ans); D.F. Easton (Douglas); S. Peock (Susan); M. Cook (Margaret); C.T. Oliver (Clare); D. Frost (Debra); C. Luccarini (Craig); D.G. Evans (Gareth); F. Lalloo (Fiona); R. Eeles (Rosalind); G. Pichert (Gabriella); J. Cook (Jackie); S.V. Hodgson (Shirley); P.J. Morrison (Patrick); F. Douglas (Fiona); A.K. Godwin (Andrew); O. Sinilnikova (Olga); L. Barjhoux (Laure); D. Stoppa-Lyonnet (Dominique); V. Moncoutier (Virginie); S. Giraud (Sophie); C. Cassini (C.); L. Faivre (Laurence); F. Révillion (Françoise); J.-P. Peyrat; D.W. Muller (Danièle); J.P. Fricker (Jean Pierre); H. Lynch (Henry); E.M. John (Esther); S.S. Buys (Saundra); M.B. Daly (Mary); J.L. Hopper (John); M.-B. Terry (Mary-Beth); A. Miron (Alexander); Y. Yassin (Yosuf); D. Goldgar (David); C.F. Singer (Christian); D. Gschwantler-Kaulich (Daphne); G. Pfeiler (Georg); E. Spiess (Eberhard); T.V.O. Hansen (Thomas); O.T. Johannson (Oskar); T. Kircchoff (Tomas); K. Offit (Kenneth); K. Kosarin (Kristi); M. Piedmonte (Marion); G.C. Rodriguez (Gustavo); K. Wakeley (Katie); J.F. Boggess (John); J. Basil (Jack); P.E. Schwartz (Peter); S.V. Blank (Stephanie); A.E. Toland (Amanda); M. Montagna (Marco); C. Casella (Cinzia); E.N. Imyanitov (Evgeny); A. Allavena (Anna); R.K. Schmutzler (Rita); B. Versmold (Beatrix); C. Engel (Christoph); A. Meindl (Alfons); N. Ditsch (Nina); N. Arnold (Norbert); D. Niederacher (Dieter); H. Deiler (H.); B. Fiebig (Britta); R. Varon-Mateeva (Raymonda); D. Schaefer (D.); U.G. Froster (U.); T. Caldes (Trinidad); M. de La Hoya (Miguel); L. McGuffog (Lesley); A.C. Antoniou (Antonis); H. Nevanlinna (Heli); P. Radice (Paolo); J. Benítez (Javier)

    2009-01-01

    textabstractBackground: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. Methods:

  3. Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years : a national cohort study

    NARCIS (Netherlands)

    Saadatmand, Sepideh; Vos, Janet R; Hooning, Maartje J; Oosterwijk, Jan C; Koppert, Linetta B; de Bock, Geertruida H; Ausems, Margreet G; van Asperen, Christi J; Aalfs, Cora M; Gómez Garcia, Encarna B; Meijers-Heijboer, Hanne; Hoogerbrugge, Nicoline; Piek, Marianne; Seynaeve, Caroline; Verhoef, Cornelis; Rookus, Matti; Tilanus-Linthorst, Madeleine M

    2014-01-01

    Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised ≥60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom screen

  4. Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years : A national cohort study

    NARCIS (Netherlands)

    Saadatmand, Sepideh; Vos, Janet R.; Hooning, Maartje J.; Oosterwijk, Jan C.; Koppert, Linetta B.; de Bock, Geertruida H.; Ausems, Margreet G.; van Asperen, Christi J.; Aalfs, Cora M.; Garcia, Encarna B. Gomez; Meijers-Heijboer, Hanne; Hoogerbrugge, Nicoline; Piek, Marianne; Seynaeve, Caroline; Verhoef, Cornelis; Rookus, Matti; Tilanus-Linthorst, Madeleine M.

    2014-01-01

    Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised >= 60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom scre

  5. Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years: a national cohort study

    NARCIS (Netherlands)

    Saadatmand, S.; Vos, J.R.; Hooning, M.J.; Oosterwijk, J.C.; Koppert, L.B.; Bock, G.H. de; Ausems, M.G.; Asperen, C.J. van; Aalfs, C.M.; Garcia, E.B.; Meijers-Heijboer, H.; Hoogerbrugge, N.; Piek, M.; Seynaeve, C.; Verhoef, C.; Rookus, M.; Tilanus-Linthorst, M.M.

    2014-01-01

    Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised >/=60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom s

  6. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Vigorito, Elena; Kuchenbaecker, Karoline B; Beesley, Jonathan;

    2016-01-01

    Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 ...

  7. Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families : high cancer incidence at older age

    NARCIS (Netherlands)

    van der Kolk, Dorina M.; de Bock, Geertruida H.; Leegte, Beike K.; Schaapveld, Michael; Mourits, Marian J. E.; de Vries, J; van der Hout, Annemieke H.; Oosterwijk, Jan C.

    2010-01-01

    Accurate estimations of lifetime risks of breast and ovarian cancer are crucial for counselling women from BRCA1/2 families. We therefore determined breast and ovarian cancer penetrance in BRCA1/2 mutation families in the northern Netherlands and compared them with the incidence of cancers in the ge

  8. Impact of BRCA1/2 testing and disclosure of a positive test result on women affected and unaffected with breast or ovarian cancer

    NARCIS (Netherlands)

    van Roosmalen, MS; Stalmeier, PFM; Verhoef, LCG; Hoekstra-Weebers, JEHM; Oosterwijk, JC; Hoogerbrugge, N; Moog, U; van Daal, WAJ

    2004-01-01

    To evaluate the impact of BRCA1/2 testing and disclosure of a positive test result on women affected and unaffected with cancer. Longitudinal cohort study including women affected and unaffected with breast or ovarian cancer testing for a BRCA1/2 mutation. Data on well-being (anxiety, depression, ca

  9. Breast and ovarian cancer risks in a large series of clinically ascertained families with a high proportion of BRCA1 and BRCA2 Dutch founder mutations

    NARCIS (Netherlands)

    Brohet, Richard M.; Velthuizen, Maria E.; Hogervorst, Frans B. L.; Meijers-Heijboer, Hanne E. J.; Seynaeve, Caroline; Collee, Margriet J.; Verhoef, Senno; Ausems, Margreet G. E. M.; Hoogerbrugge, Nicoline; van Asperen, Christi J.; Garcia, Encarna Gomez; Menko, Fred; Oosterwijk, Jan C.; Devilee, Peter; van't Veer, Laura J.; van Leeuwen, Flora E.; Easton, Douglas F.; Rookus, Matti A.; Antoniou, Antonis C.

    2014-01-01

    Background BRCA1 or BRCA2 mutations confer increased risks of breast and ovarian cancer, but risks have been found to vary across studies and populations. Methods We ascertained pedigree data of 582 BRCA1 and 176 BRCA2 families and studied the variation in breast and ovarian cancer risks using a mod

  10. Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

    DEFF Research Database (Denmark)

    Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel;

    2015-01-01

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between ...

  11. "Targeting" triple-negative breast cancer: the lessons learned from BRCA1-associated breast cancers.

    Science.gov (United States)

    Nanda, Rita

    2011-04-01

    Breast cancer has long been recognized as a heterogeneous entity, with distinct subsets characterized by differences in tumor biology and response to therapy. With the advent of molecular profiling, we have gained a further appreciation of the heterogeneity of this complex disease. While the last decade has seen advances in the treatment of hormone receptor (HR) and human epidermal growth factor receptor 2/erb-B2 (HER2)-positive breast cancers, outcomes for women with estrogen receptor (ER)-, progesterone receptor (PR)-, and HER2-negative-or "triple-negative"-breast cancer (TNBC) remain poor. A better understanding of the shared biology of BRCA1-associated breast cancer and sporadic TNBC holds much promise for changing the outlook for women with this aggressive disease. This review focuses on our current understanding of the clinicopathological features of TNBC, therapeutic options and ongoing research efforts.

  12. Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Bancroft, Elizabeth K; Page, Elizabeth C; Castro, Elena;

    2014-01-01

    BACKGROUND: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening...... were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease....... These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease. PATIENT SUMMARY: In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer...

  13. Ovarian cancer risk in Polish BRCA1 mutation carriers is not associated with the prohibitin 3' untranslated region polymorphism

    Directory of Open Access Journals (Sweden)

    Benner Axel

    2008-04-01

    Full Text Available Abstract Background The variable penetrance of ovarian cancer in BRCA1 mutation carriers suggests that other genetic or environmental factors modify disease risk. The C to T transition in the 3' untranslated region of the prohibitin (PHB gene alters mRNA function and has recently been shown to be associated with hereditary breast cancer risk in Polish women harbouring BRCA1 mutations. Methods To investigate whether the PHB 3'UTR polymorphism also modifies hereditary ovarian cancer risk, we performed a case-control study among Polish women carrying one of the three common founder mutations (5382insC, 300 T > G, 4154delA including 127 ovarian cases and 127 unaffected controls who had both breasts and ovaries intact. Controls were matched to cases by year of birth and BRCA1 mutation. Genotyping analysis was performed using PCR-based restriction fragment length polymorphism analysis. Odds ratios (OR were calculated using conditional and penalized univariable and multivariable logistic regression. Results A comparison of the genotype frequencies between cases and controls revealed no association of the PHB 3'UTR _CT+TT genotypes with ovarian cancer risk (ORadj 1.34; 95% CI, 0.59–3.11. Conclusion Our data suggest that the PHB 3'UTR polymorphism does not modify ovarian cancer risk in women carrying one of the three Polish BRCA1 founder mutations.

  14. Low incidence of germline mutation in BRCA1 Exon 11 among early-onset and familial Filipino breast cancer patients

    International Nuclear Information System (INIS)

    Breast cancer susceptibility gene, type 1 (BRCA1) has been thought to be responsible for about 45% of families with multiple breast carcinoma cases and for more than 80% of hereditary breast and ovarian cancer (HBOC) families. About 61-75% of the reported distinct alterations that result in truncated protein products have been found in exon 11 which comprises 61% (3427bp) of the coding sequence of BRCA1(5592bp). Protein truncation test (PTT) has become a popular method as an efficient means of screening mutations in a coding sequence that lead to a truncated protein product. In this study, 34 early-onset and/or familial breast cancer (FBC) patients were investigated. Twenty-six patients are early-onset B(o)C cases (diagnosed≤40 years old), 14 of which have familiality of the disease. Among the 8 patients that have been diagnosed above 40 years old, 7 have familial clustering. Through radioactive PTT analysis of the 34 BC cases in a 5-20% denaturing gradient polyacrylamide gel, we found only one mutation in exon 11 having a 29.7 kDa truncated protein product. Our results corroborate the findings of a recently reported study of unselected incident breast cancer cases in the Philippines where the prevalence of BRCA1 mutation is also low. This would, however, be the second documented mutation in BRCA1 exon 11 in a Filipino BC patient since 1998. (author)

  15. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    Peterlongo, P.; Chang-Claude, J.; Moysich, K.B.; Rudolph, A.; Schmutzler, R.K.; Simard, J.; Soucy, P.; Eeles, R.A.; Easton, D.F.; Hamann, U.; Wilkening, S.; Chen, B.; Rookus, M.A.; Schmidt, M.K.; Baan, F.H. van der; Spurdle, A.B.; Walker, L.C.; Lose, F.; Maia, A.T.; Montagna, M.; Matricardi, L.; Lubinski, J.; Jakubowska, A.; Garcia, E.B.; Olopade, O.I.; Nussbaum, R.L.; Nathanson, K.L.; Domchek, S.M.; Rebbeck, T.R.; Arun, B.K.; Karlan, B.Y.; Orsulic, S.; Lester, J.; Chung, W.K.; Miron, A.; Southey, M.C.; Goldgar, D.E.; Buys, S.S.; Janavicius, R.; Dorfling, C.M.; Rensburg, E.J. van; Ding, Y.C.; Neuhausen, S.L.; Hansen, T.V.; Gerdes, A.M.; Ejlertsen, B.; Jonson, L.; Osorio, A.; Martinez-Bouzas, C.; Benitez, J.; Conway, E.E.; Blazer, K.R.; Weitzel, J.N.; Manoukian, S.; Peissel, B.; Zaffaroni, D.; Scuvera, G.; Barile, M.; Ficarazzi, F.; Mariette, F.; Fortuzzi, S.; Viel, A.; Giannini, G.; Papi, L.; Martayan, A.; Tibiletti, M.G.; Radice, P.; Vratimos, A.; Fostira, F.; Garber, J.E.; Donaldson, A.; Brewer, C.; Foo, C.; Evans, D.G.; Frost, D.; Eccles, D.; Brady, A.; Cook, J.; Tischkowitz, M.; Adlard, J.; Barwell, J.; Walker, L.; Izatt, L.; Side, L.E.; Kennedy, M.J.; Rogers, M.T.; Porteous, M.E.; Morrison, P.J.; Platte, R.; Davidson, R.; Hodgson, S.V.; Ellis, S.; Cole, T.; Godwin, A.K.; Claes, K.; Maerken, T. Van; Meindl, A.; Gehrig, A.; Sutter, C.; Engel, C.; Hoogerbrugge, N.

    2015-01-01

    BACKGROUND: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In thi

  16. Prevalence of BRCA1 and BRCA2 Germline Mutations in Breast Cancer Women of Multiple Ethnic Region in Northwest China

    NARCIS (Netherlands)

    Ou, Jianghua; Wu, Tao; Sijmons, Rolf; Ni, Duo; Xu, Wenting; Upur, Halmurat

    2013-01-01

    Purpose: The aim of this study is to further understand the status of BRCA1 and BRCA2 mutation among Chinese high-risk breast cancer patients in multiple-ethnic regions of China. Methods: A total of 79 blood samples of high-risk breast cancer patients from Xinjiang Uyghur autonomous region were anal

  17. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    S.J. Ramus (Susan); C. Kartsonaki (Christiana); S.A. Gayther (Simon); P.D.P. Pharoah (Paul); O. Sinilnikova (Olga); J. Beesley (Jonathan); G. Chenevix-Trench (Georgia); L. McGuffog (Lesley); S. Healey (Sue); F.J. Couch (Fergus); X. Wang (Xing); Z. Fredericksen (Zachary); P. Peterlongo (Paolo); S. Manoukian (Siranoush); B. Peissel (Bernard); D. Zaffaroni (D.); G. Roversi (Gaia); M. Barile (Monica); A. Viel (Alessandra); A. Allavena (Anna); L. Ottini (Laura); L. Papi (Laura); V. Gismondi (Viviana); F. Capra (Fabio); P. Radice (Paolo); M.H. Greene (Mark); P.L. Mai (Phuong); I.L. Andrulis (Irene); G. Glendon (Gord); H. Ozcelik (Hilmi); M. Thomassen (Mads); A-M. Gerdes (Anne-Marie); T.A. Kruse (Torben); D. Cruger (Dorthe); U.B. Jensen; M.A. Caligo (Maria); H. Olsson (Hkan); U. Kristoffersson (Ulf); A. Lindblom (Annika); B. Arver (Brita Wasteson); P. Karlsson (Per); M. Stenmark-Askmalm (M.); Å. Borg (Åke); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); K.L. Nathanson (Katherine); S.M. Domchek (Susan); A. Jakubowska (Anna); J. Lubinski (Jan); T. Huzarski (Tomasz); T. Byrski (Tomasz); J. Gronwald (Jacek); B. Górski (Bohdan); C. Cybulski (Cezary); T. Dbniak (Tadeusz); A. Osorio (Ana); M. Durán (Mercedes); M.-I. Tejada; J. Benitez (Javier); U. Hamann (Ute); M.A. Rookus (Matti); S. Verhoef; M.A. Tilanus-Linthorst (Madeleine); M.P. Vreeswijk (Maaike); D. Bodmer (Danielle); M.G.E.M. Ausems (Margreet); T.A.M. van Os (Theo); M.J. Blok (Marinus); H. Meijers-Heijboer (Hanne); S. Peock (Susan); M. Cook (Margaret); C.T. Oliver (Clare); D. Frost (Debra); A.M. Dunning (Alison); D.G. Evans (Gareth); R. Eeles (Rosalind); G. Pichert (Gabriella); T.J. Cole (Trevor); S.V. Hodgson (Shirley); C. Brewer (Carole); P.J. Morrison (Patrick); M.E. Porteous (Mary); M.J. Kennedy (John); M.T. Rogers (Mark); L. Side (Lucy); A. Donaldson (Alan); H. Gregory (Helen); A.K. Godwin (Andrew); D. Stoppa-Lyonnet (Dominique); V. Moncoutier (Virginie); L. Castera (Laurent); S. Mazoyer (Sylvie); L. Barjhoux (Laure); V. Bonadona (Valérie); D. Leroux (Dominique); L. Faivre (Laurence); R. Lidereau (Rosette); C. Nogues (Catherine); Y.-J. Bignon (Yves-Jean); F. Prieur (Fabienne); M.-A. Collonge-Rame; L. Vénat-Bouvet (Laurence); S. Fert-Ferrer (Sandra); A. Miron (Alexander); S.S. Buys (Saundra); J. Hopper (John); M.J. Daly (Mark); E.M. John (Esther); M-B. Terry (Mary-beth); D. Goldgar (David); T.V.O. Hansen (Thomas); L. Jønson (Lars); B.A. Agnarsson (Bjarni); K. Offit (Kenneth); T. Kircchoff (Tomas); J. Vijai (Joseph); A. Dutra-Clarke (Ana); J.A. Przybylo (Jennifer); M. Montagna (Marco); C. Casella (Cinzia); E.N. Imyanitov (Evgeny); R. Janavicius (Ramunas); I. Blanco (Ignacio); C. Lazaro (Conxi); K.B. Moysich (Kirsten); B.Y. Karlan (Beth); J. Gross (Jenny); M.S. Beattie (Mary); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); A. Meindl (Alfons); I. Ruehl (Ina); B. Fiebig (Britta); C. Sutter (Christian); N. Arnold (Norbert); H. Deissler (Helmut); R. Varon-Mateeva (Raymonda); K. Kast (Karin); D. Niederacher (Dieter); D. Gadzicki (Dorothea); B. Ejlertsen (Bent); T. Caldes (Trinidad); M. de La Hoya (Miguel); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); J. Simard (Jacques); P. Soucy (Penny); A.B. Spurdle (Amanda); H. Holland (Helene); D.F. Easton (Douglas); A.C. Antoniou (Antonis); C.J. van Asperen (Christi)

    2011-01-01

    textabstractBackground Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer suscep

  18. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B;

    2015-01-01

    BACKGROUND: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In ...

  19. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    Ramus, S.J.; Antoniou, A.C.; Kuchenbaecker, K.B.; Soucy, P.; Beesley, J.; Chen, X.; McGuffog, L.; Sinilnikova, O.M.; Healey, S.; Barrowdale, D.; Lee, A.; Thomassen, M.; Gerdes, A.M.; Kruse, T.A.; Jensen, U.B.; Skytte, A.B.; Caligo, M.A.; Liljegren, A.; Lindblom, A.; Olsson, H.; Kristoffersson, U.; Stenmark-Askmalm, M.; Melin, B.; Swe, B.; Domchek, S.M.; Nathanson, K.L.; Rebbeck, T.R.; Jakubowska, A.; Lubinski, J.; Jaworska, K.; Durda, K.; Zlowocka, E.; Gronwald, J.; Huzarski, T.; Byrski, T.; Cybulski, C.; Toloczko-Grabarek, A.; Osorio, A.; Benitez, J.; Duran, M.; Tejada, M.I.; Hamann, U.; Rookus, M.; Leeuwen, F.E. van; Aalfs, C.M.; Meijers-Heijboer, H.E.; Asperen, C.J. van; Roozendaal, K.E. van; Hoogerbrugge-van der Linden, N.; Collee, J.M.; Kriege, M.; Luijt, R.B. van der; Hebon, .; Embrace, .; Peock, S.; Frost, D.; Ellis, S.D.; Platte, R.; Fineberg, E.; Evans, D.G.; Lalloo, F.; Jacobs, C.; Eeles, R.; Adlard, J.; Davidson, R.; Eccles, D.; Cole, T.; Cook, J.; Paterson, J.; Douglas, F.; Brewer, C.; Hodgson, S.; Morrison, P.J.; Walker, L.; Porteous, M.E.; Kennedy, M.J.; Pathak, H.; Godwin, A.K.; Stoppa-Lyonnet, D.; Caux-Moncoutier, V.; Pauw, A. de; Gauthier-Villars, M.; Mazoyer, S.; Leone, M.; Calender, A.; Lasset, C.; Bonadona, V.; Hardouin, A.; Berthet, P.; Bignon, Y.J.; Uhrhammer, N.; Faivre, L.; Loustalot, C.; Gemo, .; Buys, S.; Daly, M.; Miron, A.; Terry, M.B.; Chung, W.K.; John, E.M.; Ligtenberg, M.J.

    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

  20. Is there a correlation between the structure of hair and breast cancer or BRCA1/2 mutations?

    Science.gov (United States)

    Laaziri, Khalid; Sutton, M.; Ghadirian, P.; Scott, A. S.; Paradis, A.-J.; Tonin, P. N.; Foulkes, W. D.

    2002-05-01

    It has been suggested that the small angle x-ray scattering (SAXS) pattern of human hair can be used to diagnose breast cancer and possibly to identify BRCA1/2 mutation carriers, who are at significantly elevated risk for developing breast cancer. In particular, the presence of a diffuse ring in the SAXS pattern was said to be diagnostic of either breast cancer or an increased risk thereof. To test this hypothesis, we measured SAXS from the pubic hair of 56 subjects with known BRCA1/2 and breast cancer status. We found that there is no clear association between the pattern of SAXS seen in human pubic hair and the risk of breast cancer or the presence of BRCA1/2 mutations. The possible use of SAXS to diagnose cancer remains conjectural, but this and previous studies do not suggest that SAXS can be used as a reliable method of identifying either BRCA1/2 mutation carriers or women who have had breast cancer.

  1. Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    NARCIS (Netherlands)

    Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B.; Rudolph, Anja; Schmutzler, Rita K.; Simard, Jacques; Soucy, Penny; Eeles, Rosalind A.; Easton, Douglas F.; Hamann, Ute; Wilkening, Stefan; Chen, Bowang; Rookus, Matti A.; Schmidt, MarjankaK.; van der Baan, Frederieke H.; Spurdle, Amanda B.; Walker, Logan C.; Lose, Felicity; Maia, Ana-Teresa; Montagna, Marco; Matricardi, Laura; Lubinski, Jan; Jakubowska, Anna; Garcia, Encarna B. Gomez; Olopade, Olufunmilayo I.; Nussbaum, Robert L.; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Arun, Banu K.; Karlan, Beth Y.; Orsulic, Sandra; Lester, Jenny; Chung, Wendy K.; Miron, Alex; Southey, Melissa C.; Goldgar, David E.; Buys, Saundra S.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Ding, Yuan Chun; Neuhausen, Susan L.; Hansen, Thomas V. O.; Gerdes, Anne-Marie; Ejlertsen, Bent; Jonson, Lars; Osorio, Ana; Martinez-Bouzas, Cristina; Benitez, Javier; Conway, Edye E.; Blazer, Kathleen R.; Weitzel, Jeffrey N.; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Barile, Monica; Ficarazzi, Filomena; Mariette, Frederique; Fortuzzi, Stefano; Viel, Alessandra; Giannini, Giuseppe; Papi, Laura; Martayan, Aline; Tibiletti, Maria Grazia; Radice, Paolo; Vratimos, Athanassios; Fostira, Florentia; Garber, Judy E.; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D. Gareth R.; Frost, Debra; Eccles, Diana; Brady, Angela; Cook, Jackie; Tischkowitz, Marc; Adlard, Julian; Barwell, Julian; Walker, Lisa; Izatt, Louise; Side, Lucy E.; Kennedy, M. John; Rogers, Mark T.; Porteous, Mary E.; Morrison, Patrick J.; Platte, Radka; Davidson, Rosemarie; Hodgson, Shirley V.; Ellis, Steve; Cole, Trevor; Godwin, Andrew K.; Claes, Kathleen; Van Maerken, Tom; Meindl, Alfons; Gehrig, Andrea; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Plendl, Hansjoerg; Kast, Karin; Rhiem, Kerstin; Ditsch, Nina; Arnold, Norbert; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Wang-Gohrke, Shan; Bressac-de Paillerets, Brigitte; Buecher, Bruno; Delnatte, Capucine; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Coupier, Isabelle; Barjhoux, Laure; Venat-Bouvet, Laurence; Golmard, Lisa; Boutry-Kryza, Nadia; Sinilnikova, Olga M.; Caron, Olivier; Pujol, Pascal; Mazoyer, Sylvie; Belotti, Muriel; Piedmonte, Marion; Friedlander, Michael L.; Rodriguez, Gustavo C.; Copeland, Larry J.; de la Hoya, Miguel; Perez Segura, Pedro; Nevanlinna, Heli; Aittomaeki, Kristiina; van Os, Theo A. M.; Meijers-Heijboer, Hanne E. J.; van der Hout, Annemarie H.; Vreeswijk, Maaike P. G.; Hoogerbrugge, Nicoline; Ausems, Margreet G. E. M.; van Doorn, Helena C.; Collee, J. Margriet; Olah, Edith; Diez, Orland; Blanco, Ignacio; Lazaro, Conxi; Brunet, Joan; Feliubadalo, Lidia; Cybulski, Cezary; Gronwald, Jacek; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Sukiennicki, Grzegorz; Arason, Adalgeir; Chiquette, Jocelyne; Teixeira, Manuel R.; Olswold, Curtis; Couch, Fergus J.; Lindor, Noralane M.; Wang, Xianshu; Szabo, Csilla I.; Offit, Kenneth; Corines, Marina; Jacobs, Lauren; Robson, Mark E.; Zhang, Liying; Joseph, Vijai; Berger, Andreas; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng M.; Phelan, Catherine M.; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Mulligan, Anna Marie; Glendon, Gord; Tchatchou, Sandrine; Andrulis, Irene L.; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Thomassen, Mads; Jensen, Uffe Birk; Laitman, Yael; Rantala, Johanna; von Wachenfeldt, Anna; Ehrencrona, Hans; Askmalm, Marie Stenmark; Borg, Ake; Kuchenbaecker, Karoline B.; McGuffog, Lesley; Barrowdale, Daniel; Healey, Sue; Lee, Andrew; Pharoah, Paul D. P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Friedman, Eitan; Oosterwijk, Jan C.; van der Hout, Annemarie H.; Ligtenberg, Jakobus J. M.

    2015-01-01

    Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In thi

  2. Candidate genetic modifiers for breast and ovarian cancer risk inBRCA1andBRCA2 mutation carriers

    NARCIS (Netherlands)

    P. Peterlongo (Paolo); J. Chang-Claude (Jenny); K.B. Moysich (Kirsten); A. Rudolph (Anja); R.K. Schmutzler (Rita); J. Simard (Jacques); P. Soucy (Penny); R. Eeles (Rosalind); D.F. Easton (Douglas); U. Hamann (Ute); S. Wilkening (Stefan); B. Chen (Bowang); M.A. Rookus (Matti); M.K. Schmidt (Marjanka K.); F.H. Van Der Baan (Frederieke H.); A.B. Spurdle (Amanda); L.C. Walker (Logan); F. Lose (Felicity); A.-T. Maia (Ana-Teresa); M. Montagna (Marco); L. Matricardi (Laura); J. Lubinski (Jan); A. Jakubowska (Anna); E.B.G. Garcia; O.I. Olopade (Olofunmilayo); R.L. Nussbaum (Robert L.); K.L. Nathanson (Katherine); S.M. Domchek (Susan); R. Rebbeck (Timothy); B.K. Arun (Banu); B. Karlan; S. Orsulic (Sandra); K.J. Lester (Kathryn); W.K. Chung (Wendy K.); A. Miron (Alexander); M.C. Southey (Melissa); D. Goldgar (David); S.S. Buys (Saundra); R. Janavicius (Ramunas); C.M. Dorfling (Cecilia); E.J. van Rensburg (Elizabeth); Y.C. Ding (Yuan Chun); S.L. Neuhausen (Susan); T.V.O. Hansen (Thomas); A.-M. Gerdes (Anne-Marie); B. Ejlertsen (Bent); L. Jønson (Lars); A. Osorio (Ana); C. Martínez-Bouzas (Cristina); J. Benítez (Javier); E.E. Conway (Edye E.); K.R. Blazer (Kathleen R.); J.N. Weitzel (Jeffrey); S. Manoukian (Siranoush); B. Peissel (Bernard); D. Zaffaroni (Daniela); G. Scuvera (Giulietta); M. Barile (Monica); F. Ficarazzi (Filomena); F. Mariette (F.); S. Fortuzzi (S.); A. Viel (Alessandra); G. Giannini (Giuseppe); L. Papi (Laura); A. Martayan (Aline); M.G. Tibiletti (Maria Grazia); P. Radice (Paolo); A. Vratimos (Athanassios); F. Fostira (Florentia); J. Garber (Judy); A. Donaldson (Alan); C. Brewer (Carole); C. Foo (Claire); D.G. Evans (Gareth); D. Frost (Debra); D. Eccles (Diana); A. Brady (A.); J. Cook (Jackie); M. Tischkowitz (Marc); L. Adlard; J. Barwell (Julian); L.J. Walker (Lisa); L. Izatt (Louise); L. Side (Lucy); M.J. Kennedy (John); M.T. Rogers (Mark); M.E. Porteous (Mary); P.J. Morrison (Patrick); R. Platte (Radka); R. Davidson (Rosemarie); S. Hodgson (Shirley); S.D. Ellis (Steve); T. Cole (Trevor); A.K. Godwin (Andrew); K.B.M. Claes (Kathleen B.M.); T. Van Maerken (Tom); A. Meindl (Alfons); P.A. Gehrig (Paola A.); C. Sutter (Christian); C. Engel (Christoph); D. Niederacher (Dieter); D. Steinemann (Doris); H. Plendl (Hansjoerg); K. Kast (Karin); K. Rhiem (Kerstin); N. Ditsch (Nina); N. Arnold (Norbert); R. Varon-Mateeva (Raymonda); B. Wapenschmidt (Barbara); S. Wang-Gohrke (Shan); B. Bressac-de Paillerets (Brigitte); B. Buecher (Bruno); C.D. Delnatte (Capucine); C. Houdayer (Claude); D. Stoppa-Lyonnet (Dominique); F. Damiola (Francesca); I. Coupier (Isabelle); L. Barjhoux (Laure); L. Vénat-Bouvet (Laurence); L. Golmard (Lisa); N. Boutry-Kryza (N.); O. Sinilnikova (Olga); O. Caron (Olivier); P. Pujol (Pascal); S. Mazoyer (Sylvie); M. Belotti (Muriel); M. Piedmonte (Marion); M.L. Friedlander (Michael L.); G. Rodriguez (Gustavo); L.J. Copeland (Larry J.); M. de La Hoya (Miguel); P. Perez-Segura (Pedro); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); T.A.M. van Os (Theo); E.J. Meijers-Heijboer (Hanne); A.H. van der Hout (Annemarie); M.P. Vreeswijk (Maaike); N. Hoogerbrugqe (N.); M.G.E.M. Ausems (Margreet); H.C. van Doorn (Helena); J.M. Collee (Margriet); E. Olah; O. Díez (Orland); I. Blanco (Ignacio); C. Lazaro (Conxi); J. Brunet (Joan); L. Feliubadaló (L.); C. Cybulski (Cezary); J. Gronwald (Jacek); K. Durda (Katarzyna); K. Jaworska-Bieniek (Katarzyna); G. Sukiennicki (Grzegorz); A. Arason (Adalgeir); J. Chiquette (Jocelyne); P.J. Teixeira; C. Olswold (Curtis); F.J. Couch (Fergus); N.M. Lindor (Noralane); X. Wang (X.); C. Szabo (Csilla); K. Offit (Kenneth); M. Corines (Marina); L. Jacobs (Lauren); M.E. Robson (Mark E.); L. Zhang (Lingling); V. Joseph (Vijai); A. Berger (Andreas); C.F. Singer (Christian); C. Rappaport (Christine); D.G. Kaulich (Daphne Gschwantler); G. Pfeiler (Georg); M.-K. Tea; C. Phelan (Catherine); M.H. Greene (Mark); P.L. Mai (Phuong); G. Rennert (Gad); A.-M. Mulligan (Anna-Marie); G. Glendon (Gord); S. Tchatchou (Sandrine); I.L. Andrulis (Irene); A.E. Toland (Amanda); A. Bojesen (Anders); I.S. Pedersen (Inge Sokilde); M. Thomassen (Mads); U.B. Jensen; Y. Laitman (Yael); J. Rantala (Johanna); A. von Wachenfeldt (Anna); H. Ehrencrona (Hans); M.S. Askmalm (Marie); Å. Borg (Åke); K.B. Kuchenbaecker (Karoline); L. McGuffog (Lesley); D. Barrowdale (Daniel); S. Healey (Sue); A. Lee (Andrew); P.D.P. Pharoah (Paul D.P.); G. Chenevix-Trench (Georgia); A.C. Antoniou (Antonis C.); E. Friedman (Eitan)

    2015-01-01

    textabstractBackground: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying fac

  3. PGD for hereditary breast and ovarian cancer : the route to universal tests for BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    Drusedau, Marion; Dreesen, Jos C.; Derks-Smeets, Inge; Coonen, Edith; van Golde, Ron; van Echten-Arends, Jannie; Kastrop, Peter M. M.; Blok, Marinus J.; Gomez-Garcia, Encarna; Geraedts, Joep P.; Smeets, Hubert J.; de Die-Smulders, Christine E.; Paulussen, Aimee D.

    2013-01-01

    Preimplantation Genetic Diagnosis (PGD) is a method of testing in vitro embryos as an alternative to prenatal diagnosis with possible termination of pregnancy in case of an affected child. Recently, PGD for hereditary breast and ovarian cancer caused by BRCA1 and BRCA2 mutations has found its way in

  4. Identification of a Danish breast/ovarian cancer family double heterozygote for BRCA1 and BRCA2 mutations

    DEFF Research Database (Denmark)

    Steffensen, Ane Y; Jønson, Lars; Ejlertsen, Bent;

    2010-01-01

    (RT)-PCR analysis revealed that the BRCA2 mutation results in skipping of exon 7, thereby introducing a frameshift and a premature stop codon. We therefore classify the mutation as disease causing. Since the BRCA1 Arg1699Gln mutation is also suggested to be disease-causing, we consider this family...

  5. Increased Chromosomal Radiosensitivity in Women Carrying BRCA1/BRCA2 Mutations Assessed With the G2 Assay

    International Nuclear Information System (INIS)

    Purpose: Several in vitro studies suggest that BRCA1 and BRCA2 mutation carriers present increased sensitivity to ionizing radiation. Different assays for the assessment of deoxyribonucleic acid double-strand break repair capacity have been used, but results are rather inconsistent. Given the concerns about the possible risks of breast screening with mammography in mutation carrier women and the potentially damaging effects of radiotherapy, the purpose of this study was to further investigate the radiosensitivity of this population. Methods and Materials: The G2 chromosomal radiosensitivity assay was used to assess chromosomal breaks in lymphocyte cultures after exposure to 1 Gy. A group of familiar breast cancer patients carrying a mutation in the BRCA1 or BRCA2 gene (n = 15) and a group of healthy mutation carriers (n = 5) were investigated and compared with a reference group of healthy women carrying no mutation (n = 21). Results: BRCA1 and BRCA2 mutation carriers had a significantly higher number of mean chromatid breaks per cell (p = 0.006) and a higher maximum number of breaks (p = 0.0001) as compared with their matched controls. Both healthy carriers and carriers with a cancer history were more radiosensitive than controls (p = 0.002 and p = 0.025, respectively). Age was not associated with increased radiosensitivity (p = 0.868). Conclusions: Our results indicate that BRCA1 and BRCA2 mutation carriers show enhanced radiosensitivity, presumably because of the involvement of the BRCA genes in deoxyribonucleic acid repair and cell cycle control mechanisms.

  6. Survival benefit in women with BRCA1 mutation or familial risk in the MRI screening study (MRISC)

    NARCIS (Netherlands)

    Saadatmand, Sepideh; Obdeijn, Inge-Marie; Rutgers, Emiel J.; Oosterwijk, Jan C.; Tollenaar, Rob A.; Woldringh, Gwendolyn H.; Bergers, Elisabeth; Verhoef, Cornelis; Heijnsdijk, Eveline A.; Hooning, Maartje J.; de Koning, Harry J.; Tilanus-Linthorst, Madeleine M.

    2015-01-01

    Adding MRI to annual mammography screening improves early breast cancer detection in women with familial risk or BRCA1/2 mutation, but breast cancer specific metastasis free survival (MFS) remains unknown. We compared MFS of patients from the largest prospective MRI Screening Study (MRISC) with 1:1

  7. Breast cancer screening in BRCA1 and BRCA2 mutation carriers after risk reducing salpingo-oophorectomy

    NARCIS (Netherlands)

    Fakkert, I.E.; Jansen, L.; Meijer, K.; Kok, Theo; Oosterwijk, J.C.; Mourits, M.J.E.; de Bock, G.H.

    2011-01-01

    Breast cancer screening is offered to BRCA1 and BRCA2 mutation carriers from the age of 25 years because of their increased risk of breast cancer. As ovarian cancer screening is not effective, risk-reducing salpingho-oophorectomy (RRSO) is offered after child bearing age. RRSO before menopause reduc

  8. Exome mutation burden predicts clinical outcome in ovarian cancer carrying mutated BRCA1 and BRCA2 genes

    DEFF Research Database (Denmark)

    Birkbak, Nicolai Juul; Kochupurakkal, Bose; Gonzalez-Izarzugaza, Jose Maria;

    2013-01-01

    BRCA HGSOC. Our observations are consistent with the new concept that BRCA1/2 critically regulate error-free repair of nucleotide damage to suppress mutation formation, and may imply an activation of alternative repair mechanism(s) capable of bypassing the BRCA defect and restoring error-free DNA repair....

  9. No evidence of increased breast cancer risk for proven noncarriers from BRCA1 and BRCA2 families

    DEFF Research Database (Denmark)

    Nielsen, Henriette Roed; Petersen, Janne; Krogh, Lotte;

    2016-01-01

    In families screened for mutations in the BRCA1 or BRCA2 genes and found to have a segregating mutation the breast cancer risk for women shown not to carry the family-specific mutation might be at above "average" risk. We assessed the risk of breast cancer in a clinic based cohort of 725 female...

  10. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Ramus, Susan J; Kartsonaki, Christiana; Gayther, Simon A;

    2011-01-01

    Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-w...

  11. Genetic Variation at 9p22.2 and Ovarian Cancer Risk for BRCA1 and BRCA2 Mutation Carriers

    NARCIS (Netherlands)

    Ramus, Susan J.; Kartsonaki, Christiana; Gayther, Simon A.; Pharoah, Paul D. P.; Sinilnikova, Olga M.; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Healey, Sue; Couch, Fergus J.; Wang, Xianshu; Fredericksen, Zachary; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Roversi, Gaia; Barile, Monica; Viel, Alessandra; Allavena, Anna; Ottini, Laura; Papi, Laura; Gismondi, Viviana; Capra, Fabio; Radice, Paolo; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria Adelaide; Olsson, Hakan; Kristoffersson, Ulf; Lindblom, Annika; Arver, Brita; Karlsson, Per; Askmalm, Marie Stenmark; Borg, Ake; Neuhausen, Susan L.; Ding, Yuan Chun; Nathanson, Katherine L.; Domchek, Susan M.; Jakubowska, Anna; Lubinski, Jan; Huzarski, Tomasz; Byrski, Tomasz; Gronwald, Jacek; Gorski, Bohdan; Cybulski, Cezary; Debniak, Tadeusz; Osorio, Ana; Duran, Mercedes; Tejada, Maria-Isabel; Benitez, Javier; Hamann, Ute; Rookus, Matti A.; Verhoef, Senno; Tilanus-Linthorst, Madeleine A.; Vreeswijk, Maaike P.; Bodmer, Danielle; Ausems, Margreet G. E. M.; van Os, Theo A.; Asperen, Christi J.; Blok, Marinus J.; Meijers-Heijboer, Hanne E. J.; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Dunning, Alison M.; Evans, D. Gareth; Eeles, Ros; Pichert, Gabriella; Cole, Trevor; Hodgson, Shirley; Brewer, Carole; Morrison, Patrick J.; Porteous, Mary; Kennedy, M. John; Rogers, Mark T.; Side, Lucy E.; Donaldson, Alan; Gregory, Helen; Godwin, Andrew; Stoppa-Lyonnet, Dominique; Moncoutier, Virginie; Castera, Laurent; Mazoyer, Sylvie; Barjhoux, Laure; Bonadona, Valerie; Leroux, Dominique; Faivre, Laurence; Lidereau, Rosette; Nogues, Catherine; Bignon, Yves-Jean; Prieur, Fabienne; Collonge-Rame, Marie-Agnes; Venat-Bouvet, Laurence; Fert-Ferrer, Sandra; Miron, Alex; Buys, Saundra S.; Hopper, John L.; Daly, Mary B.; John, Esther M.; Terry, Mary Beth; Goldgar, David; Hansen, Thomas V. O.; Jonson, Lars; Ejlertsen, Bent; Agnarsson, Bjarni A.; Offit, Kenneth; Kirchhoff, Tomas; Vijai, Joseph; Dutra-Clarke, Ana V. C.; Przybylo, Jennifer A.; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny N.; Janavicius, Ramunas; Blanco, Ignacio; Lazaro, Conxi; Moysich, Kirsten B.; Karlan, Beth Y.; Gross, Jenny; Beattie, Mary S.; Schmutzler, Rita; Wappenschmidt, Barbara; Meindl, Alfons; Ruehl, Ina; Fiebig, Britta; Sutter, Christian; Arnold, Norbert; Deissler, Helmut; Varon-Mateeva, Raymonda; Kast, Karin; Niederacher, Dieter; Gadzicki, Dorothea; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomaeki, Kristiina; Simard, Jacques; Soucy, Penny; Spurdle, Amanda B.; Holland, Helene; Chenevix-Trench, Georgia; Easton, Douglas F.; Antoniou, Antonis C.

    2011-01-01

    Background Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A

  12. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

    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 ...

  13. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Ramus, Susan J; Kartsonaki, Christiana; Gayther, Simon A;

    2011-01-01

    Background Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility....

  14. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Mulligan, Anna Marie; Couch, Fergus J; Barrowdale, Daniel;

    2011-01-01

    ABSTRACT: INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtype...

  15. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Candido-dos-Reis, Francisco J; Song, Honglin; Goode, Ellen L;

    2015-01-01

    PURPOSE: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. EXPERIMENTAL DESIGN: We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4,3...

  16. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Spurdle, Amanda B; Sinilnikova, Olga M;

    2008-01-01

    Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorp...

  17. HIF-1 alpha Overexpression in Ductal Carcinoma In Situ of the Breast in BRCA1 and BRCA2 Mutation Carriers

    NARCIS (Netherlands)

    van der Groep, Petra; van Diest, Paul J.; Smolders, Yvonne H. C. M.; Ausems, Margreet G. E. M.; van der Luijt, Rob B.; Menko, Fred H.; Bart, Joost; de Vries, Elisabeth G. E.; van der Wall, Elsken

    2013-01-01

    Recent studies have revealed that BRCA1 and BRCA2 germline mutation-related breast cancers show frequent overexpression of hypoxia inducible factor-1 alpha (HIF-1 alpha), the key regulator of the hypoxia response. However, the question remained whether hypoxia is a late stage bystander or a true car

  18. BRCA1/2 testing in newly diagnosed breast and ovarian cancer patients without prior genetic counselling: the DNA-BONus study.

    Science.gov (United States)

    Høberg-Vetti, Hildegunn; Bjorvatn, Cathrine; Fiane, Bent E; Aas, Turid; Woie, Kathrine; Espelid, Helge; Rusken, Tone; Eikesdal, Hans Petter; Listøl, Wenche; Haavind, Marianne T; Knappskog, Per M; Haukanes, Bjørn Ivar; Steen, Vidar M; Hoogerbrugge, Nicoline

    2016-06-01

    Germline BRCA1/2 testing of breast and ovarian cancer patients is growing rapidly as the result affects both treatment and cancer prevention in patients and relatives. Through the DNA-BONus study we offered BRCA1/2 testing and familial risk assessment to all new patients with breast (N=893) or ovarian (N=122) cancer diagnosed between September 2012 and April 2015, irrespective of family history or age, and without prior face-to-face genetic counselling. BRCA1/2 testing was accepted by 405 (45.4%) and 83 (68.0%) of the patients with breast or ovarian cancer, respectively. A pathogenic BRCA1/2 variant was found in 7 (1.7%) of the breast cancer patients and 19 (22.3%) of the ovarian cancer patients. In retrospect, all BRCA1/2 mutation carriers appeared to fulfill current criteria for BRCA1/2 testing. Hospital Anxiety and Depression Scale (HADS) scores showed that the mean levels of anxiety and depression were comparable to those reported for breast and gynecological cancer patients in general, with a significant drop in anxiety symptoms during a 6-month follow-up period, during which the test result was forwarded to the patients. These results show that BRCA1/2 testing is well accepted in newly diagnosed breast and ovarian cancer patients. Current test criteria based on age and family history are sufficient to identify most BRCA1/2 mutation carriers among breast cancer patients. We recommend germline BRCA1/2 testing in all patients with epithelial ovarian cancer because of the high prevalence of pathogenic BRCA1/2 variants. PMID:26350514

  19. BRCA1 and ERCC1 mRNA levels are associated with lymph node metastasis in Chinese patients with colorectal cancer

    International Nuclear Information System (INIS)

    Although both excision repair cross-complementing group 1 (ERCC1) and breast cancer susceptibility gene 1 (BRCA1) can be effective biomarkers for chemosensitivity in primary malignant tumors, their applicability to metastases is poorly understood. Here, ERCC1 and BRCA1, which are linked to lymph node metastasis (LNM) in colorectal cancer (CRC), were evaluated in primary CRC samples from Chinese patients with LNM (LNM CRC) or without LNM (non-LNM CRC). mRNA levels of ERCC1 and BRCA1 in CRC samples, and their relationships to primary CRC and LNM, were also examined. Differences in BRCA1 and ERCC1 gene expression between primary CRC with or without LNM were assessed in CRC samples from 120 Chinese patients, using real-time polymerase chain reaction. Relationships between ERCC1 and BRCA1 expression and clinicopathological parameters and prognoses were also examined. ERCC1 and BRCA1 were significantly down-regulated in LNM CRC compared with non-LNM CRC. Down-expression of ERCC1 and BRCA1 was significantly associated with LNM (P < 0.001), advanced TNM stage (P < 0.001), and decreased 5-year overall survival rate (P < 0.001). Univariate and multivariate analyses showed ERCC1 and BRCA1 expression as independent predictors of recurrence and survival in CRC patients (P < 0.05). ERCC1 and BRCA1 mRNA expression levels correlate inversely to CRC metastasis. ERCC1 and BRCA1 might serve as biomarkers for LNM and as prognostic indicators for CRC; their down-expressions are predictors of poor outcome in CRC patients

  20. Germline mutations in the breast cancer susceptibility gene PTEN are rare in high-risk non-BRCA1/2 French Canadian breast cancer families.

    Science.gov (United States)

    Guénard, Frédéric; Labrie, Yvan; Ouellette, Geneviève; Beauparlant, Charles Joly; Bessette, Paul; Chiquette, Jocelyne; Laframboise, Rachel; Lépine, Jean; Lespérance, Bernard; Pichette, Roxane; Plante, Marie; Durocher, Francine

    2007-01-01

    Cowden syndrome is a disease associated with an increase in breast cancer susceptibility. Alleles in PTEN and other breast cancer susceptibility genes would be responsible for approximately 25% of the familial component of breast cancer risk, BRCA1 and BRCA2 being the two major genes responsible for this inherited risk. In order to evaluate the proportion of high-risk French Canadian non-BRCA1/BRCA2 breast/ovarian cancer families potentially harboring a PTEN germline mutation, the whole coding and flanking intronic sequences were analyzed in a series of 98 breast cancer cases. Although no germline mutation has been identified in the coding region, our study led to the identification of four intronic variants. Further investigations were performed to analyze the effect of these variants, alone and/or in combination, on splicing and PTEN protein levels. Despite suggestive evidence emerging from in silico analyses, the presence of these intronic variants do not seem to alter RNA splicing or PTEN protein levels. In addition, as loss of PTEN or part of it has been reported, Western blot analysis has also been performed. No major deletion could be identified in our cohort. Therefore, assuming a Poisson distribution for the frequency of deleterious mutation in our cohort, if the frequency of such deleterious mutation was 2%, we would have had a 90% or greater chance of observing at least one such mutation. These results suggest that PTEN germline mutations are rare and are unlikely to account for a significant proportion of familial breast cancer cases in the French Canadian population.

  1. No germline mutations in the histone acetyltransferase gene EP300 in BRCA1 and BRCA2 negative families with breast cancer and gastric, pancreatic, or colorectal cancer

    International Nuclear Information System (INIS)

    Mutations in BRCA1, BRCA2, ATM, TP53, CHK2 and PTEN account for many, but not all, multiple-case breast and ovarian cancer families. The histone acetyltransferase gene EP300 may function as a tumour suppressor gene because it is sometimes somatically mutated in breast, colorectal, gastric and pancreatic cancers, and is located on a region of chromosome 22 that frequently undergoes loss of heterozygosity in many cancer types. We hypothesized that germline mutations in EP300 may account for some breast cancer families that include cases of gastric, pancreatic and/or colorectal cancer. We screened the entire coding region of EP300 for mutations in the youngest affected members of 23 non-BRCA1/BRCA2 breast cancer families with at least one confirmed case of gastric, pancreatic and/or colorectal cancer. These families were ascertained in Australia through the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer. Denaturing HPLC analysis identified a heterozygous alteration at codon 211, specifically a GGC to AGC (glycine to serine) alteration, in two individuals. This conservative amino acid change was not within any known functional domains of EP300. The frequency of the Ser211 variant did not differ significanlty between a series of 352 breast cancer patients (4.0%) and 254 control individuals (2.8%; P = 0.5). The present study does not support a major role for EP300 mutations in breast and ovarian cancer families with a history of gastric, pancreatic and/or colorectal cancer

  2. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

    Science.gov (United States)

    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

    2012-04-01

    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.

  3. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population

    NARCIS (Netherlands)

    Antoniou, Antonis C.; Wang, Xianshu; Fredericksen, Zachary S.; McGuffog, Lesley; Tarrell, Robert; Sinilnikova, Olga M.; Healey, Sue; Morrison, Jonathan; Kartsonaki, Christiana; Lesnick, Timothy; Ghoussaini, Maya; Barrowdale, Daniel; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Eccles, Diana; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Chu, Carol; Douglas, Fiona; Paterson, Joan; Stoppa-Lyonnet, Dominique; Houdayer, Claude; Mazoyer, Sylvie; Giraud, Sophie; Lasset, Christine; Remenieras, Audrey; Caron, Olivier; Hardouin, Agnes; Berthet, Pascaline; Hogervorst, Frans B. L.; Rookus, Matti A.; Jager, Agnes; van den Ouweland, Ans; Hoogerbrugge, Nicoline; van der Luijt, Rob B.; Meijers-Heijboer, Hanne; Garcia, Encarna B. Gomez; Devilee, Peter; Vreeswijk, Maaike P. G.; Lubinski, Jan; Jakubowska, Anna; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Gorski, Bohdan; Cybulski, Cezary; Spurdle, Amanda B.; Holland, Helene; Goldgar, David E.; John, Esther M.; Hopper, John L.; Southey, Melissa; Buys, Saundra S.; Daly, Mary B.; Terry, Mary-Beth; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Preisler-Adams, Sabine; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy; Blum, Joanne L.; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Blank, Stephanie V.; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Kirchhoff, Tomas; Vijai, Joseph; Gaudet, Mia M.; Altshuler, David; Guiducci, Candace; Loman, Niklas; Harbst, Katja; Rantala, Johanna; Ehrencrona, Hans; Gerdes, Anne-Marie; Thomassen, Mads; Sunde, Lone; Peterlongo, Paolo; Manoukian, Siranoush; Bonanni, Bernardo; Viel, Alessandra; Radice, Paolo; Caldes, Trinidad; de la Hoya, Miguel; Singer, Christian F.; Fink-Retter, Anneliese; Greene, Mark H.; Mai, Phuong L.; Loud, Jennifer T.; Guidugli, Lucia; Lindor, Noralane M.; Hansen, Thomas V. O.; Nielsen, Finn C.; Blanco, Ignacio; Lazaro, Conxi; Garber, Judy; Ramus, Susan J.; Gayther, Simon A.; Phelan, Catherine; Narod, Stephen; Szabo, Csilla I.; Benitez, Javier; Osorio, Ana; Nevanlinna, Heli; Heikkinen, Tuomas; Caligo, Maria A.; Beattie, Mary S.; Hamann, Ute; Godwin, Andrew K.; Montagna, Marco; Casella, Cinzia; Neuhausen, Susan L.; Karlan, Beth Y.; Tung, Nadine; Toland, Amanda E.; Weitzel, Jeffrey; Olopade, Olofunmilayo; Simard, Jacques; Soucy, Penny; Rubinstein, Wendy S.; Arason, Adalgeir; Rennert, Gad; Martin, Nicholas G.; Montgomery, Grant W.; Chang-Claude, Jenny; Flesch-Janys, Dieter; Brauch, Hiltrud; Severi, Gianluca; Baglietto, Laura; Cox, Angela; Cross, Simon S.; Miron, Penelope; Gerty, Sue M.; Tapper, William; Yannoukakos, Drakoulis; Fountzilas, George; Fasching, Peter A.; Beckmann, Matthias W.; Silva, Isabel dos Santos; Peto, Julian; Lambrechts, Diether; Paridaens, Robert; Ruediger, Thomas; Foersti, Asta; Winqvist, Robert; Pylkaes, Katri; Diasio, Robert B.; Lee, Adam M.; Eckel-Passow, Jeanette; Vachon, Celine; Blows, Fiona; Driver, Kristy; Dunning, Alison; Pharoah, Paul P. D.; Offit, Kenneth; Pankratz, V. Shane; Hakonarson, Hakon; Chenevix-Trench, Georgia; Easton, Douglas F.; Couch, Fergus J.

    2010-01-01

    Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosi

  4. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Wang, Xianshu; Fredericksen, Zachary S;

    2010-01-01

    Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagn...

  5. BRCA Genetic Screening in Middle Eastern and North African: Mutational Spectrum and Founder BRCA1 Mutation (c.798_799delTT in North African

    Directory of Open Access Journals (Sweden)

    Abdelilah Laraqui

    2015-01-01

    Full Text Available Background. The contribution of BRCA1 mutations to both hereditary and sporadic breast and ovarian cancer (HBOC has not yet been thoroughly investigated in MENA. Methods. To establish the knowledge about BRCA1 mutations and their correlation with the clinical aspect in diagnosed cases of HBOC in MENA populations. A systematic review of studies examining BRCA1 in BC women in Cyprus, Jordan, Egypt, Lebanon, Morocco, Algeria, and Tunisia was conducted. Results. Thirteen relevant references were identified, including ten studies which performed DNA sequencing of all BRCA1 exons. For the latter, 31 mutations were detected in 57 of the 547 patients ascertained. Familial history of BC was present in 388 (71% patients, of whom 50 were mutation carriers. c.798_799delTT was identified in 11 North African families, accounting for 22% of total identified BRCA1 mutations, suggesting a founder allele. A broad spectrum of other mutations including c.68_69delAG, c.181T>G, c.5095C>T, and c.5266dupC, as well as sequence of unclassified variants and polymorphisms, was also detected. Conclusion. The knowledge of genetic structure of BRCA1 in MENA should contribute to the assessment of the necessity of preventive programs for mutation carriers and clinical management. The high prevalence of BC and the presence of frequent mutations of the BRCA1 gene emphasize the need for improving screening programs and individual testing/counseling.

  6. Pathogenicity of the BRCA1 Missense Variant M1775K is Determined by the Disruption of the BRCT Phosphopeptide-Binding Pocket: a Multi-Modal Approach

    Energy Technology Data Exchange (ETDEWEB)

    Tischkowitz,M.; Hamel, N.; Carvalho, M.; Birrane, G.; Soni, A.; van Beers, E.; Joosse, S.; Wong, N.; Novak, D.; et al

    2008-01-01

    A number of germ-line mutations in the BRCA1 gene confer susceptibility to breast and ovarian cancer. However, it remains difficult to determine whether many single amino-acid (missense) changes in the BRCA1 protein that are frequently detected in the clinical setting are pathologic or not. Here, we used a combination of functional, crystallographic, biophysical, molecular and evolutionary techniques, and classical genetic segregation analysis to demonstrate that the BRCA1 missense variant M1775K is pathogenic. Functional assays in yeast and mammalian cells showed that the BRCA1 BRCT domains carrying the amino-acid change M1775K displayed markedly reduced transcriptional activity, indicating that this variant represents a deleterious mutation. Importantly, the M1775K mutation disrupted the phosphopeptide-binding pocket of the BRCA1 BRCT domains, thereby inhibiting the BRCA1 interaction with the proteins BRIP1 and CtIP, which are involved in DNA damage-induced checkpoint control. These results indicate that the integrity of the BRCT phosphopeptide-binding pocket is critical for the tumor suppression function of BRCA1. Moreover, this study demonstrates that multiple lines of evidence obtained from a combination of functional, structural, molecular and evolutionary techniques, and classical genetic segregation analysis are required to confirm the pathogenicity of rare variants of disease-susceptibility genes and obtain important insights into the underlying pathogenetic mechanisms.

  7. Persistent Activation of NF-κB in BRCA1-Deficient Mammary Progenitors Drives Aberrant Proliferation and Accumulation of DNA Damage.

    Science.gov (United States)

    Sau, Andrea; Lau, Rosanna; Cabrita, Miguel A; Nolan, Emma; Crooks, Peter A; Visvader, Jane E; Pratt, M A Christine

    2016-07-01

    Human BRCA1 mutation carriers and BRCA1-deficient mouse mammary glands contain an abnormal population of mammary luminal progenitors that can form 3D colonies in a hormone-independent manner. The intrinsic cellular regulatory defect in these presumptive breast cancer precursors is not known. We have discovered that nuclear factor kappaB (NF-κB) (p52/RelB) is persistently activated in a subset of BRCA1-deficient mammary luminal progenitors. Hormone-independent luminal progenitor colony formation required NF-κB, ataxia telangiectasia-mutated (ATM), and the inhibitor of kappaB kinase, IKKα. Progesterone (P4)-stimulated proliferation resulted in a marked enhancement of DNA damage foci in Brca1(-/-) mouse mammary. In vivo, NF-κB inhibition prevented recovery of Brca1(-/-) hormone-independent colony-forming cells. The majority of human BRCA1(mut/+) mammary glands showed marked lobular expression of nuclear NF-κB. We conclude that the aberrant proliferative capacity of Brca1(-/-) luminal progenitor cells is linked to the replication-associated DNA damage response, where proliferation of mammary progenitors is perpetuated by damage-induced, autologous NF-κB signaling. PMID:27292187

  8. Use of Gene Expression Profiles of Peripheral Blood Lymphocytes to Distinguish BRCA1 Mutation Carriers in High Risk Breast Cancer Families

    Directory of Open Access Journals (Sweden)

    Marie-Laure Vuillaume

    2009-01-01

    Full Text Available Mutations in two major genes, BRCA1 and BRCA2, account for up to 30% of families with hereditary breast cancer. Unfortunately, in most families there is little to indicate which gene should be targeted first for mutation screening, which is labor intensive, time consuming and often prohibitively expensive. As BRCA1 is a tumor suppressor gene involved in various cellular processes, heterozygous mutations could deregulate dependent pathways, such as DNA damage response, and disturb transcriptional activity of genes involved in the downstream signaling cascade. We investigated gene expression profiling in peripheral blood lymphocytes to evaluate this strategy for distinguishing BRCA1 mutation carriers from non-carriers. RNA from whole blood samples of 15 BRCA1 mutation carriers and 15 non-carriers from BRCA1 or BRCA2 families were hybridized to Agilent Technologies Whole Human Genome OligoMicroarrays (4 × 44 K multiplex format containing 41,000 unique human genes and transcripts. Gene expression data were analyzed with Welch’s t-tests and submitted to hierarchical clustering (GeneSpring GX software, Agilent Technologies. Statistical analysis revealed a slight tendency for 133 genes to be differentially expressed between BRCA1 mutation carriers and non-carriers. However, hierarchical clustering of these genes did not accurately discriminate BRCA1 mutation carriers from non-carriers. Expression variation for these genes according to BRCA1 mutation status was weak. In summary, microarray profiling of untreated whole blood does not appear to be informative in identifying breast cancer risk due to BRCA1 mutation.

  9. The Occurrence and Contribution of Germline BRCA1/2 Sequence Alterations in Iranian Patients With Breast Cancer

    Directory of Open Access Journals (Sweden)

    Zeinali S

    2011-12-01

    Full Text Available Background: Breast cancer is the most common form of hereditary cancer worldwide and is an important cause of morbidity and mortality. Approximately 5-10% of breast and ovarian cancers are due to the highly penetrating germline mutations in cancer predisposing genes. Two genes, BRCA1 and BRCA2, account for at least half of these cases. The demand for BRCA1 and BRCA2 mutation screening is rapidly increasing as their identification will affect the medical management of people at increased risk for the disease. Therefore, the aim of this study was to investigate BRCA1/2 mutations in 100 high risk Iranian families.Methods: One hundred families who met the minimal risk factors for breast/ovarian cancer were screened among the families referred to Kawsar Human Genetics Research Center for the diseases in 2009-2011. The entire coding sequences and each intron/exon boundaries of BRCA1/2 genes were screened for by direct sequencing and MLPA in both patients and the controls.Results: In the present study, we could detect the following novel mutations: p.Gly1140Ser, p.Ile26Val, p.Leu1418X, p.Glu23Gln, p.Leu3X, p.Asn1403His, p.Asn1403Asp, p.Lys581X, p.Pro938Arg, p.Thr77Arg, p.Leu6Val, p.Arg7Cys, p.Leu15Ile, p.Ser177Thr, IVS7+83(-TT, IVS8 -70(-CATT, IVS2+9(G>C, IVS1-20(G>A, IVS1-8(A>G, p.Met1Ile, IVS2+24(A>G, IVS5-8 (A>G, IVS2(35-39TTcctatGAT, IVS13+9 G>C in BRCA1 and p.Glu1391Gly, p. Val1852Ile, IVS6-70(T>G, 1994-1995 (InsA in BRCA2.Conclusion: Ten mutations seemed to be pathogenic and the disease-causing mutations were seen in 16% of the families. In addition, from the total number of substitutions and reassortments (42, 80% related to BRCA1 and 20% to mutations in BRCA2 genes.

  10. DNA repair genes BRCA1 and DNA-PKcs have great potential in radiation therapy%DNA修复基因BRCA1和DNA-PKcs在放射治疗中有很大的潜能

    Institute of Scientific and Technical Information of China (English)

    Jiao Yang; Ximing Xu; Yanrong Hao

    2012-01-01

    Radiotherapy is a part of the front-line treatment regime for many cancers. The mechanisms of radiation-induced effects in cancers mainly involves double-strand breaks (DBS) which plays very important role in maintaining the stability of gene. As DNA repair gene breast cancer 1 (BRCA1) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) can act to maintain genetic stability though two distinct and complementary mechanisms for DNA DSB repair-homologous recombination (HR) and non-homologous end joining (NHEJ). Therefor, BRCA1 and DNA-PKcs are closely associated with radiation sensitivity, which means that they may be used as a useful tool to predict radio sensitivity in human tumour cells.

  11. Predisposición genética para el cáncer de mama: genes BRCA1 y BRCA2 Genetic predisposition for breast cancer: BRCA1 and BRCA2 genes

    Directory of Open Access Journals (Sweden)

    Steven A Narod

    2011-10-01

    Full Text Available El descubrimiento de los genes BRCA1 y BRCA2 ha llevado a la introducción de pruebas genéticas cada vez más sofisticadas para medir el riesgo de cáncer de mama de origen hereditario, entre otras cosas. En el presente artículo exploramos los criterios a seguir para realizar pruebas para estos genes, así como las implicaciones en el tratamiento para los pacientes en caso de identificarlos.The discovery of genes BRCA1 and BRCA2 has led to the introduction of genetic tests more complex every time for the evaluation ofthehereditarycancerrisk,amongothers.In the present paper we explore the criteria to decide when to run the testing for the genes, as well as the implications for the treatment of patients who are identified with them.

  12. BRCA1 and ERCC1 mRNA levels are associated with lymph node metastasis in Chinese patients with colorectal cancer

    OpenAIRE

    Yuanming, Lu; Lineng, Zhang; Baorong, Song; Junjie, Peng; Sanjun, Cai

    2013-01-01

    Background Although both excision repair cross-complementing group 1 (ERCC1) and breast cancer susceptibility gene 1 (BRCA1) can be effective biomarkers for chemosensitivity in primary malignant tumors, their applicability to metastases is poorly understood. Here, ERCC1 and BRCA1, which are linked to lymph node metastasis (LNM) in colorectal cancer (CRC), were evaluated in primary CRC samples from Chinese patients with LNM (LNM CRC) or without LNM (non-LNM CRC). mRNA levels of ERCC1 and BRCA1...

  13. The role of BRCA1 and BRCA2 in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Elena Castro; Rosalind Eeles

    2012-01-01

    One of the strongest risk factors for prostate cancer is a family history of the disease.Germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk of prostate cancer (8.6-fold in men ≤ 65 years).Although the role of BRCA2 and BRCA1 in prostate tumorigenesis remains unrevealed,deleterious mutations in both genes have been associated with more aggressive disease and poor clinical outcomes.The increasing incidence of prostate cancer worldwide supports the need for new methods to predict outcome and identify patients with potentially lethal forms of the disease.As we present here,BRCA germline mutations,mainly in the BRCA2gene,are one of those predictive factors.We will also discuss the implications of these mutations in the management of prostate cancer and hypothesize on the potential for the development of strategies for sporadic cases with similar characteristics.

  14. Gene Expression Profiling in Hereditary, BRCA1-linked Breast Cancer: Preliminary Report

    Directory of Open Access Journals (Sweden)

    Dudaladava Volha

    2006-01-01

    Full Text Available Abstract Global analysis of gene expression by DNA microarrays is nowadays a widely used tool, especially relevant for cancer research. It helps the understanding of complex biology of cancer tissue, allows identification of novel molecular markers, reveals previously unknown molecular subtypes of cancer that differ by clinical features like drug susceptibility or general prognosis. Our aim was to compare gene expression profiles in breast cancer that develop against a background of inherited predisposing mutations versus sporadic breast cancer. In this preliminary study we analysed seven hereditary, BRCA1 mutation-linked breast cancer tissues and seven sporadic cases that were carefully matched by histopathology and ER status. Additionally, we analysed 6 samples of normal breast tissue. We found that while the difference in gene expression profiles between tumour tissue and normal breast can be easily recognized by unsupervised algorithms, the difference between those two types of tumours is more discrete. However, by supervised methods of data analysis, we were able to select a set of genes that may differentiate between hereditary and sporadic tumours. The most significant difference concerns genes that code for proteins engaged in regulation of transcription, cellular metabolism, signalling, proliferation and cell death. Microarray results for chosen genes (TOB1, SEPHS2 were validated by real-time RT-PCR.

  15. Germline truncating-mutations in BRCA1 and MSH6 in a patient with early onset endometrial cancer

    Directory of Open Access Journals (Sweden)

    Kast Karin

    2012-11-01

    Full Text Available Abstract Background Hereditary Breast and Ovarian Cancer Syndrome (HBOCS and Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC, Lynch Syndrome are two tumor predisposition syndromes responsible for the majority of hereditary breast and colorectal cancers. Carriers of both germline mutations in breast cancer genes BRCA1 or BRCA2 and in mismatch repair (MMR genes MLH1, MSH2, MSH6 or PMS2 are very rare. Case presentation We identified germline mutations in BRCA1 and in MSH6 in a patient with increased risk for HBOC diagnosed with endometrial cancer at the age of 46 years. Conclusions Although carriers of mutations in both MMR and BRCA genes are rare in Caucasian populations and anamnestical and histopathological findings may guide clinicians to identify these families, both syndromes can only be diagnosed through a complete gene analysis of the respective genes.

  16. BRCA1 185delAG MUTATION CAN BE EASILY DETECTED BY AN ADAPTED ALLELE-SPECIFIC PCR

    Directory of Open Access Journals (Sweden)

    Anca Negura

    2012-03-01

    Full Text Available BRCA1 gene accounts for a majority of hereditary breast and ovarian cancers. Germinal deleteriousmutations within this gene are directly responsible for the disease, with a lifetime risk of cancer for mutations carriers ofabout 80%. While outbred and western populations usually show a heterogeneous profile of unique and familialmutations, in isolated and eastern European populations some recurrent mutations can be afforded the most responsibilityfor familial hereditary cases. In Ashkenazi Jewish and most Slavic eastern population, the BRCA1 185delAG is one of themost frequent mutations. Therefore, rapid screening by PCR-based methods can be useful in oncogenetic diagnosis. Herewe present implementation of an adapted allele-specific PCR for the detection of 185delAG, with wide applications indiagnosis and genotyping for large population groups.

  17. Plasma Proteomic Profiling in Hereditary Breast Cancer Reveals a BRCA1-Specific Signature: Diagnostic and Functional Implications.

    Directory of Open Access Journals (Sweden)

    Domenica Scumaci

    Full Text Available Breast cancer (BC is a leading cause of death among women. Among the major risk factors, an important role is played by familial history of BC. Germ-line mutations in BRCA1/2 genes account for most of the hereditary breast and/or ovarian cancers. Gene expression profiling studies have disclosed specific molecular signatures for BRCA1/2-related breast tumors as compared to sporadic cases, which might help diagnosis and clinical follow-up. Even though, a clear hallmark of BRCA1/2-positive BC is still lacking. Many diseases are correlated with quantitative changes of proteins in body fluids. Plasma potentially carries important information whose knowledge could help to improve early disease detection, prognosis, and response to therapeutic treatments. The aim of this study was to develop a comprehensive approach finalized to improve the recovery of specific biomarkers from plasma samples of subjects affected by hereditary BC.To perform this analysis, we used samples from patients belonging to highly homogeneous population previously reported. Depletion of high abundant plasma proteins, 2D gel analysis, liquid chromatography-tandem mass spectrometry (LC-MS/MS and bioinformatics analysis were used into an integrated approach to investigate tumor-specific changes in the plasma proteome of BC patients and healthy family members sharing the same BRCA1 gene founder mutation (5083del19, previously reported by our group, with the aim to identify specific signatures.The comparative analysis of the experimental results led to the identification of gelsolin as the most promising biomarker.Further analyses, performed using a panel of breast cancer cell lines, allowed us to further elucidate the signaling network that might modulate the expression of gelsolin in breast cancer.

  18. Mutation Screening of the BRCA1 Gene in Early Onset and Familial Breast/Ovarian Cancer in Moroccan Population

    Directory of Open Access Journals (Sweden)

    Abdelilah Laraqui, Nancy Uhrhammer, Idriss Lahlou-Amine, Hicham EL Rhaffouli, Jamila El Baghdadi, Mohamed Dehayni, Rahali Driss Moussaoui, Mohamed Ichou, Yassir Sbitti, Abderrahman Al Bouzidi, Said Amzazi, Yves-Jean Bignon

    2013-01-01

    Full Text Available Worldwide variation in the distribution of BRCA mutations is well recognised, and for the Moroccan population no comprehensive studies about BRCA mutation spectra or frequencies have been published. We therefore performed mutation analysis of the BRCA1 gene in 121 Moroccan women diagnosed with breast cancer. All cases completed epidemiology and family history questionnaires and provided a DNA sample for BRCA testing. Mutation analysis was performed by direct DNA sequencing of all coding exons and flanking intron sequences of the BRCA1 gene. 31.6 % (6/19 of familial cases and 1 % (1/102 of early-onset sporadic (< 45 years were found to be associated with BRCA1 mutations. The pathogenic mutations included two frame-shift mutations (c.798_799delTT, c.1016dupA, one missense mutation (c.5095C>T, and one nonsense mutation (c.4942A>T. The c.798_799delTT mutation was also observed in Algerian and Tunisian BC families, suggesting the first non-Jewish founder mutation to be described in Northern Africa. In addition, ten different unclassified variants were detected in BRCA1, none of which were predicted to affect splicing. Most unclassified variants were placed in Align-GVGD classes suggesting neutrality. c.5117G>C involves a highly conserved amino acid suggestive of interfering with function (Align-GVGD class C55, but has been observed in conjunction with a deleterious mutation in a Tunisian family. These findings reflect the genetic heterogeneity of the Moroccan population and are relevant to genetic counselling and clinical management. The role of BRCA2 in BC is also under study.

  19. Knockdown of COUP-TFII inhibits cell proliferation and induces apoptosis through upregulating BRCA1 in renal cell carcinoma cells.

    Science.gov (United States)

    Zheng, Jia; Qin, Weijun; Jiao, Dian; Ren, Jing; Wei, Ming; Shi, Shengjia; Xi, Wenjin; Wang, He; Yang, An-Gang; Huan, Yi; Wen, Weihong

    2016-10-01

    COUP-TFII belongs to the nuclear receptor family, which is highly expressed in many kinds of tumors. Previous studies have shown that COUP-TFII can promote tumor progression through regulating tumor angiogenesis and cell proliferation and migration of certain cancer cells. However, the function of COUP-TFII in renal cell carcinoma (RCC) is not clear. Here, we showed that clinical RCC tumor tissues showed much higher COUP-TFII expression level than adjacent normal tissues. When COUP-TFII was knocked down in RCC 769-P and 786-O cells by siRNA or shRNA-expressing lentivirus, the cell proliferation was markedly inhibited, and apoptosis increased. Moreover, the tumor growth of COUP-TFII knockdown 769-P and 786-O xenografts in nude mice was also obviously inhibited. Using qRT-PCR and Western blot, we showed that the expression of the tumor suppressor gene BRCA1 was upregulated in COUP-TFII knockdown cells. Simultaneously knockdown of BRCA1 and COUP-TFII partially rescued the inhibited cell proliferation and increased apoptosis in COUP-TFII single knockdown cells. These results indicate that COUP-TFII may play an oncogenic role in RCC, and COUP-TFII may promote tumor progression through inhibiting BRCA1. PMID:27193872

  20. Effect of Prior Bilateral Oophorectomy on the Presentation of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

    Directory of Open Access Journals (Sweden)

    Metcalfe Kelly A

    2005-04-01

    Full Text Available Abstract Purpose To compare the presentation of invasive breast cancer in BRCA1 and BRCA2 mutation carriers with and without prior bilateral oophorectomy. Patients and methods Women with a BRCA1 or BRCA2 mutation with the diagnosis of invasive breast cancer were identified from ten cancer genetics clinics. The medical history, medical treatment records and pathology reports for the breast cancers were reviewed. Information was abstracted from medical charts, including history (and date of oophorectomy, date of breast cancer diagnosis, stage of disease, and pathologic characteristics of the breast cancer. Women with prior bilateral oophorectomy were matched by age, year of diagnosis, and mutation with one or more women who had two intact ovaries at the time of breast cancer diagnosis. Characteristics of the breast tumours were compared between the two groups. Results Women with prior bilateral oophorectomy presented with smaller tumours on average compared to women without prior oophorectomy (mean size 1.50 cm vs. 1.95 cm; p = 0.01. Additionally, although not statistically significant, women with intact ovaries were more likely to have high-grade tumour (70% vs. 54%: p = 0.10 and to have positive lymph nodes (34% vs. 18%; p = 0.11 compared to women with prior bilateral oophorectomy. Conclusions Bilateral oophorectomy prior to breast cancer appears to favourably influence the biological presentation of breast cancer in BRCA1 and BRCA2 mutation carriers.

  1. Clinical Significance of Epigenetic Inactivation of hMLH1 and BRCA1 in Tunisian Patients with Invasive Breast Carcinoma

    Directory of Open Access Journals (Sweden)

    Sondes Karray-Chouayekh

    2009-01-01

    Full Text Available Aberrant hypermethylation of gene promoter regions is one of the mechanisms for inactivation of tumour suppressor genes in many human cancers including breast carcinoma. In the current study, we aimed to assess by MSP, the methylation pattern of two cancer-related genes involved in DNA repair: hMLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli and BRCA1 (breast cancer 1, early onset in 78 primary breast cancers from Tunisian patients. The methylation frequencies were 24.36% for hMLH1 and 46% for BRCA1. BRCA1 methylation correlated with age at diagnosis (P=.015 and 5-years disease free survival (P=.016 while hMLH1 methylation was more frequent in larger tumors (P=.002 and in presence of distant metastasis (P=.004. Furthermore, methylation of hMLH1 significantly correlated with high level of P53 expression (P=.006 and with overall survival (P=.015 suggesting that silencing of hMLH1 through aberrant promoter methylation could be used as a poor prognosis indicator in breast cancer.

  2. Screening for Del 185 AG and 4627C>A BRCA1 Mutations in Breast Cancer Patients from Lahore, Pakistan.

    Science.gov (United States)

    Aziz, Faiza; Fatima, Warda; Mahmood, Saqib; Khokher, Samina

    2016-01-01

    Breast cancer contributes to approximately 23% of the cancer cases identified and 14% of cancer related deaths worldwide. Including a strong association between genetic and environmental factors, breast cancer is a complex and multi factorial disorder. Two high penetration breast cancer susceptibility genes (BRCA1 and BRCA2) have been identified, and germ line mutations in these are thought to account for between 5% and 10% of all breast cancer cases. The human BRCA1 gene, located on 17q, is involved in the regulation of cell proliferation by aiding in DNA repair, transcriptional responses to DNA damage and cell cycle check points. Mutations in this gene enhance cell proliferation and facilitate formation of tumors. Two mutations, the 185 deletion of AG and the 4627 substitution from C to A, are founder mutations in the BRCA1 gene for breast cancer in Asian populations. Allele specific PCR was performed to detect these selected mutations in 120 samples. No mutation of 4627 C to A was detected in the samples and only one of the patients had the 185 del AG mutation in the heterozygous condition. Our collected samples had lower consanguinity and family history indicating the greater involvement of environmental as compared to genetic factors. PMID:27221844

  3. BRCA1-2 diagnostic workflow from next-generation sequencing technologies to variant identification and final report.

    Science.gov (United States)

    Pilato, Brunella; Pinto, Rosamaria; De Summa, Simona; Petriella, Daniela; Lacalamita, Rosanna; Danza, Katia; Paradiso, Angelo; Tommasi, Stefania

    2016-10-01

    The BRCA1-BRCA2 genes predispose to hereditary breast and ovarian cancer, and the germline and mutational status of these genes defines a target population that can benefit from PARP inhibitor treatments. To respond to the increasing number of BRCA1-BRCA2 tests, it is necessary to shift to high-throughput technologies that are reliable and less time consuming. Different methodological platforms are dedicated to this purpose with different approaches and algorithms for analysis. Our aim was to set up a cost-effective and low time-consuming BRCA1-BRCA2 mutation detection workflow using the Ion Torrent PGM technology. A retrospective cohort of 40 patients with familial breast/ovarian cancer previously tested by Sanger sequencing and a prospective cohort of 72 patients (validation set) were analyzed. The validation set included 64 patients affected by familial breast/ovarian cancer and eight sporadic ovarian cancer cases, who are potential candidates for PARPi treatments. A complete and standardized workflow easily usable and suitable in a certified laboratory has been proved and validated. This includes all steps from library preparation to the final report. The use of next-generation sequencing will be of benefit for patients enrolled in the genetic counseling process and, moreover, will enhance the process of selecting patients eligible for personalized treatments. © 2016 Wiley Periodicals, Inc. PMID:27225819

  4. Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland.

    Science.gov (United States)

    Gronwald, Jacek; Byrski, Tomasz; Huzarski, Tomasz; Cybulski, Cezary; Sun, Ping; Tulman, Anna; Narod, Steven A; Lubinski, Jan

    2006-01-01

    It has been estimated that the lifetime risk of breast cancer among women who inherit a BRCA1 or BRCA2 mutation is as high as 80%, and the risk estimates for ovarian cancer range from 15 to 40%. Several environmental and lifestyle factors are believed to contribute to the development of breast cancer in the general population and it is of interest to establish if these factors operate among mutation carriers as well. To evaluate the effects of age of menarche, parity, breast-feeding, oophorectomy and oral contraceptive use, as well as smoking and coffee consumption, on the risks of breast and ovarian cancer, we conducted a matched case-control study of Polish women with BRCA1 mutations. There were 348 breast cancer patients, 150 ovarian cancer patients and similar numbers of age-matched controls. BRCA1 carriers with late age of menarche, lower parity and long-term breast-feeding were less likely to develop breast cancer. Oral contraceptives protected against ovarian cancer. PMID:16261399

  5. Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil.

    Science.gov (United States)

    Carraro, Dirce Maria; Koike Folgueira, Maria Aparecida Azevedo; Garcia Lisboa, Bianca Cristina; Ribeiro Olivieri, Eloisa Helena; Vitorino Krepischi, Ana Cristina; de Carvalho, Alex Fiorini; de Carvalho Mota, Louise Danielle; Puga, Renato David; do Socorro Maciel, Maria; Michelli, Rodrigo Augusto Depieri; de Lyra, Eduardo Carneiro; Grosso, Stana Helena Giorgi; Soares, Fernando Augusto; Achatz, Maria Isabel Alves de Souza Waddington; Brentani, Helena; Moreira-Filho, Carlos Alberto; Brentani, Maria Mitzi

    2013-01-01

    Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC) and TP53 genes was performed in 54 unrelated patients profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22%) [7 in BRCA1 (13%), 4 in BRCA2 (7%) and one in TP53 (2%) gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes). Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients. PMID:23469205

  6. Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil.

    Directory of Open Access Journals (Sweden)

    Dirce Maria Carraro

    Full Text Available Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC and TP53 genes was performed in 54 unrelated patients <35 y; their tumors were investigated with respect to transcriptional and genomic profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22% [7 in BRCA1 (13%, 4 in BRCA2 (7% and one in TP53 (2% gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes. Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients.

  7. A prospective investigation of predictive and modifiable risk factors for breast cancer in unaffected BRCA1 and BRCA2 gene carriers

    OpenAIRE

    O'Sullivan, Jacintha

    2013-01-01

    Background Breast cancer is the most common female cancer worldwide. The lifetime risk of a woman being diagnosed with breast cancer is approximately 12.5%. For women who carry the deleterious mutation in either of the BRCA genes, BRCA1 or BRCA2, the risk of developing breast or ovarian cancer is significantly increased. In recent years there has been increased penetrance of BRCA1 and BRCA2 associated breast cancer, prompting investigation into the role of modifiable risk factors in this ...

  8. Ovarian Cancer Susceptibility Alleles and Risk of Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers

    Science.gov (United States)

    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

  9. Roles of DNA mutation in the coding region and DNA methylation in the 5' flanking region of BRCA1 in canine mammary tumors.

    Science.gov (United States)

    Qiu, Hengbin; Lin, Deigui

    2016-07-01

    The Breast cancer 1, early onset gene (BRCA1) is known to be significantly associated with human familial breast cancer and is identified to play an important role in canine mammary tumors. Here, genetic variations in the coding region and DNA methylation in the 5' flanking region of BRCA1 in canine mammary tumor samples, 15 each of benign and malignant against 10 normal canine mammary tissue samples, were analyzed using the direct sequencing method. The results indicated two point mutations each in the coding region of canine BRCA1 in one benign mammary tumor sample (4702G >T and 4765G >T) and in one malignant canine mammary tumor sample (3619A >G and 4006G >A). No mutations were detected in the normal canine mammary tissue samples. The 4702G >T mutation was found to terminate further translation. The physical effect of the 4765G >T mutation was found to be the repalacement of the glutamate residue with glutamine. The physical effect of the 3619A >G mutation was found to be the replacement of the threonine residue with alanine, and that of mutation 4006G >A was the replacement of the valine residue with isoleucine in the BRCA1 protein. Bisulfite sequencing detected methylated CpG sites in one canine malignant mammary tumor sample. In conclusion, the present study elucidated the mutational status of the BRCA1 coding region and methylation status of the 5' flanking region of BRCA1 in canine mammary tumors. PMID:26888582

  10. Detection of BRCA1 and BRCA2 gene mutation in Egyptian females with breast cancer and their relatives by PCR-SSCP method.

    Science.gov (United States)

    Fattouh, Mona; Ahmed, Hydi; Hafez, Elsayed El-Sayed

    2011-01-01

    Germline mutations in the BRCA1 or BRCA2 genes predispose their carriers to breast or/and ovarian cancers during their lifetime. This study was performed to identify germline mutations in BRCA1 and BRCA2 genes for the early detection of pre-symptomatic mutation carriers in Egyptian healthy females who were first-degree relatives of affected women from families with and without family history of breast cancer. Sixty-two patients (index cases) with invasive breast cancer belonging to sixty families and their asymptomatic female first-degree relatives (300 cases) were studied for germline mutations of BRCA1 and BRCA2 genes. Five mutations were detected in 52 families (86.7%) with inherited mutations in either BRCA1 or BRCA2. Sixty percent of these families had BRCA1 mutation and 26.7% had BRCA2 mutations. They were identified by using the combination of SSCP and heteroduplex analysis. All but one of the mutations were detected within the BRCA1 gene in addition to one mutation in the BRCA2 gene. PMID:23082475

  11. 非小细胞肺癌组织中p73、BRCA1的表达变化及临床意义

    Institute of Scientific and Technical Information of China (English)

    杨波; 房新志

    2010-01-01

    目的 观察非小细胞肺癌(NSCLC)组织中p73、BRCA1的表达变化,并探讨其临床意义.方法采用免疫组化SP法检测115例NSCLC组织、65例癌旁组织中的p73、BRCA1蛋白.结果 NSCLC组织中p73、BRCA1蛋白阳性率(66.96%、60.87%)明显高于癌旁组织(23.07%、15.38%),P均<0.05;p73、BRCA1蛋白表达与NSCLC患者年龄、性别、组织类型、分化程度和淋巴结转移均无关(P均>0.05),p73与BRCA1蛋白表达呈正相关(r=0.194,P<0.05).结论 NSCLC组织中p73、BRCA1表达上调在NSCLC发生发展中起重要作用.

  12. Detection of genomic variations in BRCA1 and BRCA2 genes by long-range PCR and next-generation sequencing.

    Science.gov (United States)

    Hernan, Imma; Borràs, Emma; de Sousa Dias, Miguel; Gamundi, María José; Mañé, Begoña; Llort, Gemma; Agúndez, José A G; Blanca, Miguel; Carballo, Miguel

    2012-01-01

    Advances in sequencing technologies, such as next-generation sequencing (NGS), represent an opportunity to perform genetic testing in a clinical scenario. In this study, we developed and tested a method for the detection of mutations in the large BRCA1 and BRCA2 tumor suppressor genes, using long-range PCR (LR-PCR) and NGS, in samples from individuals with a personal and/or family history of breast and/or ovarian cancer. Eleven LR-PCR fragments, between 3000 and 15,300 bp, containing all coding exons and flanking splice junctions of BRCA1 and BRCA2, were obtained from DNA samples of five individuals carrying mutations in either BRCA1 or BRCA2. Libraries for NGS were prepared using an enzymatic (Nextera technology) method. We analyzed five individual samples in parallel by NGS and obtained complete coverage of all LR-PCR fragments, with an average coding sequence depth for each nucleotide of >30 reads, running from ×7 (in exon 22 of BRCA1) to >×150. We detected and confirmed 100% of the mutations that predispose to the risk of cancer, together with other genomic variations in BRCA1 and BRCA2. Our approach demonstrates that genomic LR-PCR, together with NGS, using the GS Junior 454 System platform, is an effective method for patient sample analysis of BRCA1 and BRCA2 genes. In addition, this method could be performed in regular molecular genetics laboratories.

  13. β-HPV 5 and 8 E6 disrupt homology dependent double strand break repair by attenuating BRCA1 and BRCA2 expression and foci formation.

    Directory of Open Access Journals (Sweden)

    Nicholas A Wallace

    2015-03-01

    Full Text Available Recent work has explored a putative role for the E6 protein from some β-human papillomavirus genus (β-HPVs in the development of non-melanoma skin cancers, specifically β-HPV 5 and 8 E6. Because these viruses are not required for tumor maintenance, they are hypothesized to act as co-factors that enhance the mutagenic capacity of UV-exposure by disrupting the repair of the resulting DNA damage. Supporting this proposal, we have previously demonstrated that UV damage signaling is hindered by β-HPV 5 and 8 E6 resulting in an increase in both thymine dimers and UV-induced double strand breaks (DSBs. Here we show that β-HPV 5 and 8 E6 further disrupt the repair of these DSBs and provide a mechanism for this attenuation. By binding and destabilizing a histone acetyltransferase, p300, β-HPV 5 and 8 E6 reduce the enrichment of the transcription factor at the promoter of two genes critical to the homology dependent repair of DSBs (BRCA1 and BRCA2. The resulting diminished BRCA1/2 transcription not only leads to lower protein levels but also curtails the ability of these proteins to form repair foci at DSBs. Using a GFP-based reporter, we confirm that this reduced foci formation leads to significantly diminished homology dependent repair of DSBs. By deleting the p300 binding domain of β-HPV 8 E6, we demonstrate that the loss of robust repair is dependent on viral-mediated degradation of p300 and confirm this observation using a combination of p300 mutants that are β-HPV 8 E6 destabilization resistant and p300 knock-out cells. In conclusion, this work establishes an expanded ability of β-HPV 5 and 8 E6 to attenuate UV damage repair, thus adding further support to the hypothesis that β-HPV infections play a role in skin cancer development by increasing the oncogenic potential of UV exposure.

  14. Post-mortem testing; germline BRCA1/2 variant detection using archival FFPE non-tumor tissue. A new paradigm in genetic counseling.

    Science.gov (United States)

    Petersen, Annabeth Høgh; Aagaard, Mads Malik; Nielsen, Henriette Roed; Steffensen, Karina Dahl; Waldstrøm, Marianne; Bojesen, Anders

    2016-08-01

    Accurate estimation of cancer risk in HBOC families often requires BRCA1/2 testing, but this may be impossible in deceased family members. Previous, testing archival formalin-fixed, paraffin-embedded (FFPE) tissue for germline BRCA1/2 variants was unsuccessful, except for the Jewish founder mutations. A high-throughput method to systematically test for variants in all coding regions of BRCA1/2 in archival FFPE samples of non-tumor tissue is described, using HaloPlex target enrichment and next-generation sequencing. In a validation study, correct identification of variants or wild-type was possible in 25 out of 30 (83%) FFPE samples (age range 1-14 years), with a known variant status in BRCA1/2. No false positive was found. Unsuccessful identification was due to highly degraded DNA or presence of large intragenic deletions. In clinical use, a total of 201 FFPE samples (aged 0-43 years) were processed. Thirty-six samples were rejected because of highly degraded DNA or failed library preparation. Fifteen samples were investigated to search for a known variant. In the remaining 150 samples (aged 0-38 years), three variants known to affect function and one variant likely to affect function in BRCA1, six variants known to affect function and one variant likely to affect function in BRCA2, as well as four variants of unknown significance (VUS) in BRCA1 and three VUS in BRCA2 were discovered. It is now possible to test for germline BRCA1/2 variants in deceased persons, using archival FFPE samples from non-tumor tissue. Accurate genetic counseling is achievable in families where variant testing would otherwise be impossible.

  15. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

    Science.gov (United States)

    Vigorito, Elena; Kuchenbaecker, Karoline B; Beesley, Jonathan; Adlard, Julian; Agnarsson, Bjarni A; Andrulis, Irene L; Arun, Banu K; Barjhoux, Laure; Belotti, Muriel; Benitez, Javier; Berger, Andreas; Bojesen, Anders; Bonanni, Bernardo; Brewer, Carole; Caldes, Trinidad; Caligo, Maria A; Campbell, Ian; Chan, Salina B; Claes, Kathleen B M; Cohn, David E; Cook, Jackie; Daly, Mary B; Damiola, Francesca; Davidson, Rosemarie; Pauw, Antoine de; Delnatte, Capucine; Diez, Orland; Domchek, Susan M; Dumont, Martine; Durda, Katarzyna; Dworniczak, Bernd; Easton, Douglas F; Eccles, Diana; Edwinsdotter Ardnor, Christina; Eeles, Ros; Ejlertsen, Bent; Ellis, Steve; Evans, D Gareth; Feliubadalo, Lidia; Fostira, Florentia; Foulkes, William D; Friedman, Eitan; Frost, Debra; Gaddam, Pragna; Ganz, Patricia A; Garber, Judy; Garcia-Barberan, Vanesa; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Giraud, Sophie; Godwin, Andrew K; Goldgar, David E; Hake, Christopher R; Hansen, Thomas V O; Healey, Sue; Hodgson, Shirley; Hogervorst, Frans B L; Houdayer, Claude; Hulick, Peter J; Imyanitov, Evgeny N; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jacobs, Lauren; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M; Vijai, Joseph; Karlan, Beth Y; Kast, Karin; Investigators, KConFab; Khan, Sofia; Kwong, Ava; Laitman, Yael; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lubinski, Jan; Mai, Phuong L; Manoukian, Siranoush; Mazoyer, Sylvie; Meindl, Alfons; Mensenkamp, Arjen R; Montagna, Marco; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I; Ong, Kai-Ren; Osorio, Ana; Park, Sue Kyung; Paulsson-Karlsson, Ylva; Pedersen, Inge Sokilde; Peissel, Bernard; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M; Piedmonte, Marion; Poppe, Bruce; Pujana, Miquel Angel; Radice, Paolo; Rennert, Gad; Rodriguez, Gustavo C; Rookus, Matti A; Ross, Eric A; Schmutzler, Rita Katharina; Simard, Jacques; Singer, Christian F; Slavin, Thomas P; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I; Tea, Muy-Kheng; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; van Rensburg, Elizabeth J; Varesco, Liliana; Varon-Mateeva, Raymonda; Vratimos, Athanassios; Weitzel, Jeffrey N; McGuffog, Lesley; Kirk, Judy; Toland, Amanda Ewart; Hamann, Ute; Lindor, Noralane; Ramus, Susan J; Greene, Mark H; Couch, Fergus J; Offit, Kenneth; Pharoah, Paul D P; Chenevix-Trench, Georgia; Antoniou, Antonis C

    2016-01-01

    Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

  16. Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

    Science.gov (United States)

    Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel; Wang, Xianshu; Barrowdale, Daniel; de Garibay, Gorka Ruiz; Librado, Pablo; Sánchez-Gracia, Alejandro; Rozas, Julio; Bonifaci, Núria; McGuffog, Lesley; Pankratz, Vernon S; Islam, Abul; Mateo, Francesca; Berenguer, Antoni; Petit, Anna; Català, Isabel; Brunet, Joan; Feliubadaló, Lidia; Tornero, Eva; Benítez, Javier; Osorio, Ana; Ramón y Cajal, Teresa; Nevanlinna, Heli; Aittomäki, Kristiina; Arun, Banu K; Toland, Amanda E; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Greene, Mark H; Mai, Phuong L; Nussbaum, Robert L; Andrulis, Irene L; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Timothy R; Barkardottir, Rosa B; Jakubowska, Anna; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Claes, Kathleen; Van Maerken, Tom; Díez, Orland; Hansen, Thomas V; Jønson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; de la Hoya, Miguel; Caldés, Trinidad; Dunning, Alison M; Oliver, Clare; Fineberg, Elena; Cook, Margaret; Peock, Susan; McCann, Emma; Murray, Alex; Jacobs, Chris; Pichert, Gabriella; Lalloo, Fiona; Chu, Carol; Dorkins, Huw; Paterson, Joan; Ong, Kai-Ren; Teixeira, Manuel R; Hogervorst, Frans B L; van der Hout, Annemarie H; Seynaeve, Caroline; van der Luijt, Rob B; Ligtenberg, Marjolijn J L; Devilee, Peter; Wijnen, Juul T; Rookus, Matti A; Meijers-Heijboer, Hanne E J; Blok, Marinus J; van den Ouweland, Ans M W; Aalfs, Cora M; Rodriguez, Gustavo C; Phillips, Kelly-Anne A; Piedmonte, Marion; Nerenstone, Stacy R; Bae-Jump, Victoria L; O'Malley, David M; Ratner, Elena S; Schmutzler, Rita K; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg J; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Jensen, Uffe Birk; Thomassen, Mads; Kruse, Torben A; Foretova, Lenka; Peterlongo, Paolo; Bernard, Loris; Peissel, Bernard; Scuvera, Giulietta; Manoukian, Siranoush; Radice, Paolo; Ottini, Laura; Montagna, Marco; Agata, Simona; Maugard, Christine; Simard, Jacques; Soucy, Penny; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F; Rappaport, Christine; Geschwantler-Kaulich, Daphne; Tea, Muy-Kheng; Pfeiler, Georg; John, Esther M; Miron, Alex; Neuhausen, Susan L; Terry, Mary Beth; Chung, Wendy K; Daly, Mary B; Goldgar, David E; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elisabeth J; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Godwin, Andrew K; Olah, Edith; Narod, Steven A; Rennert, Gad; Paluch, Shani Shimon; Laitman, Yael; Friedman, Eitan; Liljegren, Annelie; Rantala, Johanna; Stenmark-Askmalm, Marie; Loman, Niklas; Imyanitov, Evgeny N; Hamann, Ute; Spurdle, Amanda B; Healey, Sue; Weitzel, Jeffrey N; Herzog, Josef; Margileth, David; Gorrini, Chiara; Esteller, Manel; Gómez, Antonio; Sayols, Sergi; Vidal, Enrique; Heyn, Holger; Stoppa-Lyonnet, Dominique; Léoné, Melanie; Barjhoux, Laure; Fassy-Colcombet, Marion; de Pauw, Antoine; Lasset, Christine; Ferrer, Sandra Fert; Castera, Laurent; Berthet, Pascaline; Cornelis, François; Bignon, Yves-Jean; Damiola, Francesca; Mazoyer, Sylvie; Sinilnikova, Olga M; Maxwell, Christopher A; Vijai, Joseph; Robson, Mark; Kauff, Noah; Corines, Marina J; Villano, Danylko; Cunningham, Julie; Lee, Adam; Lindor, Noralane; Lázaro, Conxi; Easton, Douglas F; Offit, Kenneth; Chenevix-Trench, Georgia; Couch, Fergus J; Antoniou, Antonis C; Pujana, Miguel Angel

    2015-01-01

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

  17. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    Science.gov (United States)

    Vigorito, Elena; Kuchenbaecker, Karoline B.; Beesley, Jonathan; Adlard, Julian; Agnarsson, Bjarni A.; Andrulis, Irene L.; Arun, Banu K.; Barjhoux, Laure; Belotti, Muriel; Benitez, Javier; Berger, Andreas; Bojesen, Anders; Bonanni, Bernardo; Brewer, Carole; Caldes, Trinidad; Caligo, Maria A.; Campbell, Ian; Chan, Salina B.; Claes, Kathleen B. M.; Cohn, David E.; Cook, Jackie; Daly, Mary B.; Damiola, Francesca; Davidson, Rosemarie; de Pauw, Antoine; Delnatte, Capucine; Diez, Orland; Domchek, Susan M.; Dumont, Martine; Durda, Katarzyna; Dworniczak, Bernd; Easton, Douglas F.; Eccles, Diana; Edwinsdotter Ardnor, Christina; Eeles, Ros; Ejlertsen, Bent; Ellis, Steve; Evans, D. Gareth; Feliubadalo, Lidia; Fostira, Florentia; Foulkes, William D.; Friedman, Eitan; Frost, Debra; Gaddam, Pragna; Ganz, Patricia A.; Garber, Judy; Garcia-Barberan, Vanesa; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Giraud, Sophie; Godwin, Andrew K.; Goldgar, David E.; Hake, Christopher R.; Hansen, Thomas V. O.; Healey, Sue; Hodgson, Shirley; Hogervorst, Frans B. L.; Houdayer, Claude; Hulick, Peter J.; Imyanitov, Evgeny N.; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jacobs, Lauren; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M.; Vijai, Joseph; Karlan, Beth Y.; Kast, Karin; Investigators, KConFab; Khan, Sofia; Kwong, Ava; Laitman, Yael; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lubinski, Jan; Mai, Phuong L.; Manoukian, Siranoush; Mazoyer, Sylvie; Meindl, Alfons; Mensenkamp, Arjen R.; Montagna, Marco; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I.; Ong, Kai-ren; Osorio, Ana; Park, Sue Kyung; Paulsson-Karlsson, Ylva; Pedersen, Inge Sokilde; Peissel, Bernard; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M.; Piedmonte, Marion; Poppe, Bruce; Pujana, Miquel Angel; Radice, Paolo; Rennert, Gad; Rodriguez, Gustavo C.; Rookus, Matti A.; Ross, Eric A.; Schmutzler, Rita Katharina; Simard, Jacques; Singer, Christian F.; Slavin, Thomas P.; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I.; Tea, Muy-Kheng; Teixeira, Manuel R.; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; van Rensburg, Elizabeth J.; Varesco, Liliana; Varon-Mateeva, Raymonda; Vratimos, Athanassios; Weitzel, Jeffrey N.; McGuffog, Lesley; Kirk, Judy; Toland, Amanda Ewart; Hamann, Ute; Lindor, Noralane; Ramus, Susan J.; Greene, Mark H.; Couch, Fergus J.; Offit, Kenneth; Pharoah, Paul D. P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.

    2016-01-01

    Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population. PMID:27463617

  18. Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

    Directory of Open Access Journals (Sweden)

    Ignacio Blanco

    Full Text Available While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR = 1.10, 95% confidence interval (CI 1.04-1.15, p = 1.9 x 10(-4 (false discovery rate (FDR-adjusted p = 0.043. Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045. Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05 for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

  19. Post-mortem testing; germline BRCA1/2 variant detection using archival FFPE non-tumor tissue. A new paradigm in genetic counseling.

    Science.gov (United States)

    Petersen, Annabeth Høgh; Aagaard, Mads Malik; Nielsen, Henriette Roed; Steffensen, Karina Dahl; Waldstrøm, Marianne; Bojesen, Anders

    2016-08-01

    Accurate estimation of cancer risk in HBOC families often requires BRCA1/2 testing, but this may be impossible in deceased family members. Previous, testing archival formalin-fixed, paraffin-embedded (FFPE) tissue for germline BRCA1/2 variants was unsuccessful, except for the Jewish founder mutations. A high-throughput method to systematically test for variants in all coding regions of BRCA1/2 in archival FFPE samples of non-tumor tissue is described, using HaloPlex target enrichment and next-generation sequencing. In a validation study, correct identification of variants or wild-type was possible in 25 out of 30 (83%) FFPE samples (age range 1-14 years), with a known variant status in BRCA1/2. No false positive was found. Unsuccessful identification was due to highly degraded DNA or presence of large intragenic deletions. In clinical use, a total of 201 FFPE samples (aged 0-43 years) were processed. Thirty-six samples were rejected because of highly degraded DNA or failed library preparation. Fifteen samples were investigated to search for a known variant. In the remaining 150 samples (aged 0-38 years), three variants known to affect function and one variant likely to affect function in BRCA1, six variants known to affect function and one variant likely to affect function in BRCA2, as well as four variants of unknown significance (VUS) in BRCA1 and three VUS in BRCA2 were discovered. It is now possible to test for germline BRCA1/2 variants in deceased persons, using archival FFPE samples from non-tumor tissue. Accurate genetic counseling is achievable in families where variant testing would otherwise be impossible. PMID:26733283

  20. Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

    Science.gov (United States)

    Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel; Wang, Xianshu; Barrowdale, Daniel; de Garibay, Gorka Ruiz; Librado, Pablo; Sánchez-Gracia, Alejandro; Rozas, Julio; Bonifaci, Núria; McGuffog, Lesley; Pankratz, Vernon S.; Islam, Abul; Mateo, Francesca; Berenguer, Antoni; Petit, Anna; Català, Isabel; Brunet, Joan; Feliubadaló, Lidia; Tornero, Eva; Benítez, Javier; Osorio, Ana; Cajal, Teresa Ramón y; Nevanlinna, Heli; Aittomäki, Kristiina; Arun, Banu K.; Toland, Amanda E.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Greene, Mark H.; Mai, Phuong L.; Nussbaum, Robert L.; Andrulis, Irene L.; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Barkardottir, Rosa B.; Jakubowska, Anna; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Claes, Kathleen; Van Maerken, Tom; Díez, Orland; Hansen, Thomas V.; Jønson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; de la Hoya, Miguel; Caldés, Trinidad; Dunning, Alison M.; Oliver, Clare; Fineberg, Elena; Cook, Margaret; Peock, Susan; McCann, Emma; Murray, Alex; Jacobs, Chris; Pichert, Gabriella; Lalloo, Fiona; Chu, Carol; Dorkins, Huw; Paterson, Joan; Ong, Kai-Ren; Teixeira, Manuel R.; Hogervorst, Frans B. L.; van der Hout, Annemarie H.; Seynaeve, Caroline; van der Luijt, Rob B.; Ligtenberg, Marjolijn J. L.; Devilee, Peter; Wijnen, Juul T.; Rookus, Matti A.; Meijers-Heijboer, Hanne E. J.; Blok, Marinus J.; van den Ouweland, Ans M. W.; Aalfs, Cora M.; Rodriguez, Gustavo C.; Phillips, Kelly-Anne A.; Piedmonte, Marion; Nerenstone, Stacy R.; Bae-Jump, Victoria L.; O'Malley, David M.; Ratner, Elena S.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg J.; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Jensen, Uffe Birk; Thomassen, Mads; Kruse, Torben A.; Foretova, Lenka; Peterlongo, Paolo; Bernard, Loris; Peissel, Bernard; Scuvera, Giulietta; Manoukian, Siranoush; Radice, Paolo; Ottini, Laura; Montagna, Marco; Agata, Simona; Maugard, Christine; Simard, Jacques; Soucy, Penny; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Geschwantler-Kaulich, Daphne; Tea, Muy-Kheng; Pfeiler, Georg; John, Esther M.; Miron, Alex; Neuhausen, Susan L.; Terry, Mary Beth; Chung, Wendy K.; Daly, Mary B.; Goldgar, David E.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elisabeth J.; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Godwin, Andrew K.; Olah, Edith; Narod, Steven A.; Rennert, Gad; Paluch, Shani Shimon; Laitman, Yael; Friedman, Eitan; Liljegren, Annelie; Rantala, Johanna; Stenmark-Askmalm, Marie; Loman, Niklas; Imyanitov, Evgeny N.; Hamann, Ute; Spurdle, Amanda B.; Healey, Sue; Weitzel, Jeffrey N.; Herzog, Josef; Margileth, David; Gorrini, Chiara; Esteller, Manel; Gómez, Antonio; Sayols, Sergi; Vidal, Enrique; Heyn, Holger; Stoppa-Lyonnet, Dominique; Léoné, Melanie; Barjhoux, Laure; Fassy-Colcombet, Marion; de Pauw, Antoine; Lasset, Christine; Ferrer, Sandra Fert; Castera, Laurent; Berthet, Pascaline; Cornelis, François; Bignon, Yves-Jean; Damiola, Francesca; Mazoyer, Sylvie; Maxwell, Christopher A.; Vijai, Joseph; Robson, Mark; Kauff, Noah; Corines, Marina J.; Villano, Danylko; Cunningham, Julie; Lee, Adam; Lindor, Noralane; Lázaro, Conxi; Easton, Douglas F.; Offit, Kenneth; Chenevix-Trench, Georgia; Couch, Fergus J.; Antoniou, Antonis C.; Pujana, Miguel Angel

    2015-01-01

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 – 1.15, p = 1.9 x 10−4 (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 – 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients’ survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers. PMID:25830658

  1. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

    Science.gov (United States)

    Vigorito, Elena; Kuchenbaecker, Karoline B; Beesley, Jonathan; Adlard, Julian; Agnarsson, Bjarni A; Andrulis, Irene L; Arun, Banu K; Barjhoux, Laure; Belotti, Muriel; Benitez, Javier; Berger, Andreas; Bojesen, Anders; Bonanni, Bernardo; Brewer, Carole; Caldes, Trinidad; Caligo, Maria A; Campbell, Ian; Chan, Salina B; Claes, Kathleen B M; Cohn, David E; Cook, Jackie; Daly, Mary B; Damiola, Francesca; Davidson, Rosemarie; Pauw, Antoine de; Delnatte, Capucine; Diez, Orland; Domchek, Susan M; Dumont, Martine; Durda, Katarzyna; Dworniczak, Bernd; Easton, Douglas F; Eccles, Diana; Edwinsdotter Ardnor, Christina; Eeles, Ros; Ejlertsen, Bent; Ellis, Steve; Evans, D Gareth; Feliubadalo, Lidia; Fostira, Florentia; Foulkes, William D; Friedman, Eitan; Frost, Debra; Gaddam, Pragna; Ganz, Patricia A; Garber, Judy; Garcia-Barberan, Vanesa; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Giraud, Sophie; Godwin, Andrew K; Goldgar, David E; Hake, Christopher R; Hansen, Thomas V O; Healey, Sue; Hodgson, Shirley; Hogervorst, Frans B L; Houdayer, Claude; Hulick, Peter J; Imyanitov, Evgeny N; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jacobs, Lauren; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M; Vijai, Joseph; Karlan, Beth Y; Kast, Karin; Investigators, KConFab; Khan, Sofia; Kwong, Ava; Laitman, Yael; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lubinski, Jan; Mai, Phuong L; Manoukian, Siranoush; Mazoyer, Sylvie; Meindl, Alfons; Mensenkamp, Arjen R; Montagna, Marco; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I; Ong, Kai-Ren; Osorio, Ana; Park, Sue Kyung; Paulsson-Karlsson, Ylva; Pedersen, Inge Sokilde; Peissel, Bernard; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M; Piedmonte, Marion; Poppe, Bruce; Pujana, Miquel Angel; Radice, Paolo; Rennert, Gad; Rodriguez, Gustavo C; Rookus, Matti A; Ross, Eric A; Schmutzler, Rita Katharina; Simard, Jacques; Singer, Christian F; Slavin, Thomas P; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I; Tea, Muy-Kheng; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; van Rensburg, Elizabeth J; Varesco, Liliana; Varon-Mateeva, Raymonda; Vratimos, Athanassios; Weitzel, Jeffrey N; McGuffog, Lesley; Kirk, Judy; Toland, Amanda Ewart; Hamann, Ute; Lindor, Noralane; Ramus, Susan J; Greene, Mark H; Couch, Fergus J; Offit, Kenneth; Pharoah, Paul D P; Chenevix-Trench, Georgia; Antoniou, Antonis C

    2016-01-01

    Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population. PMID:27463617

  2. Factors influencing ovulation and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

    Science.gov (United States)

    Kotsopoulos, Joanne; Lubinski, Jan; Gronwald, Jacek; Cybulski, Cezary; Demsky, Rochelle; Neuhausen, Susan L; Kim-Sing, Charmaine; Tung, Nadine; Friedman, Susan; Senter, Leigha; Weitzel, Jeffrey; Karlan, Beth; Moller, Pal; Sun, Ping; Narod, Steven A

    2015-09-01

    The role of the lifetime number of ovulatory cycles has not been evaluated in the context of BRCA-associated ovarian cancer. Thus, we conducted a matched case-control study to evaluate the relationship between the cumulative number of ovulatory cycles (and contributing components) and risk of developing ovarian cancer in BRCA mutation carriers (1,329 cases and 5,267 controls). Information regarding reproductive and hormonal factors was collected from a routinely administered questionnaire. Conditional logistic regression was used to evaluate all associations. We observed a 45% reduction in the risk of developing ovarian cancer among women in the lowest vs. highest quartile of ovulatory cycles (OR = 0.55; 95% CI 0.41-0.75, p = 0.0001). Breastfeeding for more than 12 months was associated with a 38% (95% CI 0.48-0.79) and 50% (95% CI 0.29-0.84) reduction in risk among BRCA1 and BRCA2 mutation carriers, respectively. For oral contraceptive use, maximum benefit was seen with five or more years of use among BRCA1 mutation carriers (OR = 0.50; 95% CI 0.40-0.63) and three or more years for BRCA2 mutation carriers (OR = 0.42; 95% CI 0.22-0.83). Increasing parity was associated with a significant inverse trend among BRCA1 (OR = 0.87; 95% CI 0.79-0.96; p-trend = 0.005) but not BRCA2 mutation carriers (OR 0.98; 95% CI 0.81-1.19; p-trend = 0.85). A later age at menopause was associated with an increased risk in women with a BRCA1 mutation (OR trend = 1.18; 95% CI 1.03-1.35; p = 0.02). These findings support an important role of breastfeeding and oral contraceptive use for the primary prevention of ovarian cancer among women carrying BRCA mutations. PMID:25482078

  3. In their own words: treating very young BRCA1/2 mutation-positive women with care and caution.

    Directory of Open Access Journals (Sweden)

    Lindsey M Hoskins

    Full Text Available PURPOSE: Young women who have been identified as carrying a deleterious mutation in BRCA1 or BRCA2 face a unique set of challenges related to managing cancer risk during a demographically-dense stage of life. They may struggle with decision-making in the absence of clear age-specific guidelines for medical management and because they have not yet fully developed the capacity to make life-altering decisions confidently. This study sought a patient-centered perspective on the dilemmas faced by 18-24 year olds who completed BRCA1/2 gene mutation testing prior to their 25(th birthdays. PATIENTS AND METHOD: This study integrated qualitative data from three independent investigations of BRCA1/2-positive women recruited through cancer risk clinics, hospital-based research centers, and online organizations. All 32 participants were women aged 21-25 who tested positive for a BRCA1/2 gene mutation between 2 and 60 months prior to data collection. Investigators used techniques of grounded theory and interpretive description to conduct both within and cross-study analysis. RESULTS: Participants expressed needs for (1 greater clarity in recommendations for screening and prevention before age 25, especially with consideration of early and regular exposure to radiation associated with mammography or to hormones used in birth control, and (2 ongoing contact with providers to discuss risk management protocols as they become available. CONCLUSIONS: Health care needs during the young adult years evolve with the cognitive capacity to address abrupt and pressing change. Specific needs of women in this population include a desire to balance autonomous decision-making with supportive guidance, a need for clear, accurate and consistent medical recommendations. Optimally, these women are best cared for by a team of genetically-oriented providers as part of a sustained program of ongoing support, rather than seen in an episodic, crisis-driven fashion. A discussion of

  4. Screening of 1331 Danish breast and/or ovarian cancer families identified 40 novel BRCA1 and BRCA2 mutations

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Jønson, Lars; Steffensen, Ane Y;

    2011-01-01

    and BRCA2 in high risk breast and/or ovarian cancer families. The mutations were detected via pre-screening using dHPLC or high-resolution melting and direct sequencing. We identified 16 variants in BRCA1, including 9 deleterious frame-shift mutations, 2 intronic variants, 4 missense mutations, and 1...... synonymous variant. The remaining 24 variants were identified in BRCA2, including 10 deleterious mutants (6 frame-shift and 4 nonsense), 2 intronic variants, 10 missense mutations and 2 synonymous variants. The frequency of the variants of unknown significance was examined in control individuals. Moreover...

  5. Characterization of a novel large deletion and single point mutations in the BRCA1 gene in a Greek cohort of families with suspected hereditary breast cancer

    Directory of Open Access Journals (Sweden)

    Hadjisavvas Andreas

    2004-09-01

    Full Text Available Abstract Background Germline mutations in BRCA1 and BRCA2 predispose to breast and ovarian cancer. A multitude of mutations have been described and are found to be scattered throughout these two large genes. We describe analysis of BRCA1 in 25 individuals from 18 families from a Greek cohort. Methods The approach used is based on dHPLC mutation screening of the BRCA1 gene, followed by sequencing of fragments suspected to carry a mutation including intron – exon boundaries. In patients with a strong family history but for whom no mutations were detected, analysis was extended to exons 10 and 11 of the BRCA2 gene, followed by MLPA analysis for screening for large genomic rearrangements. Results A pathogenic mutation in BRCA1 was identified in 5/18 (27.7 % families, where four distinct mutations have been observed. Single base putative pathogenic mutations were identified by dHPLC and confirmed by sequence analysis in 4 families: 5382insC (in two families, G1738R, and 5586G > A (in one family each. In addition, 18 unclassified variants and silent polymorphisms were detected including a novel silent polymorphism in exon 11 of the BRCA1 gene. Finally, MLPA revealed deletion of exon 20 of the BRCA1 gene in one family, a deletion that encompasses 3.2 kb of the gene starting 21 bases into exon 20 and extending 3.2 kb into intron 20 and leads to skipping of the entire exon 20. The 3' breakpoint lies within an AluSp repeat but there are no recognizable repeat motifs at the 5' breakpoint implicating a mechanism different to Alu-mediated recombination, responsible for the majority of rearrangements in the BRCA1 gene. Conclusions We conclude that a combination of techniques capable of detecting both single base mutations and small insertions / deletions and large genomic rearrangements is necessary in order to accurately analyze the BRCA1 gene in patients at high risk of carrying a germline mutation as determined by their family history. Furthermore, our

  6. Targeted Prostate Cancer Screening in BRCA1 and BRCA2 Mutation Carriers: Results from the Initial Screening Round of the IMPACT Study

    Science.gov (United States)

    Bancroft, Elizabeth K.; Page, Elizabeth C.; Castro, Elena; Lilja, Hans; Vickers, Andrew; Sjoberg, Daniel; Assel, Melissa; Foster, Christopher S.; Mitchell, Gillian; Drew, Kate; Mæhle, Lovise; Axcrona, Karol; Evans, D. Gareth; Bulman, Barbara; Eccles, Diana; McBride, Donna; van Asperen, Christi; Vasen, Hans; Kiemeney, Lambertus A.; Ringelberg, Janneke; Cybulski, Cezary; Wokolorczyk, Dominika; Selkirk, Christina; Hulick, Peter J.; Bojesen, Anders; Skytte, Anne-Bine; Lam, Jimmy; Taylor, Louise; Oldenburg, Rogier; Cremers, Ruben; Verhaegh, Gerald; van Zelst-Stams, Wendy A.; Oosterwijk, Jan C.; Blanco, Ignacio; Salinas, Monica; Cook, Jackie; Rosario, Derek J.; Buys, Saundra; Conner, Tom; Ausems, Margreet G.; Ong, Kai-ren; Hoffman, Jonathan; Domchek, Susan; Powers, Jacquelyn; Teixeira, Manuel R.; Maia, Sofia; Foulkes, William D.; Taherian, Nassim; Ruijs, Marielle; den Enden, Apollonia T. Helderman-van; Izatt, Louise; Davidson, Rosemarie; Adank, Muriel A.; Walker, Lisa; Schmutzler, Rita; Tucker, Kathy; Kirk, Judy; Hodgson, Shirley; Harris, Marion; Douglas, Fiona; Lindeman, Geoffrey J.; Zgajnar, Janez; Tischkowitz, Marc; Clowes, Virginia E.; Susman, Rachel; Ramón y Cajal, Teresa; Patcher, Nicholas; Gadea, Neus; Spigelman, Allan; van Os, Theo; Liljegren, Annelie; Side, Lucy; Brewer, Carole; Brady, Angela F.; Donaldson, Alan; Stefansdottir, Vigdis; Friedman, Eitan; Chen-Shtoyerman, Rakefet; Amor, David J.; Copakova, Lucia; Barwell, Julian; Giri, Veda N.; Murthy, Vedang; Nicolai, Nicola; Teo, Soo-Hwang; Greenhalgh, Lynn; Strom, Sara; Henderson, Alex; McGrath, John; Gallagher, David; Aaronson, Neil; Ardern-Jones, Audrey; Bangma, Chris; Dearnaley, David; Costello, Philandra; Eyfjord, Jorunn; Rothwell, Jeanette; Falconer, Alison; Gronberg, Henrik; Hamdy, Freddie C.; Johannsson, Oskar; Khoo, Vincent; Kote-Jarai, Zsofia; Lubinski, Jan; Axcrona, Ulrika; Melia, Jane; McKinley, Joanne; Mitra, Anita V.; Moynihan, Clare; Rennert, Gad; Suri, Mohnish; Wilson, Penny; Killick, Emma; Moss, Sue; Eeles, Rosalind A.

    2014-01-01

    Background Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. Objective To report the first year's screening results for all men at enrolment in the study. Design, setting and participants We recruited men aged 40–69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA >3 ng/ml were offered prostate biopsy. Outcome measurements and statistical analysis PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. Results and limitations We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%—double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. Conclusions The IMPACT screening network will be useful

  7. The VEGF_936_C>T 3'UTR polymorphism reduces BRCA1-associated breast cancer risk in Polish women.

    Science.gov (United States)

    Jakubowska, Anna; Gronwald, Jacek; Menkiszak, Janusz; Górski, Bohdan; Huzarski, Tomasz; Byrski, Tomasz; Edler, Lutz; Lubiński, Jan; Scott, Rodney J; Hamann, Ute

    2008-04-01

    The vascular endothelial growth factor (VEGF) plays a crucial role in the initiation of angiogenesis, which is an important stage in tumor development. A functional 936_C>T polymorphism in the VEGF gene and its association with sporadic breast cancer risk has been analyzed in various studies yielding conflicting results. To analyze the role of this polymorphism in modifying hereditary breast and ovarian cancer risks, we conducted a case-control study and genotyped 755 Polish BRCA1 carriers, including 319 breast cancer cases, 146 ovarian cancer cases, and 290 unaffected controls. The results revealed an association of the CT+TT genotypes with a reduced breast cancer risk (OR(adj) 0.63, 95% CI, 0.41-0.98; OR(clustered) 0.63, 95% CI, 0.48-0.83), and a potential effect on ovarian cancer risk (OR(adj) 0.62, 95% CI, 0.33-1.18; OR(clustered) 0.62, 95% CI, 0.47-0.83). Thus, the 936_C>T polymorphism appears to modify disease risks in BRCA1 carriers. PMID:18171601

  8. Dealing with the tests for BRCA1 and BRCA2 screening from the clinicians point of view

    International Nuclear Information System (INIS)

    The two major hereditary breast cancer susceptibility genes, BRCA1 and BRCA2 are associated with 85 to 90% of all hereditary breast and ovarian cancers. They encode for two proteins who participate in a common DNA damage response pathway associated with the double-strand break repair. The standard of gene analysis is complete gene sequencing, although this is a very expensive and time-consuming method. Therefore, it is necessary to select families with a high a-priori risk for having a mutation. Interpretation of gene testing results may be difficult as penetrance is not hundred percent and due to unclassified variants. Prevention of breast and ovarian cancer is possible with prophylactic surgery. Alternatively, endocrine prevention or intensified surveillance could be tried. The evidence of BRCA1 and BRCA2 concerning radiosensitivity is not clear yet. The susceptibility to radiation-induced DNA damage could have implications for therapy options. As the benefits of so far used diagnostic or therapeutic tools are high, they outweigh the possible risks due to increased radiosensitivity. (orig.)

  9. BRCA1 and BRCA2 mutation prevalence and clinical characteristics of a population-based series of ovarian cancer cases from Denmark

    DEFF Research Database (Denmark)

    Soegaard, M.; Kjaer, S.K.; Cox, M.;

    2008-01-01

    PURPOSE: To evaluate the prevalence of BRCA1 and BRCA2 mutations and associations with clinical correlates of disease in a population-based series of ovarian cancer cases from Denmark. METHODS: DNA sequencing and multiplex ligation-dependent probe amplification analysis were used to analyze...... the BRCA1 and BRCA2 genes for coding sequence mutations and large genomic rearrangements in 445 confirmed cases of ovarian cancer. We evaluated associations between mutation status and clinical characteristics, including cancer risks for first-degree relatives and clinicopathologic features of tumors....... RESULTS: Deleterious BRCA1 or BRCA2 mutations were identified in 26 cases; thus, mutations in these genes are responsible for at least 5.8% of ovarian cancer cases in this population. Five different mutations were identified in more than one individual, suggesting that they may be founder mutations...

  10. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

    DEFF Research Database (Denmark)

    Couch, Fergus J; Gerdes, Anne-Marie Axø; Nielsen, Finn Cilius;

    2013-01-01

    ), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303......, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also...

  11. NGS-based BRCA1/2 mutation testing of high-grade serous ovarian cancer tissue: results and conclusions of the first international round robin trial.

    Science.gov (United States)

    Endris, Volker; Stenzinger, Albrecht; Pfarr, Nicole; Penzel, Roland; Möbs, Markus; Lenze, Dido; Darb-Esfahani, Silvia; Hummel, Michael; Sabine-Merkelbach-Bruse; Jung, Andreas; Lehmann, Ulrich; Kreipe, Hans; Kirchner, Thomas; Büttner, Reinhard; Jochum, Wolfram; Höfler, Gerald; Dietel, Manfred; Weichert, Wilko; Schirmacher, Peter

    2016-06-01

    With the approval of olaparib as monotherapy treatment in platinum-sensitive, relapsed high-grade serous ovarian cancer by the European Medical Agency (EMA), comprehensive genotyping of BRCA1 and BRCA2 in tumor tissue has become a mandatory pre-therapeutic test. This requires significant advances in routine tumor test methodologies due to the large size of both genes and the lack of mutational hot spots. Classical focused screening approaches, like Sanger sequencing, do not allow for a sensitive, rapid, and economic analysis of tumor tissue. Next-generation sequencing (NGS) approaches employing targeted panels for BRCA1/2 to interrogate formalin-fixed and paraffin-embedded tumor samples from either surgical resection or biopsy specimens can overcome these limitations. Although focused NGS methods have been implemented by few centers in routine molecular diagnostics for the analysis of some druggable oncogenic mutations, the reliable diagnostic testing of the entire coding regions of BRCA1 and BRCA2 was a new challenge requiring extensive technological improvement and quality management. Here, we describe the implementation and results of the first round robin trial for BRCA1/2 mutation testing in tumor tissue that was conducted in central Europe on May 2015, shortly after the approval and prior to the official release of olaparib. The high success rate of 81 % (21/26 test centers) demonstrates that BRCA1/2 multicenter mutation testing is well feasible in FFPE tumor tissue, extending to other tumor entities beyond ovarian cancer. The high number of test centers passing the trial demonstrates the success of the concerted efforts by German, Swiss, and Austrian pathology centers to ensure quality-controlled NGS-based testing and proves the potential of this technology in routine molecular pathology. On the basis of our results, we provide recommendations for predictive testing of tumor tissue for BRCA1/2 to clinical decision making in ovarian cancer patients.

  12. After BRCA1 and BRCA2-what next? Multifactorial segregation analyses of three-generation, population-based Australian families affected by female breast cancer.

    Science.gov (United States)

    Cui, J; Antoniou, A C; Dite, G S; Southey, M C; Venter, D J; Easton, D F; Giles, G G; McCredie, M R; Hopper, J L

    2001-02-01

    Mutations in BRCA1 and BRCA2 that cause a dominantly inherited high risk of female breast cancer seem to explain only a small proportion of the aggregation of the disease. To study the possible additional genetic components, we conducted single-locus and two-locus segregation analyses, with and without a polygenic background, using three-generation families ascertained through 858 women with breast cancer diagnosed at age Australia. Extensive testing for deleterious mutations in BRCA1 and BRCA2, to date, has identified 34 carriers. Our analysis suggested that, after other possible unmeasured familial factors are adjusted for and the known BRCA1 and BRCA2 mutation carriers are excluded, there appears to be a residual dominantly inherited risk of female breast cancer in addition to that derived from mutations in BRCA1 and BRCA2. This study also suggests that there is a substantial recessively inherited risk of early-onset breast cancer. According to the best-fitting model, after excluding known carriers of mutations in BRCA1 and BRCA2, about 1/250 (95% confidence interval [CI] 1/500 to 1/125) women have a recessive risk of 86% (95% CI 69%-100%) by age 50 years and of almost 100% by age 60 years. Possible reasons that our study has implicated a novel strong recessive effect include our inclusion of data on lineal aunts and grandmothers, study of families ascertained through women with early-onset breast cancer, allowance for multiple familial factors in the analysis, and removal of families for whom the cause (i.e., BRCA1 or BRCA2) is known. Our findings may have implications for attempts to identify new breast cancer-susceptibility genes. PMID:11133358

  13. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

    Science.gov (United States)

    Osorio, Ana; Milne, Roger L; Kuchenbaecker, Karoline; Vaclová, Tereza; Pita, Guillermo; Alonso, Rosario; Peterlongo, Paolo; Blanco, Ignacio; de la Hoya, Miguel; Duran, Mercedes; Díez, Orland; Ramón Y Cajal, Teresa; Konstantopoulou, Irene; Martínez-Bouzas, Cristina; Andrés Conejero, Raquel; Soucy, Penny; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; Swe-Brca; Arver, Brita; Rantala, Johanna; Loman, Niklas; Ehrencrona, Hans; Olopade, Olufunmilayo I; Beattie, Mary S; Domchek, Susan M; Nathanson, Katherine; Rebbeck, Timothy R; Arun, Banu K; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; John, Esther M; Whittemore, Alice S; Daly, Mary B; Southey, Melissa; Hopper, John; Terry, Mary B; Buys, Saundra S; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Steele, Linda; Neuhausen, Susan L; Ding, Yuan Chun; Hansen, Thomas V O; Jønson, Lars; Ejlertsen, Bent; Gerdes, Anne-Marie; Infante, Mar; Herráez, Belén; Moreno, Leticia Thais; Weitzel, Jeffrey N; Herzog, Josef; Weeman, Kisa; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Bonanni, Bernardo; Mariette, Frederique; Volorio, Sara; Viel, Alessandra; Varesco, Liliana; Papi, Laura; Ottini, Laura; Tibiletti, Maria Grazia; Radice, Paolo; Yannoukakos, Drakoulis; Garber, Judy; Ellis, Steve; Frost, Debra; Platte, Radka; Fineberg, Elena; Evans, Gareth; Lalloo, Fiona; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Cole, Trevor; Eccles, Diana; Cook, Jackie; Hodgson, Shirley; Brewer, Carole; Tischkowitz, Marc; Douglas, Fiona; Porteous, Mary; Side, Lucy; Walker, Lisa; Morrison, Patrick; Donaldson, Alan; Kennedy, John; Foo, Claire; Godwin, Andrew K; Schmutzler, Rita Katharina; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hans Jörg; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M; Mazoyer, Sylvie; Damiola, Francesca; Poppe, Bruce; Claes, Kathleen; Piedmonte, Marion; Tucker, Kathy; Backes, Floor; Rodríguez, Gustavo; Brewster, Wendy; Wakeley, Katie; Rutherford, Thomas; Caldés, Trinidad; Nevanlinna, Heli; Aittomäki, Kristiina; Rookus, Matti A; van Os, Theo A M; van der Kolk, Lizet; de Lange, J L; Meijers-Heijboer, Hanne E J; van der Hout, A H; van Asperen, Christi J; Gómez Garcia, Encarna B; Hoogerbrugge, Nicoline; Collée, J Margriet; van Deurzen, Carolien H M; van der Luijt, Rob B; Devilee, Peter; Hebon; Olah, Edith; Lázaro, Conxi; Teulé, Alex; Menéndez, Mireia; Jakubowska, Anna; Cybulski, Cezary; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Johannsson, Oskar Th; Maugard, Christine; Montagna, Marco; Tognazzo, Silvia; Teixeira, Manuel R; Healey, Sue; Investigators, Kconfab; Olswold, Curtis; Guidugli, Lucia; Lindor, Noralane; Slager, Susan; Szabo, Csilla I; Vijai, Joseph; Robson, Mark; Kauff, Noah; Zhang, Liying; Rau-Murthy, Rohini; Fink-Retter, Anneliese; Singer, Christian F; Rappaport, Christine; Geschwantler Kaulich, Daphne; Pfeiler, Georg; Tea, Muy-Kheng; Berger, Andreas; Phelan, Catherine M; Greene, Mark H; Mai, Phuong L; Lejbkowicz, Flavio; Andrulis, Irene; Mulligan, Anna Marie; Glendon, Gord; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Thomassen, Mads; Kruse, Torben A; Jensen, Uffe Birk; Friedman, Eitan; Laitman, Yael; Shimon, Shani Paluch; Simard, Jacques; Easton, Douglas F; Offit, Kenneth; Couch, Fergus J; Chenevix-Trench, Georgia; Antoniou, Antonis C; Benitez, Javier

    2014-04-01

    Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

  14. High frequency and allele-specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus.

    Science.gov (United States)

    Bogdanova, N V; Antonenkova, N N; Rogov, Y I; Karstens, J H; Hillemanns, P; Dörk, T

    2010-10-01

    Breast cancer and ovarian cancer are common malignancies in Belarus accounting for about 3500 and 800 new cases per year, respectively. For breast cancer, the rates and age of onset appear to vary significantly in regions differentially affected by the Chernobyl accident. We assessed the frequency and distribution of three BRCA1 founder mutations 5382insC, 4153delA and Cys61Gly in two hospital-based series of 1945 unselected breast cancer patients and of 201 unselected ovarian cancer patients from Belarus as well as in 1019 healthy control females from the same population. Any of these mutations were identified in 4.4% of the breast cancer patients, 26.4% of the ovarian cancer patients and 0.5% of the controls. In the breast cancer patients, BRCA1 mutations were strongly associated with earlier age at diagnosis, with oestrogen receptor (ER) negative tumours and with a first-degree family history of breast cancer, although only 35% of the identified BRCA1 mutation carriers had such a family history. There were no marked differences in the regional distribution of BRCA1 mutations, so that the significant differences in age at diagnosis and family history of breast cancer patients from areas afflicted by the Chernobyl accident could not be explained by BRCA1. We next observed a higher impact and a shifted mutational spectrum of BRCA1 in the series of Byelorussian ovarian cancer patients where the three founder mutations accounted for 26.4% (53/201). While the Cys61Gly mutation appeared underrepresented in ovarian cancer as compared with breast cancer cases from the same population (p = 0.01), the 4153delA mutation made a higher contribution to ovarian cancer than to breast cancer (p Belarus and might have implications for cancer prevention, treatment and genetic counselling in this population.

  15. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

    Directory of Open Access Journals (Sweden)

    Ana Osorio

    2014-04-01

    Full Text Available Single Nucleotide Polymorphisms (SNPs in genes involved in the DNA Base Excision Repair (BER pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase, and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2 gene (HR: 1.09, 95% CI (1.03-1.16, p = 2.7 × 10(-3 for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3. DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

  16. BRCA1 mRNA expression as a predictive and prognostic marker in advanced esophageal squamous cell carcinoma treated with cisplatin- or docetaxel-based chemotherapy/chemoradiotherapy.

    Directory of Open Access Journals (Sweden)

    Yong Gao

    Full Text Available BACKGROUND: The molecular backgrounds that determine therapeutic effectiveness in esophageal cancer remain largely unknown. Breast cancer susceptibility gene 1 (BRCA1 expression has been found to switch the response to cisplatin- or paclitaxel-based chemotherapy. It remains unclear how variations in BRCA1 expression influence clinical outcomes in esophageal cancer. PATIENTS AND METHODS: Quantitative real-time polymerase chain reaction (qPCR was performed to examine BRCA1 mRNA expressions in paraffin-embedded specimens from 144 patients with advanced or metastatic esophageal squamous cell carcinoma who received cisplatin- or docetaxel-based first-line treatments. RESULTS: Low BRCA1 mRNA expression correlated with increased response rate (RR; P = 0.025 and 0.017, respectively and median overall survival (mOS; P = 0.002 and P<0.001, respectively in cisplatin-based chemotherapy or chemoradiotherapy group and also correlated with decreased RR (P = 0.017 and 0.024, respectively and mOS (both P<0.001 in docetaxel-based chemotherapy or chemoradiotherapy group. Multivariate analysis revealed that low BRCA1 expression was an independent prognostic factor in cisplatin-based chemotherapy (HR 0.29; 95%CI 0.12-0.71; P = 0.007 or chemoradiotherapy (HR 0.12; 95%CI 0.04-0.37; P<0.001 group and higher risk for mortality in docetaxel-based chemotherapy (HR 5.02; 95%CI 2.05-12.28; P<0.001 or chemoradiotherapy (HR 7.02; 95%CI 2.37-27.77; P<0.001 group. CONCLUSIONS: BRCA1 mRNA expression could be used as a predictive and prognostic marker in esophageal cancer who underwent first-line cisplatin- or docetaxel-based treatments.

  17. Breast and Ovarian Cancer Risk due to Prevalence of BRCA1 and BRCA2 Variants in Pakistani Population: A Pakistani Database Report

    Directory of Open Access Journals (Sweden)

    Ayesha Farooq

    2011-01-01

    Mutational screening of the exons in all the samples of our study group did not reveal any pathogenic mutation. These results along with the results of the previous Pakistani studies for both BRCA1 and BRCA2 genes were summed up to prepare a Pakistani database. Percentage involvement of these genes was estimated. Nine percent of these cancers show alterations in BRCA1 gene while 3 percent have shown BRCA2 variants. The remaining 88 percent of breast and ovarian cancers can be attributed to the involvement of other genes.

  18. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families.

    OpenAIRE

    Friedman, L S; Szabo, C.I.; Ostermeyer, E A; Dowd, P; Butler, L; Park, T.; Lee, M K; Goode, E.L.; Rowell, S E; King, M C

    1995-01-01

    Thirty-seven families with four or more cases of breast cancer or breast and ovarian cancer were analyzed for mutations in BRCA1. Twelve different germ-line mutations, four novel and eight previously observed, were detected in 16 families. Five families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at eight polymorphic markers spanning approximately 850 kb at BRCA1. Expressivity of 185delAG in these families varied, from early-onset breast cancer with...

  19. Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

    DEFF Research Database (Denmark)

    Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel;

    2015-01-01

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between ...

  20. The Study of CpG Island Methylation of BRCA1 Gene Promoter in a Taxol Induced Drug-resistant Human Lung Aadenocarcinoma Cell Line A549%耐紫杉醇人肺腺癌A549细胞株中BRCA1基因启动子CpG岛甲基化的研究

    Institute of Scientific and Technical Information of China (English)

    尹红英; 王红兵

    2012-01-01

    目的 检测耐紫杉醇人肺腺癌A549细胞株(A549/Taxol)中BRCA1基因启动子CpG岛甲基化状态,探讨A549/Taxol细胞对紫杉醇的耐药机制.方法 应用甲基化特异性聚合酶链反应(MSP)技术,检测耐紫杉醇人肺腺癌A549细胞株BRCA1基因启动子CpG岛甲基化状态.结果 A549/Taxol细胞存在BRCA1基因异常甲基化,呈部分甲基化.结论 A549/Taxol细胞存在BRCA1基因异常甲基化,可能是A549/Taxol细胞对紫杉醇耐药的机制之一.%Objective To detect the CpG island methylation status of BRCA1 gene promoter in the Taxol induced drug-resistant human lung adenocarcinoma cell line A549 ( A549/Taxol ), and to explore the resistance mechanisms of A549/Taxol. Methods A549/Taxol were examined CpG island methylation of BRCA1 gene promoter by methylation specific PCR ( MSP ). Results IBRCA1 gene aberrant methylation of A549/Taxol cells is part of methylation. Conclusion BRCA1 gene aberrant methylation of A549/Taxol may be one of the resistance mechanisms of taxol in A549/Taxol.

  1. Large-scale genomic analyses link reproductive ageing to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

    Science.gov (United States)

    Lunetta, Kathryn L.; Pervjakova, Natalia; Chasman, Daniel I.; Stolk, Lisette; Finucane, Hilary K.; Sulem, Patrick; Bulik-Sullivan, Brendan; Esko, Tõnu; Johnson, Andrew D.; Elks, Cathy E.; Franceschini, Nora; He, Chunyan; Altmaier, Elisabeth; Brody, Jennifer A.; Franke, Lude L.; Huffman, Jennifer E.; Keller, Margaux F.; McArdle, Patrick F.; Nutile, Teresa; Porcu, Eleonora; Robino, Antonietta; Rose, Lynda M.; Schick, Ursula M.; Smith, Jennifer A.; Teumer, Alexander; Traglia, Michela; Vuckovic, Dragana; Yao, Jie; Zhao, Wei; Albrecht, Eva; Amin, Najaf; Corre, Tanguy; Hottenga, Jouke-Jan; Mangino, Massimo; Smith, Albert V.; Tanaka, Toshiko; Abecasis, Goncalo; Andrulis, Irene L.; Anton-Culver, Hoda; Antoniou, Antonis C.; Arndt, Volker; Arnold, Alice M.; Barbieri, Caterina; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Bernstein, Leslie; Bielinski, Suzette J.; Blomqvist, Carl; Boerwinkle, Eric; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Borresen-Dale, Anne-Lise; Boutin, Thibaud S; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Campbell, Archie; Campbell, Harry; Chanock, Stephen J.; Chapman, J. Ross; Chen, Yii-Der Ida; Chenevix-Trench, Georgia; Couch, Fergus J.; Coviello, Andrea D.; Cox, Angela; Czene, Kamila; Darabi, Hatef; De Vivo, Immaculata; Demerath, Ellen W.; Dennis, Joe; Devilee, Peter; Dörk, Thilo; dos-Santos-Silva, Isabel; Dunning, Alison M.; Eicher, John D.; Fasching, Peter A.; Faul, Jessica D.; Figueroa, Jonine; Flesch-Janys, Dieter; Gandin, Ilaria; Garcia, Melissa E.; García-Closas, Montserrat; Giles, Graham G.; Girotto, Giorgia G.; Goldberg, Mark S.; González-Neira, Anna; Goodarzi, Mark O.; Grove, Megan L.; Gudbjartsson, Daniel F.; Guénel, Pascal; Guo, Xiuqing; Haiman, Christopher A.; Hall, Per; Hamann, Ute; Henderson, Brian E.; Hocking, Lynne J.; Hofman, Albert; Homuth, Georg; Hooning, Maartje J.; Hopper, John L.; Hu, Frank B.; Huang, Jinyan; Humphreys, Keith; Hunter, David J.; Jakubowska, Anna; Jones, Samuel E.; Kabisch, Maria; Karasik, David; Knight, Julia A.; Kolcic, Ivana; Kooperberg, Charles; Kosma, Veli-Matti; Kriebel, Jennifer; Kristensen, Vessela; Lambrechts, Diether; Langenberg, Claudia; Li, Jingmei; Li, Xin; Lindström, Sara; Liu, Yongmei; Luan, Jian’an; Lubinski, Jan; Mägi, Reedik; Mannermaa, Arto; Manz, Judith; Margolin, Sara; Marten, Jonathan; Martin, Nicholas G.; Masciullo, Corrado; Meindl, Alfons; Michailidou, Kyriaki; Mihailov, Evelin; Milani, Lili; Milne, Roger L.; Müller-Nurasyid, Martina; Nalls, Michael; Neale, Ben M.; Nevanlinna, Heli; Neven, Patrick; Newman, Anne B.; Nordestgaard, Børge G.; Olson, Janet E.; Padmanabhan, Sandosh; Peterlongo, Paolo; Peters, Ulrike; Petersmann, Astrid; Peto, Julian; Pharoah, Paul D.P.; Pirastu, Nicola N.; Pirie, Ailith; Pistis, Giorgio; Polasek, Ozren; Porteous, David; Psaty, Bruce M.; Pylkäs, Katri; Radice, Paolo; Raffel, Leslie J.; Rivadeneira, Fernando; Rudan, Igor; Rudolph, Anja; Ruggiero, Daniela; Sala, Cinzia F.; Sanna, Serena; Sawyer, Elinor J.; Schlessinger, David; Schmidt, Marjanka K.; Schmidt, Frank; Schmutzler, Rita K.; Schoemaker, Minouk J.; Scott, Robert A.; Seynaeve, Caroline M.; Simard, Jacques; Sorice, Rossella; Southey, Melissa C.; Stöckl, Doris; Strauch, Konstantin; Swerdlow, Anthony; Taylor, Kent D.; Thorsteinsdottir, Unnur; Toland, Amanda E.; Tomlinson, Ian; Truong, Thérèse; Tryggvadottir, Laufey; Turner, Stephen T.; Vozzi, Diego; Wang, Qin; Wellons, Melissa; Willemsen, Gonneke; Wilson, James F.; Winqvist, Robert; Wolffenbuttel, Bruce B.H.R.; Wright, Alan F.; Yannoukakos, Drakoulis; Zemunik, Tatijana; Zheng, Wei; Zygmunt, Marek; Bergmann, Sven; Boomsma, Dorret I.; Buring, Julie E.; Ferrucci, Luigi; Montgomery, Grant W.; Gudnason, Vilmundur; Spector, Tim D.; van Duijn, Cornelia M; Alizadeh, Behrooz Z.; Ciullo, Marina; Crisponi, Laura; Easton, Douglas F.; Gasparini, Paolo P.; Gieger, Christian; Harris, Tamara B.; Hayward, Caroline; Kardia, Sharon L.R.; Kraft, Peter; McKnight, Barbara; Metspalu, Andres; Morrison, Alanna C.; Reiner, Alex P.; Ridker, Paul M.; Rotter, Jerome I.; Toniolo, Daniela; Uitterlinden, André G.; Ulivi, Sheila; Völzke, Henry; Wareham, Nicholas J.; Weir, David R.; Yerges-Armstrong, Laura M.; Price, Alkes L.; Stefansson, Kari; Visser, Jenny A.; Ong, Ken K.; Chang-Claude, Jenny; Murabito, Joanne M.; Perry, John R.B.; Murray, Anna

    2015-01-01

    Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ~70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two harbouring additional rare missense alleles of large effect. We found enrichment of signals in/near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses revealed a major association with DNA damage-response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomisation analyses supported a causal effect of later ANM on breast cancer risk (~6% risk increase per-year, P=3×10−14), likely mediated by prolonged sex hormone exposure, rather than DDR mechanisms. PMID:26414677

  2. Genomewide high-density SNP linkage analysis of non-BRCA1/2 breast cancer families identifies various candidate regions and has greater power than microsatellite studies

    NARCIS (Netherlands)

    A. González-Neira (Anna); J.M. Rosa-Rosa; A. Osorio (Ana); E. Gonzalez (Emilio); M.C. Southey (Melissa); O. Sinilnikova (Olga); H. Lynch (Henry); R.A. Oldenburg (Rogier); C.J. van Asperen (Christi); N. Hoogerbrugge (Nicoline); G. Pita (G.); P. Devilee (Peter); D. Goldgar (David); J. Benítez (Javier)

    2007-01-01

    textabstractBackground: The recent development of new high-throughput technologies for SNP genotyping has opened the possibility of taking a genome-wide linkage approach to the search for new candidate genes involved in heredity diseases. The two major breast cancer susceptibility genes BRCA1 and BR

  3. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    K.B. Kuchenbaecker (Karoline); S.L. Neuhausen (Susan); M. Robson (Mark); D. Barrowdale (Daniel); L. McGuffog (Lesley); A.M. Mulligan (Anna Marie); I.L. Andrulis (Irene); A.B. Spurdle (Amanda); M.K. Schmidt (Marjanka); R.K. Schmutzler (Rita); C. Engel (Christoph); B. Wapenschmidt (Barbara); H. Nevanlinna (Heli); M. Thomassen (Mads); M.C. Southey (Melissa); P. Radice (Paolo); S.J. Ramus (Susan); S.M. Domchek (Susan); K.L. Nathanson (Katherine); A. Lee (Andrew); S. Healey (Sue); R. Nussbaum (Robert); R. Rebbeck (Timothy); B.K. Arun (Banu); M. James (Margaret); B. Karlan; K.J. Lester (Kathryn); I. Cass (Ilana); M.B. Terry (Mary Beth); M.J. Daly (Mark); D. Goldgar (David); S.S. Buys (Saundra); R. Janavicius (Ramunas); L. Tihomirova (Laima); N. Tung (Nadine); C.M. Dorfling (Cecilia); E.J. van Rensburg (Elizabeth); L. Steele (Linda); T. v O Hansen (Thomas); B. Ejlertsen (Bent); A-M. Gerdes (Anne-Marie); F. Nielsen (Finn); J. Dennis (Joe); J.M. Cunningham (Julie); S. Hart (Stewart); S. Slager (Susan); A. Osorio (Ana); J. Benítez (Javier); M. Duran (Mercedes); J.N. Weitzel (Jeffrey); I. Tafur (Isaac); M. Hander (Mary); P. Peterlongo (Paolo); S. Manoukian (Siranoush); B. Peissel (Bernard); G. Roversi (Gaia); G. Scuvera (Giulietta); B. Bonnani (Bernardo); P. Mariani (Paolo); S. Volorio (Sara); R. Dolcetti (Riccardo); L. Varesco (Liliana); L. Papi (Laura); M.G. Tibiletti (Maria Grazia); G. Giannini (Giuseppe); F. Fostira (Florentia); I. Konstantopoulou (I.); J. Garber (Judy); U. Hamann (Ute); A. Donaldson (Alan); C. Brewer (Carole); C. Foo (Claire); D.G. Evans (Gareth); D. Frost (Debra); D. Eccles (Diana); F. Douglas (Fiona); A. Brady (A.); J. Cook (Jackie); M. Tischkowitz (Marc); L. Adlard; J. Barwell (Julian); K. Ong; L.J. Walker (Lisa); L. Izatt (Louise); L. Side (Lucy); M.J. Kennedy (John); M.T. Rogers (Mark); M.E. Porteous (Mary); P.J. Morrison (Patrick); R. Platte (Radka); R. Eeles (Ros); R. Davidson (Rosemarie); S. Hodgson (Shirley); S.D. Ellis (Steve); A.K. Godwin (Andrew); K. Rhiem (Kerstin); A. Meindl (Alfons); N. Ditsch (Nina); N. Arnold (Norbert); H. Plendl (Hansjoerg); D. Niederacher (Dieter); C. Sutter (Christian); D. Steinemann (Doris); N. Bogdanova-Markov (Nadja); K. Kast (Karin); R. Varon-Mateeva (Raymonda); S. Wang-Gohrke (Shan); P.A. Gehrig (Paola A.); B. Markiefka (Birgid); B. Buecher (Bruno); C. Lefol (Cédrick); D. Stoppa-Lyonnet (Dominique); E. Rouleau (Etienne); F. Prieur (Fabienne); F. Damiola (Francesca); L. Barjhoux (Laure); L. Faivre (Laurence); M. Longy (Michel); N. Sevenet (Nicolas); O. Sinilnikova (Olga); S. Mazoyer (Sylvie); V. Bonadona (Valérie); V. Caux-Moncoutier (Virginie); C. Isaacs (Claudine); T. Van Maerken (Tom); K.B.M. Claes (Kathleen B.M.); M. Piedmonte (Marion); L. Andrews (Lesley); J. Hays (John); G.C. Rodriguez (Gustavo); T. Caldes (Trinidad); M. de La Hoya (Miguel); S. Khan (Sofia); F.B.L. Hogervorst (Frans); C.M. Aalfs (Cora); J.L. de Lange (J.); E.J. Meijers-Heijboer (Hanne); A.H. van der Hout (Annemarie); J.T. Wijnen (Juul); K.E. van Roozendaal (Kees); A.R. Mensenkamp (Arjen); A.M.W. van den Ouweland (Ans); C.H.M. van Deurzen (Carolien); R.B. van der Luijt (Rob); E. Olah; O. Díez (Orland); C. Lazaro (Conxi); I. Blanco (Ignacio); A. Teulé (A.); M. Menéndez (Mireia); A. Jakubowska (Anna); J. Lubinski (Jan); C. Cybulski (Cezary); J. Gronwald (Jacek); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); A. Arason (Adalgeir); C. Maugard; P. Soucy (Penny); M. Montagna (Marco); S. Agata (Simona); P.J. Teixeira; C. Olswold (Curtis); N.M. Lindor (Noralane); V.S. Pankratz (Shane); B. Hallberg (Boubou); X. Wang (Xianshu); C. Szabo (Csilla); J. Vijai (Joseph); L. Jacobs (Lauren); M. Corines (Marina); A. Lincoln (Anne); A. Berger (Andreas); A. Fink-Retter (Anneliese); C.F. Singer (Christian); C. Rappaport (Christine); D.G. Kaulich (Daphne Gschwantler); G. Pfeiler (Georg); M.-K. Tea; C. Phelan (Catherine); P.L. Mai (Phuong); M.H. Greene (Mark); G. Rennert (Gad); E.N. Imyanitov (Evgeny); G. Glendon (Gord); A.E. Toland (Amanda); A. Bojesen (Anders); I.S. Pedersen (Inge Sokilde); U.B. Jensen; M.A. Caligo (Maria); E. Friedman (Eitan); R. Berger (Raanan); Y. Laitman (Yael); J. Rantala (Johanna); B. Arver (Brita Wasteson); N. Loman (Niklas); Å. Borg (Åke); H. Ehrencrona (Hans); O.I. Olopade (Olofunmilayo); J. Simard (Jacques); D.F. Easton (Douglas); G. Chenevix-Trench (Georgia); K. Offit (Kenneth); F.J. Couch (Fergus); A.C. Antoniou (Antonis C.); CIMBA; EMBRACE Study; Breast Cancer Family; GEMO Study Collaborators; HEBON; KConFab Investigators

    2014-01-01

    textabstractIntroduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 muta

  4. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: Implications for risk prediction

    NARCIS (Netherlands)

    A.C. Antoniou (Antonis); J. Beesley (Jonathan); L. McGuffog (Lesley); O. Sinilnikova (Olga); S. Healey (Sue); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); R. Rebbeck (Timothy); J.N. Weitzel (Jeffrey); H. Lynch (Henry); C. Isaacs (Claudine); P.A. Ganz (Patricia); G. Tomlinson (Gail); O.I. Olopade (Olofunmilayo); F.J. Couch (Fergus); X. Wang (Xing); N.M. Lindor (Noralane); V.S. Pankratz (Shane); P. Radice (Paolo); S. Manoukian (Siranoush); B. Peissel (Bernard); D. Zaffaroni (D.); M. Barile (Monica); A. Viel (Alessandra); A. Allavena (Anna); V. Dall'Olio (Valentina); P. Peterlongo (Paolo); C. Szabo (Csilla); M. Zikan (Michal); K. Claes (Kathleen); B. Poppe (Bruce); L. Foretova (Lenka); P.L. Mai (Phuong); M.H. Greene (Mark); G. Rennert (Gad); F. Lejbkowicz (Flavio); G. Glendon (Gord); H. Ozcelik (Hilmi); I.L. Andrulis (Irene); M. Thomassen (Mads); A-M. Gerdes (Anne-Marie); L. Sunde (Lone); D. Cruger (Dorthe); U.B. Jensen; M.A. Caligo (Maria); E. Friedman (Eitan); B. Kaufman (Bella); Y. Laitman (Yael); R. Milgrom (Roni); M. Dubrovsky (Maya); S. Cohen (Shimrit); Å. Borg (Åke); H. Jernström (H.); A. Lindblom (Annika); J. Rantala (Johanna); M. Stenmark-Askmalm (M.); B. Melin (Beatrice); K.L. Nathanson (Katherine); S.M. Domchek (Susan); A. Jakubowska (Anna); J. Lubinski (Jan); T. Huzarski (Tomasz); A. Osorio (Ana); A. Lasa (Adriana); M. Durán (Mercedes); M.I. Tejada; J. Godino (Javier); J. Benitez (Javier); U. Hamann (Ute); M. Kriege (Mieke); N. Hoogerbrugge (Nicoline); R.B. van der Luijt (Rob); C.J. van Asperen (Christi); P. Devilee (Peter); E.J. Meijers-Heijboer (Hanne); M.J. Blok (Marinus); C.M. Aalfs (Cora); F.B.L. Hogervorst (Frans); M.A. Rookus (Matti); M. Cook (Margaret); C.T. Oliver (Clare); D. Frost (Debra); D. Conroy (Don); D.G. Evans (Gareth); F. Lalloo (Fiona); G. Pichert (Gabriella); R. Davidson (Rosemarie); T.J. Cole (Trevor); J. Paterson (Joan); S.V. Hodgson (Shirley); P.J. Morrison (Patrick); M.E. Porteous (Mary); L.J. Walker (Lisa); M.J. Kennedy (John); H. Dorkins (Huw); S. Peock (Susan); A.K. Godwin (Andrew); D. Stoppa-Lyonnet (Dominique); A. de Pauw (Antoine); S. Mazoyer (Sylvie); V. Bonadona (Valérie); C. Lasset (Christine); H. Dreyfus (Hélène); D. Leroux (Dominique); A. hardouin (Agnès); P. Berthet (Pascaline); L. Faivre (Laurence); C. Loustalot (Catherine); T. Noguchi (Tetsuro); H. Sobol (Hagay); E. Rouleau (Etienne); C. Nogues (Catherine); M. Frenay (Marc); L. Vénat-Bouvet (Laurence); J. Hopper (John); M.J. Daly (Mark); M-B. Terry (Mary-beth); E.M. John (Esther); S.S. Buys (Saundra); Y. Yassin (Yosuf); A. Miron (Alexander); D. Goldgar (David); C.F. Singer (Christian); C. Dressler (Catherina); D. Gschwantler-Kaulich (Daphne); G. Pfeiler (Georg); T.V.O. Hansen (Thomas); L. Jnson (Lars); B.A. Agnarsson (Bjarni); T. Kircchoff (Tomas); K. Offit (Kenneth); V. Devlin (Vincent); A. Dutra-Clarke (Ana); M. Piedmonte (Marion); G.C. Rodriguez (Gustavo); K. Wakeley (Katie); J.F. Boggess (John); J. Basil (Jack); P.E. Schwartz (Peter); S.V. Blank (Stephanie); A.E. Toland (Amanda); M. Montagna (Marco); C. Casella (Cinzia); E.N. Imyanitov (Evgeny); L. Tihomirova (Laima); I. Blanco (Ignacio); C. Lazaro (Conxi); S.J. Ramus (Susan); L. Sucheston (Lara); B.Y. Karlan (Beth); J. Gross (Jenny); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); C. Engel (Christoph); A. Meindl (Alfons); M. Lochmann (Magdalena); N. Arnold (Norbert); S. Heidemann (Simone); R. Varon-Mateeva (Raymonda); D. Niederacher (Dieter); C. Sutter (Christian); H. Deissler (Helmut); D. Gadzicki (Dorothea); S. Preisler-Adams (Sabine); K. Kast (Karin); I. Schönbuchner (Ines); T. Caldes (Trinidad); M. de La Hoya (Miguel); K. Aittomäki (Kristiina); H. Nevanlinna (Heli); J. Simard (Jacques); A.B. Spurdle (Amanda); H. Holland (Helene); G. Chenevix-Trench (Georgia); R. Platte (Radka); D.F. Easton (Douglas)

    2010-01-01

    textabstractThe known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10,

  5. Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers : Implications for Risk Prediction

    NARCIS (Netherlands)

    Antoniou, Antonis C.; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Neuhausen, Susan L.; Ding, Yuan Chun; Rebbeck, Timothy R.; Weitzel, Jeffrey N.; Lynch, Henry T.; Isaacs, Claudine; Ganz, Patricia A.; Tomlinson, Gail; Olopade, Olufunmilayo I.; Couch, Fergus J.; Wang, Xianshu; Lindor, Noralane M.; Pankratz, Vernon S.; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall'Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I.; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L.; Greene, Mark H.; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernstroem, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Duran, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B.; van Asperen, Christi J.; Devilee, Peter; Meijers-Heijboer, E. J.; Blok, Marinus J.; Aalfs, Cora M.; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D. Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary E.; Walker, Lisa; Kennedy, M. John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valerie; Lasset, Christine; Dreyfus, Helene; Leroux, Dominique; Hardouin, Agnes; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frenay, Marc; Venat-Bouvet, Laurence; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F.; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V. O.; Jnson, Lars; Agnarsson, Bjarni A.; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Schwartz, Peter E.; Blank, Stephanie V.; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J.; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schoenbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomaeki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B.; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F.

    2010-01-01

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 i

  6. Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

    NARCIS (Netherlands)

    A.C. Antoniou; J. Beesley; L. McGuffog; O.M. Sinilnikova; S. Healey; S.L. Neuhausen; Y.C. Ding; T.R. Rebbeck; J.N. Weitzel; H.T. Lynch; C. Isaacs; P.A. Ganz; G. Tomlinson; O.I. Olopade; F.J. Couch; X. Wang; N.M. Lindor; V.S. Pankratz; P. Radice; S. Manoukian; B. Peissel; D. Zaffaroni; M. Barile; A. Viel; A. Allavena; V. Dall'olio; P. Peterlongo; C.I. Szabo; M. Zikan; K. Claes; B. Poppe; L. Foretova; P.L. Mai; M.H. Greene; G. Rennert; F. Lejbkowicz; G. Glendon; H. Ozcelik; I.L. Andrulis; M. Thomassen; A.M. Gerdes; L. Sunde; D. Cruger; M. Caligo; E. Friedman; B. Kaufman; Y. Laitman; R. Milgrom; M. Dubrovsky; S. Cohen; A. Borg; H. Jernström; A. Lindblom; J. Rantala; M. Stenmark-Askmalm; B. Melin; K. Nathanson; S. Domchek; A. Jakubowska; J. Lubinski; T. Huzarski; A. Osorio; A. Lasa; M. Durán; M.I. Tejada; J. Godino; J. Benitez; U. Hamann; M. Kriege; N. Hoogerbrugge; R.B. van der Luijt; C.J. van Asperen; P. Devilee; E.J. Meijers-Heijboer; M.J. Blok; C.M. Aalfs; F. Hogervorst; M. Rookus; M. Cook; C. Oliver; D. Frost; D. Conroy; D.G. Evans; F. Lalloo; G. Pichert; R. Davidson; T. Cole; J. Cook; J. Paterson; S. Hodgson; P.J. Morrison; M.E. Porteous; L. Walker; M.J. Kennedy; H. Dorkins; S. Peock; A.K. Godwin; D. Stoppa-Lyonnet

    2010-01-01

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 i

  7. Bias explains most of the parent-of-origin effect on breast cancer risk in BRCA1/2 mutation carriers

    NARCIS (Netherlands)

    Vos, Janet R; Oosterwijk, Jan C; Aalfs, Cora M; Rookus, Matti A; Adank, Muriel A; van der Hout, Annemarie H; van Asperen, Christi J; Gomez-Garcia, Encarna B; Mensenkamp, Arjen R; Jager, Agnes; Ausems, Margreet G E M; Mourits, Marian J; de Bock, Geertruida H

    2016-01-01

    BACKGROUND: Paternal transmission of a BRCA mutation has been reported to increase the risk of breast cancer in offspring more than when the mutation is maternally inherited. As this effect might be caused by referral bias, the aim of this study was to assess the parent-of-origin effect of the BRCA1

  8. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

    NARCIS (Netherlands)

    A.B. Spurdle (Amanda); F.J. Couch (Fergus); M. Parsons (Marilyn); L. McGuffog (Lesley); D. Barrowdale (Daniel); M.K. Bolla (Manjeet); Q. Wang (Qing); S. Healey (Sue); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); K. Rhiem (Kerstin); E. Hahnen (Eric); C. Engel (Christoph); A. Meindl (Alfons); N. Ditsch (Nina); N. Arnold (Norbert); H. Plendl (Hansjoerg); D. Niederacher (Dieter); C. Sutter (Christian); S. Wang-Gohrke (Shan); D. Steinemann (Doris); S. Preisler-Adams (Sabine); K. Kast (Karin); R. Varon-Mateeva (Raymonda); S.D. Ellis (Steve); D. Frost (Debra); R. Platte (Radka); J. Perkins (Jo); D.G. Evans (Gareth); L. Izatt (Louise); R. Eeles (Rosalind); L. Adlard; R. Davidson (Rosemarie); T.J. Cole (Trevor); G. Scuvera (Giulietta); S. Manoukian (Siranoush); B. Bonnani (Bernardo); F. Mariette (F.); S. Fortuzzi (S.); A. Viel (Alessandra); B. Pasini (Barbara); L. Papi (Laura); L. Varesco (Liliana); R. Balleine (Rosemary); K.L. Nathanson (Katherine); S.M. Domchek (Susan); K. Offitt (Kenneth); A. Jakubowska (Anna); N.M. Lindor (Noralane); M. Thomassen (Mads); U.B. Jensen; J. Rantala (Johanna); Å. Borg (Åke); I.L. Andrulis (Irene); A. Miron (Alexander); T.V.O. Hansen (Thomas); T. Caldes (Trinidad); S.L. Neuhausen (Susan); A.E. Toland (Amanda); H. Nevanlinna (Heli); M. Montagna (Marco); J. Garber (Judy); A.K. Godwin (Andrew); A. Osorio (Ana); R.E. Factor (Rachel E.); M.B. Terry (Mary B.); R. Rebbeck (Timothy); B. Karlan; M.C. Southey (Melissa); M.U. Rashid (Muhammad); N. Tung (Nadine); P.D.P. Pharoah (Paul); F. Blows (Fiona); A.M. Dunning (Alison); E. Provenzano (Elena); P. Hall (Per); K. Czene (Kamila); M.K. Schmidt (Marjanka); A. Broeks (Annegien); S. Cornelissen (Sten); S. Verhoef; P.A. Fasching (Peter); M.W. Beckmann (Matthias); A.B. Ekici (Arif); D.J. Slamon (Dennis); S.E. Bojesen (Stig); B.G. Nordestgaard (Børge); S.F. Nielsen (Sune); H. Flyger (Henrik); J. Chang-Claude (Jenny); D. Flesch-Janys (Dieter); A. Rudolph (Anja); P. Seibold (Petra); K. Aittomäki (Kristiina); T.A. Muranen (Taru); P. Heikkilä (Päivi); C. Blomqvist (Carl); J.D. Figueroa (Jonine); S.J. Chanock (Stephen); L.A. Brinton (Louise); J. Lissowska (Jolanta); J.E. Olson (Janet); V.S. Pankratz (Shane); E.M. John (Esther); A.S. Whittemore (Alice); D. van West; U. Hamann (Ute); D. Torres (Diana); H.U. Ulmer (Hans); T. Rud̈iger (Thomas); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); C.M. Seynaeve (Caroline); C.J. van Asperen (Christi); D. Eccles (Diana); W. Tapper (William); L. Durcan (Lorraine); L. Jones (Louise); J. Peto (Julian); I. dos Santos Silva (Isabel); O. Fletcher (Olivia); N. Johnson (Nichola); M. Dwek (Miriam); R. Swann (Ruth); A.L. Bane (Anita L.); G. Glendon (Gord); A.M. Mulligan (Anna Marie); G.G. Giles (Graham); R.L. Milne (Roger); L. Baglietto (Laura); C.A. McLean (Catriona Ann); J. Carpenter (Jane); C. Clarke (Christine); R.J. Scott (Rodney); H. Brauch (Hiltrud); T. Brüning (Thomas); Y-D. Ko (Yon-Dschun); A. Cox (Angela); S.S. Cross (Simon); M.W.R. Reed (Malcolm); J. Lubinski (Jan); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); J. Gronwald (Jacek); T. Dörk (Thilo); N.V. Bogdanova (Natalia); T.-W. Park-Simon; P. Hillemanns (Peter); C.A. Haiman (Christopher); B.E. Henderson (Brian); F.R. Schumacher (Fredrick); L. Le Marchand (Loic); B. Burwinkel (Barbara); F. Marme (Federick); H. Surovy (Harald); R. Yang (Rongxi); H. Anton-Culver (Hoda); A. Ziogas (Argyrios); M.J. Hooning (Maartje); J.M. Collee (Margriet); J.W.M. Martens (John); M.M.A. Tilanus-Linthorst (Madeleine); H. Brenner (Hermann); A.K. Dieffenbach (Aida Karina); V. Arndt (Volker); C. Stegmaier (Christa); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); A. Lindblom (Annika); S. Margolin (Sara); V. Joseph (Vijai); M. Robson (Mark); R. Rau-Murthy (Rohini); A. González-Neira (Anna); J.I. Arias Pérez (José Ignacio); P. Zamora (Pilar); J. Benítez (Javier); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); P. Peterlongo (Paolo); D. Zaffaroni (D.); M. Barile (Monica); F. Capra (Fabio); P. Radice (Paolo); S.-H. Teo; D.F. Easton (Douglas); A.C. Antoniou (Antonis C.); G. Chenevix-Trench (Georgia); D. Goldgar (David)

    2014-01-01

    textabstractIntroduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modelin

  9. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley;

    2010-01-01

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs650495...

  10. A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers

    NARCIS (Netherlands)

    Ding, Yuan C.; McGuffog, Lesley; Healey, Sue; Friedman, Eitan; Laitman, Yael; Shani-Paluch-Shimon, [No Value; Kaufman, Bella; Liljegren, Annelie; Lindblom, Annika; Olsson, Hakan; 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; Ramony Cajal, Teresa; Stavropoulou, Alexandra V.; Benitez, Javier; Hamann, Ute; Rookus, Matti; Aalfs, Cora M.; de Lange, Judith L.; Meijers-Heijboer, Hanne E. J.; Oosterwijk, Jan C.; van Asperen, Christi J.; Garcia, Encarna B. Gomez; 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; Leone, Melanie; Gauthier-Villars, Marion; Caux-Moncoutier, Virginie; de Pauw, Antoine; Hardouin, Agnes; Berthet, Pascaline; Dreyfus, Helene; Ferrer, Sandra Fert; Collonge-Rame, Marie-Agnes; Sokolowska, Johanna; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy; John, Esther M.; Southey, Melissa; Goldgar, David; Singer, Christian F.; Tea, Muy-Kheng Maria; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Hansen, Thomas V. O.; Ejlertsen, Bent; Johannsson, Oskar T.; 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; Aittomaki, 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 assoc

  11. A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

    NARCIS (Netherlands)

    Y.C. Ding (Yuan); L. McGuffog (Lesley); S. Healey (Sue); E. Friedman (Eitan); Y. Laitman (Yael); S.-P. Shimon (Shani-Paluch); B. Kaufman (Bella); A. Liljegren (Annelie); A. Lindblom (Annika); H. Olsson; U. Kristoffersson (Ulf); M. Stenmark-Askmalm (M.); B. Melin (Beatrice); S.M. Domchek (Susan); K.L. Nathanson (Katherine); R. Rebbeck (Timothy); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska (Katarzyna); K. Durda (Katarzyna); J. Gronwald (Jacek); T. Huzarski (Tomasz); C. Cybulski (Cezary); T. Byrski (Tomasz); A. Osorio (Ana); T.R. Cajal; A. Stavropoulou (Alexandra); J. Benítez (Javier); U. Hamann (Ute); M.A. Rookus (Matti); C.M. Aalfs (Cora); J.L. de Lange (J.); E.J. Meijers-Heijboer (Hanne); J.C. Oosterwijk (Jan); C.J. van Asperen (Christi); E.B. Gómez García (Encarna); N. Hoogerbrugge (Nicoline); A. Jager (Agnes); R.B. van der Luijt (Rob); D.F. Easton (Douglas); S. Peock (Susan); D. Frost (Debra); S.D. Ellis (Steve); R. Platte (Radka); E. Fineberg (Elena); D.G. Evans (Gareth); F. Lalloo (Fiona); L. Izatt (Louise); R. Eeles (Rosalind); J.W. Adlard (Julian); R. Davidson (Rosemarie); D. Eccles (Diana); T.J. Cole (Trevor); J. Cook (Jackie); C. Brewer (Carole); M. Tischkowitz (Marc); A.K. Godwin (Andrew); S.S. Pathak; D. Stoppa-Lyonnet (Dominique); O. Sinilnikova (Olga); S. Mazoyer (Sylvie); L. Barjhoux (Laure); M. Léone (Mélanie); M. Gauthier-Villars (Marion); V. Caux-Moncoutier (Virginie); A. de Pauw (Antoine); A. Hardouin (Agnès); P. Berthet (Pascaline); H. Dreyfus (Hélène); S.F. Ferrer; M.-A. Collonge-Rame; J. Sokolowska (Johanna); S.S. Buys (Saundra); M.B. Daly (Mary); A. Miron (Alexander); M.-B. Terry (Mary-Beth); W. Chung (Wendy); E.M. John (Esther); M.C. Southey (Melissa); D. Goldgar (David); C.F. Singer (Christian); M.-K. Tea; D. Gschwantler-Kaulich (Daphne); A. Fink-Retter (Anneliese); T.V.O. Hansen (Thomas); B. Ejlertsen (Bent); O.T. Johannson (Oskar); K. Offit (Kenneth); K. Sarrel (Kara); M.M. Gaudet (Mia); J. Vijai (Joseph); M. Robson (Mark); M. Piedmonte (Marion); L. Andrews (Lesley); D.E. Cohn (David); L.R. DeMars (Leslie); P. DiSilvestro (Paul); G.C. Rodriguez (Gustavo); A.E. Toland (Amanda); M. Montagna (Marco); S. Agata (Simona); E.N. Imyanitov (Evgeny); C. Isaacs (Claudine); R. Janavicius (Ramunas); C. Lazaro (Conxi); I. Blanco (Ignacio); S.J. Ramus (Susan); L. Sucheston (Lara); B. Karlan; J. Gross (Jenny); P.A. Ganz (Patricia); M.S. Beattie (Mary); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); A. Meindl (Alfons); N. Arnold (Norbert); D. Niederacher (Dieter); S. Preisler-Adams (Sabine); D. Gadzicki (Dorothea); R. Varon-Mateeva (Raymonda); H. Deissler (Helmut); P.A. Gehrig (Paola A.); C. Sutter (Christian); K. Kast (Karin); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); J. Simard (Jacques); A.B. Spurdle (Amanda); J. Beesley (Jonathan); X. Chen (Xiaoqing); G. Tomlinson (Gail); J.N. Weitzel (Jeffrey); J. Garber; O.I. Olopade (Olofunmilayo); W.S. Rubinstein (Wendy); N. Tung (Nadine); J.L. Blum (Joann); S. Narod (Steven); S. Brummel (Sean); D.L. Gillen (Daniel); N.M. Lindor (Noralane); Z. Fredericksen (Zachary); V.S. Pankratz (Shane); F.J. Couch (Fergus); P. Radice (Paolo); P. Peterlongo (Paolo); M.H. Greene (Mark); J.T. Loud (Jennifer); P.L. Mai (Phuong); I.L. Andrulis (Irene); G. Glendon (Gord); H. Ozcelik (Hilmi); A-M. Gerdes (Anne-Marie); M. Thomassen (Mads); U.B. Jensen; A.-B. Skytte (Anne-Bine); M.A. Caligo (Maria); A. Lee (Andrew); G. Chenevix-Trench (Georgia); A.C. Antoniou (Antonis); S.L. Neuhausen (Susan)

    2012-01-01

    textabstractBackground: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk inwomen carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and

  12. A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers.

    NARCIS (Netherlands)

    Ding, Y.C.; McGuffog, L.; Healey, S.; Friedman, E.; Laitman, Y.; Paluch-Shimon, S.; Kaufman, B.; Liljegren, A.; Lindblom, A.; Olsson, H.; Kristoffersson, U.; Stenmark-Askmalm, M.; Melin, B.; Domchek, S.M.; Nathanson, K.L.; Rebbeck, T.R.; Jakubowska, A.; Lubinski, J.; Jaworska, K.; Durda, K.; Gronwald, J.; Huzarski, T.; Cybulski, C.; Byrski, T.; Osorio, A.; Cajal, T.R.; Stavropoulou, A.V.; Benitez, J.; Hamann, U.; Rookus, M.; Aalfs, C.M.; Lange, J.L. de; Meijers-Heijboer, H.E.; Oosterwijk, J.C.; Asperen, C.J. van; Gomez Garcia, E.B.; Hoogerbrugge, N.; Jager, A.; Luijt, R.B. van der; Easton, D.F.; Peock, S.; Frost, D.; Ellis, S.D.; Platte, R.; Fineberg, E.; Evans, D.G.; Lalloo, F.; Izatt, L.; Eeles, R.; Adlard, J.; Davidson, R.; Eccles, D.; Cole, T.; Cook, J.; Brewer, C.; Tischkowitz, M.; Godwin, A.K.; Pathak, H.; Stoppa-Lyonnet, D.; Sinilnikova, O.M.; Mazoyer, S.; Barjhoux, L.; Leone, M.; Gauthier-Villars, M.; Caux-Moncoutier, V.; Pauw, A. de; Hardouin, A.; Berthet, P.; Dreyfus, H.; Ferrer, S.F.; Collonge-Rame, M.A.; Sokolowska, J.; Buys, S.; Daly, M.; Miron, A.; Terry, M.B.; Chung, W.; John, E.M.; Southey, M.; Goldgar, D.; Singer, C.F.; Tea, M.K.; Gschwantler-Kaulich, D.; Fink-Retter, A.; Hansen, T.V.; Ejlertsen, B.; Johannsson, O.T.; Offit, K.; Sarrel, K.; Gaudet, M.M.; Vijai, J.; Robson, M.; Piedmonte, M.R.; Andrews, L.; Cohn, D.; Demars, L.R.; Disilvestro, P.; Rodriguez, G.; Toland, A.E.; Montagna, M.; Agata, S.; Imyanitov, E.; Isaacs, C.; Janavicius, R.; Lazaro, C.; Blanco, I.; Ramus, S.J.; Sucheston, L.; Karlan, B.Y.; Gross, J.; Ganz, P.A.; Beattie, M.S.; Schmutzler, R.K.; Wappenschmidt, B.; Meindl, A.; Arnold, N.; Niederacher, D.; Preisler-Adams, S.; Gadzicki, D.; Varon-Mateeva, R.; Deissler, H.; Gehrig, A.; Sutter, C.; Kast, K.; Nevanlinna, H.; Aittomaki, K.; Simard, J.; Spurdle, A.B.; Beesley, J.; Chen, X.; Tomlinson, G.E.; Weitzel, J.; Garber, J.E.; Olopade, O.I.; Rubinstein, W.S.; Tung, N.; Blum, J.L.; Narod, S.A.; Brummel, S.; Gillen, D.L.; Lindor, N.; Fredericksen, Z.; Pankratz, V.S.; Couch, F.J.; Radice, P.; Peterlongo, P.; Greene, M.H.; Loud, J.T.; Mai, P.L.; Andrulis, I.L.; Glendon, G.; Ozcelik, H.; Gerdes, A.M.; Thomassen, M.; Jensen, U.B.; Skytte, A.B.; Caligo, M.A.; Lee, A.; Chenevix-Trench, G.; Antoniou, A.C.; Neuhausen, S.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 assoc

  13. Endometrium is not the primary site of origin of pelvic high-grade serous carcinoma in BRCA1 or BRCA2 mutation carriers

    NARCIS (Netherlands)

    Reitsma, Welmoed; Mourits, Marian J. E.; de Bock, Geertruida H.; Hollema, Harry

    2013-01-01

    Serous endometrial intraepithelial carcinoma has been proposed to be a potential precursor lesion of pelvic high-grade serous carcinoma. If true, an increased incidence of uterine papillary serous carcinomas would be expected in BRCA1 and BRCA2 mutation carriers, who are at high-risk of developing p

  14. Presymptomatic testing for BRCA1 and BRCA2: how distressing are the pre-test weeks? Rotterdam/Leiden Genetics Working Group

    NARCIS (Netherlands)

    L.N. Lodder; P. Devilee (Peter); M.F. Niermeijer (Martinus); C.J. Cornelisse (Cees); P.G. Frets; R.W. Trijsburg (Wim); E.J. Meijers-Heijboer (Hanne); J.G.M. Klijn (Jan); H.J. Duivenvoorden (Hugo); A. Tibben (Arend); A. Wagner (Anja); C.A. van der Meer

    1999-01-01

    textabstractPresymptomatic DNA testing for autosomal dominant hereditary breast/ovarian cancer (HBOC) became an option after the identification of the BRCA1 and BRCA2 genes in 1994-1995. Healthy female mutation carriers have a high lifetime risk for breast cancer (56-87

  15. The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families

    NARCIS (Netherlands)

    Oldenburg, RA; Kroeze-Jansema, K; Kraan, J; Morreau, H; Klijn, JGM; Hoogerbrugge, N; Ligtenberg, MJL; van Asperen, CJ; Vasen, HFA; Meijers, C; Meijers-Heijboer, H; de Bock, TH; Cornelisse, CJ; Devilee, P

    2003-01-01

    The frame-shifting mutation 1100delC in the cell-cycle-checkpoint kinase 2 gene (CHEK2) has been reported to be associated with familial breast cancer in families in which mutations in BRCA1 and BRCA2 were excluded. To investigate the role of,this variant as a candidate breast cancer susceptibility

  16. Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations : retrospective cohort study (GENE-RAD-RISK)

    NARCIS (Netherlands)

    Pijpe, Anouk; Andrieu, Nadine; Easton, Douglas F.; Kesminiene, Ausrele; Cardis, Elisabeth; Nogues, Catherine; Gauthier-Villars, Marion; Lasset, Christine; Fricker, Jean-Pierre; Peock, Susan; Frost, Debra; Evans, D. Gareth; Eeles, Rosalind A.; Paterson, Joan; Manders, Peggy; van Asperen, Christi J.; Ausems, Margreet G. E. M.; Meijers-Heijboer, Hanne; Thierry-Chef, Isabelle; Hauptmann, Michael; Goldgar, David; Rookus, Matti A.; van Leeuwen, Flora E.

    2012-01-01

    Objective To estimate the risk of breast cancer associated with diagnostic radiation in carriers of BRCA1/2 mutations. Design Retrospective cohort study (GENE-RAD-RISK). Setting Three nationwide studies (GENEPSO, EMBRACE, HEBON) in France, United Kingdom, and the Netherlands, Participants 1993 femal

  17. Randomized trial of a shared decision-making intervention consisting of trade-offs and individualized treatment information for BRCA1/2 mutation carriers

    NARCIS (Netherlands)

    van Roosmalen, MS; Stalmeier, PFM; Verhoef, LCG; Hoekstra-Weebers, JEHM; Oosterwijk, JC; Hoogerbrugge, N; Moog, U; van Daal, WAJ

    2004-01-01

    Purpose To evaluate a shared decision-making intervention (SDMI) for BRCA1/2 mutation carriers who have to make a choice between screening and prophylactic surgery for breasts and/or ovaries. Patients and Methods The SDMI consisted of two value assessment sessions, using the time trade-off method, f

  18. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Kartsonaki, Christiana; Sinilnikova, Olga M;

    2011-01-01

    11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers...... for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95......% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead...

  19. Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers.

    NARCIS (Netherlands)

    Wang, X.; Pankratz, V.S.; Fredericksen, Z.; Tarrell, R.; Karaus, M.; McGuffog, L.; Pharaoh, P.D.; Ponder, B.A.J.; Dunning, A.M.; Peock, S.; Cook, M.; Oliver, C.; Frost, D.; Sinilnikova, O.M.; Stoppa-Lyonnet, D.; Mazoyer, S.; Houdayer, C.; Hogervorst, F.B.L.; Hooning, M.J.; Ligtenberg, M.J.L.; Spurdle, A.; Chenevix-Trench, G.; Schmutzler, R.K.; Wappenschmidt, B.; Engel, C.; Meindl, A.; Domchek, S.M.; Nathanson, K.L.; Rebbeck, T.R.; Singer, C.F.; Gschwantler-Kaulich, D.; Dressler, C.; Fink, A.; Szabo, C.I.; Zikan, M.; Foretova, L.; Claes, K.; Thomas, G.; Hoover, R.N.; Hunter, D.J.; Chanock, S.J.; Easton, D.F.; Antoniou, A.C.; Couch, F.J.

    2010-01-01

    Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additio

  20. Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    Wang, Xianshu; Pankratz, V. Shane; Fredericksen, Zachary; Tarrell, Robert; Karaus, Mary; McGuffog, Lesley; Pharaoh, Paul D. P.; Ponder, Bruce A. J.; Dunning, Alison M.; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Sinilnikova, Olga M.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Houdayer, Claude; Hogervorst, Frans B. L.; Hooning, Maartje J.; Ligtenberg, Marjolijn J.; Spurdle, Amanda; Chenevix-Trench, Georgia; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Singer, Christian F.; Gschwantler-Kaulich, Daphne; Dressler, Catherina; Fink, Anneliese; Szabo, Csilla I.; Zikan, Michal; Foretova, Lenka; Claes, Kathleen; Thomas, Gilles; Hoover, Robert N.; Hunter, David J.; Chanock, Stephen J.; Easton, Douglas F.; Antoniou, Antonis C.; Couch, Fergus J.

    2010-01-01

    Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additio

  1. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Antoniou, A.C.; Sinilnikova, O.M.; McGuffog, L.;

    2009-01-01

    Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9...... their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit...... for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA...

  2. DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Osorio, Ana; Milne, Roger L; Kuchenbaecker, Karoline;

    2014-01-01

    Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of th...

  3. A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Ding, Yuan C; McGuffog, Lesley; Healey, Sue;

    2012-01-01

    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 wit...

  4. DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    NARCIS (Netherlands)

    Osorio, Ana; Milne, Roger L.; Kuchenbaecker, Karoline; Vaclova, Tereza; Pita, Guillermo; Alonso, Rosario; Peterlongo, Paolo; Blanco, Ignacio; de la Hoya, Miguel; Duran, Mercedes; Diez, Orland; Ramon y Cajal, Teresa; Konstantopoulou, Irene; Martinez-Bouzas, Cristina; Conejero, Raquel Andres; Soucy, Penny; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; Arver, Brita; Rantala, Johanna; Loman, Niklas; Ehrencrona, Hans; Olopade, Olufunmilayo I.; Beattie, Mary S.; Domchek, Susan M.; Nathanson, Katherine; Rebbeck, Timothy R.; Arun, Banu K.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; John, Esther M.; Whittemore, Alice S.; Daly, Mary B.; Southey, Melissa; Hopper, John; Terry, Mary B.; Buys, Saundra S.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Steele, Linda; Neuhausen, Susan L.; Ding, Yuan Chun; Hansen, Thomas V. O.; Jonson, Lars; Ejlertsen, Bent; Gerdes, Anne-Marie; Infante, Mar; Herraez, Belen; Moreno, Leticia Thais; Weitzel, Jeffrey N.; Herzog, Josef; Weeman, Kisa; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Bonanni, Bernardo; Mariette, Frederique; Volorio, Sara; Viel, Alessandra; Varesco, Liliana; Papi, Laura; Ottini, Laura; Tibiletti, Maria Grazia; Radice, Paolo; Yannoukakos, Drakoulis; Garber, Judy; Ellis, Steve; Frost, Debra; Platte, Radka; Fineberg, Elena; Evans, Gareth; Lalloo, Fiona; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Cole, Trevor; Eccles, Diana; Cook, Jackie; Hodgson, Shirley; Brewer, Carole; Tischkowitz, Marc; Douglas, Fiona; Porteous, Mary; Side, Lucy; Walker, Lisa; Morrison, Patrick; Donaldson, Alan; Kennedy, John; Foo, Claire; Godwin, Andrew K.; Schmutzler, Rita Katharina; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hans Joerg; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M.; Mazoyer, Sylvie; Damiola, Francesca; Poppe, Bruce; Claes, Kathleen; Piedmonte, Marion; Tucker, Kathy; Backes, Floor; Rodriguez, Gustavo; Brewster, Wendy; Wakeley, Katie; Rutherford, Thomas; Caldes, Trinidad; Nevanlinna, Heli; Aittomaki, Kristiina; Rookus, Matti A.; van Os, Theo A. M.; van der Kolk, Lizet; de Lange, J. L.; Meijers-Heijboer, Hanne E. J.; van der Hout, A. H.; van Asperen, Christi J.; Gomez Garcia, Encarna B.; Hoogerbrugge, Nicoline; Collee, J. Margriet; van Deurzen, Carolien H. M.; van der Luijt, Rob B.; Devilee, Peter; Olah, Edith; Lazaro, Conxi; Teule, Alex; Menendez, Mireia; Jakubowska, Anna; Cybulski, Cezary; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Johannsson, Oskar Th; Maugard, Christine; Montagna, Marco; Tognazzo, Silvia; Teixeira, Manuel R.; Healey, Sue; Olswold, Curtis; Guidugli, Lucia; Lindor, Noralane; Slager, Susan; Szabo, Csilla I.; Vijai, Joseph; Robson, Mark; Kauff, Noah; Zhang, Liying; Rau-Murthy, Rohini; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng; Berger, Andreas; Phelan, Catherine M.; Greene, Mark H.; Mai, Phuong L.; Lejbkowicz, Flavio; Andrulis, Irene; Mulligan, Anna Marie; Glendon, Gord; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Thomassen, Mads; Kruse, Torben A.; Jensen, Uffe Birk; Friedman, Eitan; Laitman, Yael; Shimon, Shani Paluch; Simard, Jacques; Easton, Douglas F.; Offit, Kenneth; Couch, Fergus J.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Benitez, Javier

    2014-01-01

    Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the c

  5. Inverse birth cohort effects in ovarian cancer : Increasing risk in BRCA1/2 mutation carriers and decreasing risk in the general population

    NARCIS (Netherlands)

    Vos, Janet R.; Mourits, Marian J.; Teixeira, Natalia; Jansen, Liesbeth; Oosterwijk, Jan C.; de Bock, Geertruida H.

    2016-01-01

    Objective. BRCA1/2 carriers are at increased risk of ovarian cancer, and some reports suggest an increasing risk in more recent birth cohorts. In contrast, decreasing incidences have been observed in the general population. The aim was to assess the birth cohort effect on ovarian cancer risk in BRCA

  6. Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers

    DEFF Research Database (Denmark)

    Jakubowska, A; Rozkrut, D; Antoniou, A;

    2012-01-01

    The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly...... or indirectly in maintaining genomic integrity....

  7. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

    DEFF Research Database (Denmark)

    Mitra, Anita V; Bancroft, Elizabeth K; Barbachano, Yolanda;

    2011-01-01

    Study Type - Diagnostic (validating cohort)
Level of Evidence 1b OBJECTIVES: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening ...

  8. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer

    Directory of Open Access Journals (Sweden)

    Kosinova Veronika

    2008-05-01

    Full Text Available Abstract Background The incidence of breast cancer has doubled over the past 20 years in the Czech Republic. Hereditary factors may be a cause of young onset, bilateral breast or ovarian cancer, and familial accumulation of the disease. BRCA1 and BRCA2 mutations account for an important fraction of hereditary breast and ovarian cancer cases. One thousand and ten unrelated high-risk probands with breast and/or ovarian cancer were analysed for the presence of a BRCA1 or BRCA2 gene mutation at the Masaryk Memorial Cancer Institute (Czech Republic during 1999–2006. Methods The complete coding sequences and splice sites of both genes were screened, and the presence of large intragenic rearrangements in BRCA1 was verified. Putative splice-site variants were analysed at the cDNA level for their potential to alter mRNA splicing. Results In 294 unrelated families (29.1% of the 1,010 probands pathogenic mutations were identified, with 44 different BRCA1 mutations and 41 different BRCA2 mutations being detected in 204 and 90 unrelated families, respectively. In total, three BRCA1 founder mutations (c.5266dupC; c.3700_3704del5; p.Cys61Gly and two BRCA2 founder mutations (c.7913_7917del5; c.8537_8538del2 represent 52% of all detected mutations in Czech high-risk probands. Nine putative splice-site variants were evaluated at the cDNA level. Three splice-site variants in BRCA1 (c.302-3C>G; c.4185G>A and c.4675+1G>A and six splice-site variants in BRCA2 (c.475G>A; c.476-2>G; c.7007G>A; c.8755-1G>A; c.9117+2T>A and c.9118-2A>G were demonstrated to result in aberrant transcripts and are considered as deleterious mutations. Conclusion This study represents an evaluation of deleterious genetic variants in the BRCA1 and 2 genes in the Czech population. The classification of several splice-site variants as true pathogenic mutations may prove useful for genetic counselling of families with high risk of breast and ovarian cancer.

  9. Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis.

    Directory of Open Access Journals (Sweden)

    Ava Kwong

    Full Text Available BACKGROUND: Ethnic variations in breast cancer epidemiology and genetics have necessitated investigation of the spectra of BRCA1 and BRCA2 mutations in different populations. Knowledge of BRCA mutations in Chinese populations is still largely unknown. We conducted a multi-center study to characterize the spectra of BRCA mutations in Chinese breast and ovarian cancer patients from Southern China. METHODOLOGY/PRINCIPAL FINDINGS: A total of 651 clinically high-risk breast and/or ovarian cancer patients were recruited from the Hong Kong Hereditary Breast Cancer Family Registry from 2007 to 2011. Comprehensive BRCA1 and BRCA2 mutation screening was performed using bi-directional sequencing of all coding exons of BRCA1 and BRCA2. Sequencing results were confirmed by in-house developed full high resolution DNA melting (HRM analysis. Among the 451 probands analyzed, 69 (15.3% deleterious BRCA mutations were identified, comprising 29 in BRCA1 and 40 in BRCA2. The four recurrent BRCA1 mutations (c.470_471delCT, c.3342_3345delAGAA, c.5406+1_5406+3delGTA and c.981_982delAT accounted for 34.5% (10/29 of all BRCA1 mutations in this cohort. The four recurrent BRCA2 mutations (c.2808_2811delACAA, c.3109C>T, c.7436_7805del370 and c.9097_9098insA accounted for 40% (16/40 of all BRCA2 mutations. Haplotype analysis was performed to confirm 1 BRCA1 and 3 BRCA2 mutations are putative founder mutations. Rapid HRM mutation screening for a panel of the founder mutations were developed and validated. CONCLUSION: In this study, our findings suggest that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer in Southern Chinese population. Knowing the spectrum and frequency of the founder mutations in this population will assist in the development of a cost-effective rapid screening assay, which in turn facilitates genetic counseling and testing for the purpose of cancer risk assessment.

  10. 中国汉族人群中BRCA1和BRCA2基因突变携带者患乳腺癌风险的研究%Breast cancer risk in BRCA1 and BRCA2 mutation carriers in Chinese Han population

    Institute of Scientific and Technical Information of China (English)

    杨晓晨; 胡震; 吴炅; 柳光宇; 沈镇宙; 邵志敏

    2015-01-01

    背景与目的:BRCA1和BRCA2基因突变携带者终生患乳腺癌和卵巢癌的风险显著增高。通过遗传咨询,突变携带者可采取适当的措施来降低相应肿瘤的发生风险。目前,相关的报道几乎均为白种人,尚缺乏中国人群的资料。该研究旨在探索中国汉族人群中BRCA1和BRCA2基因突变携带者患乳腺癌的风险。方法:回顾20个经基因检测证实携带BRCA1或BRCA2致病性基因突变的汉族乳腺癌高风险家系。利用Kaplan-Meier生存分析法对女性BRCA1/2基因突变携带者单侧乳腺癌及对侧乳腺癌的累积发病风险进行估算。结果:BRCA1和BRCA2基因突变携带者70岁时单侧乳腺癌的累积发病风险(外显率)分别为67.2%(sx 0.100)和76.8%(sx 0.079)。与BRCA1不同的是,BRCA2基因突变携带者70岁后乳腺癌累积发病率继续增加,到80岁时达93.1%。BRCA1/2基因突变携带者对侧乳腺癌10年和20年的累积发病率分别为19.4%(sx 0.089)和50.3%(sx 0.155)。结论:中国汉族人群中BRCA1和BRCA2基因突变携带者具有很高的乳腺癌发病风险。因而对中国高风险人群进行BRCA1/2基因突变检测具有重要临床意义。%Background and purpose: BRCA1 and BRCA2 mutation carriers have a high lifetime risk of developing breast and ovarian cancer. Through genetic counseling, mutation carriers can take the appropriate measures to reduce such cancer risk. At present, almost all related studies were conducted in Caucasian, while, the studies in Chinese population were rare. This study aimed to investigate the risk of breast cancer in BRCA1 and BRCA2 mutation carriers in Chinese Han population. Methods:Twenty unrelated families with BRCA1 or BRCA2 mutations were re-viewed. Kaplan-Meier analyses were used to estimate the cumulative risks of unilateral breast cancer and contralateral breast cancer for female BRCA1 and BRCA2 mutation carriers. Results:Breast cancer risk to 70 years (penetrance) was 67

  11. Clinical follow up of Mexican women with early onset of breast cancer and mutations in the BRCA1 and BRCA2 genes Estudio de seguimiento clínico de mujeres mexicanas con cáncer de mama de inicio temprano y mutaciones en los genes BRCA1 y BRCA2

    Directory of Open Access Journals (Sweden)

    Ana Laura Calderón-Garcidueñas

    2005-04-01

    Full Text Available OBJECTIVE: This study describes the presence of mutations in BRCA1 and BRCA2 genes in a group of Mexican women and the clinical evolution of early onset breast cancer (EOBC. MATERIAL AND METHODS: A prospective hospital-based study was performed in a sample of 22 women with EOBC (7 in clinical stage IIA, 8 in IIB, and 7 in IIIA. The patients attended a tertiary care hospital in northeastern Mexico in 1997 and were followed up over a 5-year period. Molecular analysis included: 1 a mutation screening by heteroduplex analysis (HA of BRCA1 and BRCA2 genes and 2 a sequence analysis. RESULTS: Of 22 patients, 14 (63.6% showed a variant band detected by heteroduplex analysis of the BRCA1 and BRCA2 genes: 8 polymorphisms, 4 mutations of uncertain significance, and 2 novel truncated protein mutations, one in BRCA1 (exon 11, 3587delT and the other in the BRCA2 gene (exon 11, 2664InsA. CONCLUSIONS: These findings support future studies to determine the significance and impact of the genetic factor in this Mexican women population.OBJETIVO: Describir la presencia de mutaciones en los genes BRCA1 y BRCA2 y la evolución clínica de un grupo de mujeres con carcinoma mamario de inicio temprano (CMIT. MATERIAL Y MÉTODOS: Se realizó un estudio hospitalario, prospectivo, en una muestra de 22 pacientes con CMIT (siete en etapa clínica IIA, ocho en la IIB y siete en etapa IIIA. Las pacientes fueron atendidas en un hospital del noreste de México en 1997 y se realizó un seguimiento clínico durante cinco años. El análisis molecular incluyó: 1 análisis heterodúplex (AH para detectar bandas variantes en la secuencia de ADN de los genes BRCA1 y BRCA2, y 2 análisis de secuenciación. RESULTADOS: De 22 pacientes, 14 (63.6% mostraron banda variante por AH en los genes BRCA1 y BRCA2: ocho polimorfismos, cuatro mutaciones de significado incierto y dos mutaciones noveles con proteína truncada, una en BRCA1 (exón 11, 3587delT y otra en BRCA2 (exón 11, 2664Ins

  12. BRCA1 and BRCA2 germline mutation analysis among Indian women from south India: identification of four novel mutations and high-frequency occurrence of 185delAG mutation

    Indian Academy of Sciences (India)

    Kannan Vaidyanathan; Smita Lakhotia; H M Ravishankar; Umaira Tabassum; Geetashree Mukherjee; Kumaravel Somasundaram

    2009-09-01

    Mutations in the BRCA1 and BRCA2 genes profoundly increase the risk of developing breast and/or ovarian cancer among women. To explore the contribution of BRCA1 and BRCA2 mutations in the development of hereditary breast cancer among Indian women, we carried out mutation analysis of the BRCA1 and BRCA2 genes in 61 breast or ovarian cancer patients from south India with a positive family history of breast and/or ovarian cancer. Mutation analysis was carried out using conformation-sensitive gel electrophoresis (CSGE) followed by sequencing. Mutations were identified in 17 patients (28.0%); 15 (24.6%) had BRCA1 mutations and two (3.28%) had BRCA2 mutations. While no specific association between BRCA1 or BRCA2 mutations with cancer type was seen, mutations were more often seen in families with ovarian cancer. While 40% (4/10) and 30.8% (4/12) of families with ovarian or breast and ovarian cancer had mutations, only 23.1% (9/39) of families with breast cancer carried mutations in the BRCA1 and BRCA2 genes. In addition, while BRCA1 mutations were found in all age groups, BRCA2 mutations were found only in the age group of ≤ 40 years. Of the BRCA1 mutations, there were three novel mutations (295delCA; 4213T → A; 5267T → G) and three mutations that have been reported earlier. Interestingly, 185delAG, a BRCA1 mutation which occurs at a very high frequency in Ashkenazi Jews, was found at a frequency of 16.4% (10/61). There was one novel mutation (4866insT) and one reported mutation in BRCA2. Thus, our study emphasizes the importance of mutation screening in familial breast and/or ovarian cancers, and the potential implications of these findings in genetic counselling and preventive therapy.

  13. The spectrum of BRCA1 and BRCA2 alleles in Latin America and the Caribbean: a clinical perspective.

    Science.gov (United States)

    Dutil, Julie; Golubeva, Volha A; Pacheco-Torres, Alba L; Diaz-Zabala, Hector J; Matta, Jaime L; Monteiro, Alvaro N

    2015-12-01

    Hereditary cancer predisposition gene testing allows the identification of individuals at high risk of cancer that may benefit from increased surveillance, chemoprevention, and prophylactic surgery. In order to implement clinical genetic strategies adapted to each population's needs and intrinsic genetic characteristic, this review aims to present the current status of knowledge about the spectrum of BRCA pathogenic variants in Latin American populations. We have conducted a comprehensive review of 33 studies published between 1994 and 2015 reporting the prevalence and/or spectrum of BRCA1 (OMIM 113705) and BRCA2 (OMIM 600185) variants. The combined sample size for these studies consisted of 4835 individuals from 13 countries in Latin America and the Caribbean, as well as in Hispanics in the United States. A total of 167 unique pathogenic variants have been reported in the existing literature. In unselected breast cancer cases, the prevalence ranged from 1.2 to 27.1%. Some countries presented a few recurrent pathogenic variants, while others were characterized by diverse, non-recurrent variants. The proportion of BRCA pathogenic variants shared between Hispanics in the United States and Latin American populations was estimated at 10.4%. Within Latin America and the Caribbean, 8.2% of the BRCA variants reported were present in more than one country. Countries with high prevalence of BRCA pathogenic variants may benefit from more aggressive testing strategies, while testing of recurrent variant panels might present a cost-effective solution for improving genetic testing in some, but not all, countries.

  14. KOHBRA BRCA risk calculator (KOHCal): a model for predicting BRCA1 and BRCA2 mutations in Korean breast cancer patients.

    Science.gov (United States)

    Kang, Eunyoung; Park, Sue K; Lee, Jong Won; Kim, Zisun; Noh, Woo-Chul; Jung, Yongsik; Yang, Jung-Hyun; Jung, Sung Hoo; Kim, Sung-Won

    2016-05-01

    The widely used Western BRCA mutation prediction models underestimated the risk of having a BRCA mutation in Korean breast cancer patients. This study aimed to identify predictive factors for BRCA1/2 mutations and to develop a Korean BRCA risk calculator. The model was constructed by logistic regression model, and it was based on the Korean Hereditary Breast Cancer study, in which 1669 female patients were enrolled between May 2007 and December 2010. A separate data set of 402 patients, who were enrolled from Jan 2011 to August 2012, was used to test the performance of our model. In total, 264 (15.8%) and 67 (16.7%) BRCA mutation carriers were identified in the model and validation set, respectively. Multivariate analysis showed that age at breast cancer diagnosis, bilateral breast cancer, triple-negative breast cancer (TNBC) and the number of relatives with breast or ovarian cancer within third-degree relatives were independent predictors of the BRCA mutation among familial breast cancer patients. An age cancer, both breast and ovarian cancer and TNBC remained significant predictors in non-familial breast cancer cases. Our model was developed based on logistic regression models. The validation results showed no differences between the observed and expected carrier probabilities. This model will be a useful tool for providing genetic risk assessments in Korean populations. PMID:26763880

  15. Impact of Genetic Counseling and Testing on Altruistic Motivations to Test for BRCA1/2: a Longitudinal Study.

    Science.gov (United States)

    Garg, Rahul; Vogelgesang, Joseph; Kelly, Kimberly

    2016-06-01

    Despite the importance of altruism in an individual's participation in genetic counseling and testing, little research has explored the change in altruistic motivations to test over time. This study analyzed altruistic motivations to test and change in altruistic motivations after genetic counseling and testing among individuals (N = 120) at elevated risk for BRCA1/2 mutations. The perceived benefits of genetic testing were assessed and utilized in a mixed-methods, repeated measures design at three time points: pre-counseling, counseling and post-genetic testing, along with transcripts of genetic counseling sessions. Qualitative analysis using an immersion/crystallization method resulted in six common perceived benefits of testing: cancer prevention, awareness, family's survival, relief from anxiety, for science, and future planning. Perceived benefits were then coded into three categories according to Hamilton's kin selection theory: altruistic motivation, personal motivation, and motivation for mutual benefit. At pre-counseling, those with a personal cancer history (p = 0.003) and those with one or more children (p = 0.013), were significantly more likely to cite altruistic motivations to test. Altruistic motivations significantly increased post-counseling (p = 0.01) but declined post-testing (p cancer to have altruistic motivations for testing. Genetic counseling may have increased altruistic motivations to help family and may be a prime opportunity to discuss other forms of altruism. PMID:26578231

  16. On the development of a decision support intervention for mothers undergoing BRCA1/2 cancer genetic testing regarding communicating test results to their children

    OpenAIRE

    Peshkin, Beth N.; DeMarco, Tiffani A.; Tercyak, Kenneth P.

    2009-01-01

    Parent communication of BRCA1/2 test results to minor-age children is an important, yet understudied, clinical issue that is commonly raised in the management of familial cancer risk. Genetic counseling professionals and others who work with parents undergoing this form of testing often confront questions about the risks/benefits and timing of such disclosures, as well as the psychosocial impact of disclosure and nondisclosure on children’s health and development. This paper briefly reviews l...

  17. Mutation of the BRCA1 SQ-cluster results in aberrant mitosis, reduced homologous recombination, and a compensatory increase in non-homologous end joining.

    Science.gov (United States)

    Beckta, Jason M; Dever, Seth M; Gnawali, Nisha; Khalil, Ashraf; Sule, Amrita; Golding, Sarah E; Rosenberg, Elizabeth; Narayanan, Aarthi; Kehn-Hall, Kylene; Xu, Bo; Povirk, Lawrence F; Valerie, Kristoffer

    2015-09-29

    Mutations in the breast cancer susceptibility 1 (BRCA1) gene are catalysts for breast and ovarian cancers. Most mutations are associated with the BRCA1 N- and C-terminal domains linked to DNA double-strand break (DSB) repair. However, little is known about the role of the intervening serine-glutamine (SQ) - cluster in the DNA damage response beyond its importance in regulating cell cycle checkpoints. We show that serine-to-alanine alterations at critical residues within the SQ-cluster known to be phosphorylated by ATM and ATR result in reduced homologous recombination repair (HRR) and aberrant mitosis. While a S1387A BRCA1 mutant - previously shown to abrogate S-phase arrest in response to radiation - resulted in only a modest decrease in HRR, S1387A together with an additional alteration, S1423A (BRCA12P), reduced HRR to vector control levels and similar to a quadruple mutant also including S1457A and S1524A (BRCA14P). These effects appeared to be independent of PALB2. Furthermore, we found that BRCA14P promoted a prolonged and struggling HRR late in the cell cycle and shifted DSB repair from HRR to non-homologous end joining which, in the face of irreparable chromosomal damage, resulted in mitotic catastrophe. Altogether, SQ-cluster phosphorylation is critical for allowing adequate time for completing normal HRR prior to mitosis and preventing cells from entering G1 prematurely resulting in gross chromosomal aberrations.

  18. The rate of recurrent BRCA1, BRCA2, and TP53 mutations in the general population, and unselected ovarian cancer cases, in Belo Horizonte, Brazil.

    Science.gov (United States)

    Schayek, Hagit; De Marco, Luiz; Starinsky-Elbaz, Sigal; Rossette, Mariana; Laitman, Yael; Bastos-Rodrigues, Luciana; da Silva Filho, Agnaldo Lopes; Friedman, Eitan

    2016-01-01

    In Brazil, several recurring mutations in BRCA1 and BRCA2 and a TP53 mutation (R337H) have been reported in high risk breast cancer cases. We hypothesized that these recurring mutations may also be detected in the general population and ovarian cancer cases in the state of Minas Gerais. To test this notion, participants were recruited from the outpatient and the Gynecological clinic in the UFMG Medical Center in Belo Horizonte, Minas Gerais, Brazil. BRCA1 (c.68_69delAG, c.5266dupC, c.181T>G, c.4034delA, c.5123C>A), BRCA2 (c.5946delT, c.8537_8538delAG, 4936_4939delGAAA), the c.156_157insAlu* BRCA2 and the c.1010G>A *TP53 mutation were genotyped using validated techniques. Overall, 513 cancer free participants (273 men) (mean age 47.7 ± 15.1 years) and 103 ovarian cancer cases (mean age at diagnosis 58.7 ± 9.6 years) were studied. None of the participants were found to carry any of the genotyped mutations. We conclude that the recurring mutations in BRCA1, BRCA2 and TP53 cannot be detected in the general population or consecutive ovarian cancer cases in this geographical region in Brazil.

  19. Genomewide high-density SNP linkage analysis of non-BRCA1/2 breast cancer families identifies various candidate regions and has greater power than microsatellite studies

    Directory of Open Access Journals (Sweden)

    Gonzalez-Neira Anna

    2007-08-01

    Full Text Available Abstract Background The recent development of new high-throughput technologies for SNP genotyping has opened the possibility of taking a genome-wide linkage approach to the search for new candidate genes involved in heredity diseases. The two major breast cancer susceptibility genes BRCA1 and BRCA2 are involved in 30% of hereditary breast cancer cases, but the discovery of additional breast cancer predisposition genes for the non-BRCA1/2 breast cancer families has so far been unsuccessful. Results In order to evaluate the power improvement provided by using SNP markers in a real situation, we have performed a whole genome screen of 19 non-BRCA1/2 breast cancer families using 4720 genomewide SNPs with Illumina technology (Illumina's Linkage III Panel, with an average distance of 615 Kb/SNP. We identified six regions on chromosomes 2, 3, 4, 7, 11 and 14 as candidates to contain genes involved in breast cancer susceptibility, and additional fine mapping genotyping using microsatellite markers around linkage peaks confirmed five of them, excluding the region on chromosome 3. These results were consistent in analyses that excluded SNPs in high linkage disequilibrium. The results were compared with those obtained previously using a 10 cM microsatellite scan (STR-GWS and we found lower or not significant linkage signals with STR-GWS data compared to SNP data in all cases. Conclusion Our results show the power increase that SNPs can supply in linkage studies.

  20. Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds.

    Science.gov (United States)

    Zimmer, Jutta; Tacconi, Eliana M C; Folio, Cecilia; Badie, Sophie; Porru, Manuela; Klare, Kerstin; Tumiati, Manuela; Markkanen, Enni; Halder, Swagata; Ryan, Anderson; Jackson, Stephen P; Ramadan, Kristijan; Kuznetsov, Sergey G; Biroccio, Annamaria; Sale, Julian E; Tarsounas, Madalena

    2016-02-01

    G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers. Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks. We have previously shown that HR facilitates telomere replication. Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR. Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability. Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency. PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7. Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition. PMID:26748828

  1. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

    Science.gov (United States)

    Antoniou, Antonis C.; Sinilnikova, Olga M.; McGuffog, Lesley; Healey, Sue; Nevanlinna, Heli; Heikkinen, Tuomas; Simard, Jacques; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Neuhausen, Susan L.; Ding, Yuan C.; Couch, Fergus J.; Wang, Xianshu; Fredericksen, Zachary; Peterlongo, Paolo; Peissel, Bernard; Bonanni, Bernardo; Viel, Alessandra; Bernard, Loris; Radice, Paolo; Szabo, Csilla I.; Foretova, Lenka; Zikan, Michal; Claes, Kathleen; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Lejbkowicz, Flavio; Andrulis, Irene L.; Ozcelik, Hilmi; Glendon, Gord; Gerdes, Anne-Marie; Thomassen, Mads; Sunde, Lone; Caligo, Maria A.; Laitman, Yael; Kontorovich, Tair; Cohen, Shimrit; Kaufman, Bella; Dagan, Efrat; Baruch, Ruth Gershoni; Friedman, Eitan; Harbst, Katja; Barbany-Bustinza, Gisela; Rantala, Johanna; Ehrencrona, Hans; Karlsson, Per; Domchek, Susan M.; Nathanson, Katherine L.; Osorio, Ana; Blanco, Ignacio; Lasa, Adriana; Benítez, Javier; Hamann, Ute; Hogervorst, Frans B.L.; Rookus, Matti A.; Collee, J. Margriet; Devilee, Peter; Ligtenberg, Marjolijn J.; van der Luijt, Rob B.; Aalfs, Cora M.; Waisfisz, Quinten; Wijnen, Juul; van Roozendaal, Cornelis E.P.; Peock, Susan; Cook, Margaret; Frost, Debra; Oliver, Clare; Platte, Radka; Evans, D. Gareth; Lalloo, Fiona; Eeles, Rosalind; Izatt, Louise; Davidson, Rosemarie; Chu, Carol; Eccles, Diana; Cole, Trevor; Hodgson, Shirley; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; Buecher, Bruno; Léoné, Mélanie; Bressac-de Paillerets, Brigitte; Remenieras, Audrey; Caron, Olivier; Lenoir, Gilbert M.; Sevenet, Nicolas; Longy, Michel; Ferrer, Sandra Fert; Prieur, Fabienne; Goldgar, David; Miron, Alexander; John, Esther M.; Buys, Saundra S.; Daly, Mary B.; Hopper, John L.; Terry, Mary Beth; Yassin, Yosuf; Gschwantler-Kaulich, Daphne; Staudigl, Christine; Hansen, Thomas v. O.; Barkardottir, Rosa Bjork; Kirchhoff, Tomas; Pal, Prodipto; Kosarin, Kristi; Offit, Kenneth; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Schwartz, Peter E.; Blank, Stephanie V.; Toland, Amanda E.; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny N.; Allavena, Anna; Schmutzler, Rita K.; Versmold, Beatrix; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Niederacher, Dieter; Deißler, Helmut; Fiebig, Britta; Suttner, Christian; Schönbuchner, Ines; Gadzicki, Dorothea; Caldes, Trinidad; de la Hoya, Miguel; Pooley, Karen A.; Easton, Douglas F.; Chenevix-Trench, Georgia

    2009-01-01

    Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07–1.25, P-trend = 2.8 × 10−4]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04–1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04–1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98–1.14) was consistent with odds ratio estimates derived from population-based case–control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not. PMID:19656774

  2. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

    Science.gov (United States)

    Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Neuhausen, Susan L.; Ding, Yuan Chun; Rebbeck, Timothy R.; Weitzel, Jeffrey N.; Lynch, Henry T.; Isaacs, Claudine; Ganz, Patricia A.; Tomlinson, Gail; Olopade, Olufunmilayo I.; Couch, Fergus J.; Wang, Xianshu; Lindor, Noralane M.; Pankratz, Vernon S.; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall’Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I.; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L.; Greene, Mark H.; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernström, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Durán, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B; van Asperen, Christi J; Devilee, Peter; Meijers-Heijboer, E.J.; Blok, Marinus J; Aalfs, Cora M.; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D. Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary E.; Walker, Lisa; Kennedy, M. John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valérie; Lasset, Christine; Dreyfus, Hélène; Leroux, Dominique; Hardouin, Agnès; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frénay, Marc; Vénat-Bouvet, Laurence; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alex; Goldgar, David; Singer, Christian F.; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V. O.; Jønson, Lars; Agnarsson, Bjarni A.; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Schwartz, Peter E.; Blank, Stephanie V.; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J.; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomäki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B.; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F.

    2010-01-01

    The known breast cancer (BC) susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1,LSP1 and 2q35 confer increased risks of BC for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of three additional SNPs, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 at 5p12 and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased BC risk for BRCA2 carriers (per-allele Hazard Ratio (HR)=1.10, 95%CI:1.03-1.18, p=0.006 and HR=1.09, 95%CI:1.01-1.19, p=0.03, respectively). Neither SNP was associated with BC risk for BRCA1 carriers and rs6504950 was not associated with BC for either BRCA1 or BRCA2 carriers. Of the nine polymorphisms investigated, seven were associated with BC for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, p-values:7×10−11-0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (p=0.0049, 0.03 respectively). All risk associated polymorphisms appear to interact multiplicatively on BC risk for mutation carriers. Based on the joint genotype distribution of the seven risk associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e. between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing BC by age 80, compared with 42-50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences may be sufficient to influence the clinical management of mutation carriers. PMID:21118973

  3. BRCA1 Regulates IFI16 Mediated Nuclear Innate Sensing of Herpes Viral DNA and Subsequent Induction of the Innate Inflammasome and Interferon-β Responses.

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    Dipanjan Dutta

    2015-06-01

    Full Text Available The innate immune system pattern recognition receptors (PRR are the first line of host defenses recognizing the various pathogen- or danger-associated molecular patterns and eliciting defenses by regulating the production of pro-inflammatory cytokines such as IL-1β, IL-18 or interferon β (IFN-β. NOD-like receptors (NLRs and AIM2-like receptors (ALRs are cytoplasmic inflammasome sensors of foreign molecules, including DNA. IFI16, a sequence-independent nuclear innate sensor ALR, recognizes episomal dsDNA genomes of herpes viruses such as KSHV, EBV, and HSV-1 in the infected cell nuclei, forms an inflammasome complex with ASC and procaspase1, and relocates into the cytoplasm leading into Caspase-1 and IL-1β generation. IFI16 also induces IFN-β during HSV-1 infection via the cytoplasmic STING-TBK1-IRF3 pathway. Thus far, whether IFI16 recognizes foreign DNA directly or utilizes other host protein(s is unknown. Here, we demonstrate that BRCA1, a DNA damage repair sensor and transcription regulator, is in complex with IFI16 in the host cell nucleus, and their association increases in the presence of nuclear viral genomes during de novo KSHV, EBV and HSV-1 infection, and in latent KSHV or EBV infection, but not by DNA damage responses (DDR induced by bleomycin and vaccinia virus cytoplasmic dsDNA. BRCA1 is a constituent of the triggered IFI16-inflammasome and is translocated into the cytoplasm after genome recognition along with the IFI16-inflammasome. The absence of BRCA1 abrogated IFI16-viral genome association, inflammasome assembly, IFI16 cytoplasmic localization, and Caspase-1 and IL-1β production. The absence of BRCA1 also abolished the cytoplasmic IFI16-STING interaction, downstream IRF3 phosphorylation, nuclear translocation of pIRF3 and IFN-β production during de novo KSHV and HSV-1 infection. These findings highlight that BRCA1 plays a hitherto unidentified innate immunomodulatory role by facilitating nuclear foreign DNA sensing by

  4. First application of next-generation sequencing in Moroccan breast/ovarian cancer families and report of a novel frameshift mutation of the BRCA1 gene

    Science.gov (United States)

    Jouali, Farah; Laarabi, Fatima-Zahra; Marchoudi, Nabila; Ratbi, Ilham; Elalaoui, Siham Chafai; Rhaissi, Houria; Fekkak, Jamal; Sefiani, Abdelaziz

    2016-01-01

    At present, breast cancer is the most common type of cancer in females. The majority of cases are sporadic, but 5–10% are due to an inherited predisposition to develop breast and ovarian cancers, which are transmitted as an autosomal dominant form with incomplete penetrance. The beneficial effects of clinical genetic testing, including next generation sequencing (NGS) for BRCA1/2 mutations, is major; in particular, it benefits the care of patients and the counseling of relatives that are at risk of breast cancer, in order to reduce breast cancer mortality. BRCA genetic testing was performed in 15 patients with breast cancer and a family with positivity for the heterozygous c.6428C>A mutation of the BRCA2 gene. Informed consent was obtained from all the subjects. Genomic DNAs were extracted and the NGS for genes was performed using the Ion Torrent Personal Genome Machine (PGM) with a 316 chip. The reads were aligned with the human reference HG19 genome to elucidate variants in the BRCA1 and BRCA2 genes. Mutations detected by the PGM platform were confirmed by target direct Sanger sequencing on a second patient DNA sample. In total, 4 BRCA variants were identified in 6 families by NGS. Of these, 3 mutations had been previously reported: c.2126insA of BRCA1, and c.1310_1313delAAGA and c.7235insG of BRCA2. The fourth variant, c.3453delT in BRCA1, has, to the best of our knowledge, never been previously reported. The present study is the first to apply NGS of the BRCA1 and BRCA2 genes to a Moroccan population, prompting additional investigation into local founder mutations and variant characteristics in the region. The variants with no clear clinical significance may present a diagnostic challenge when performing targeted resequencing. These results confirm that an NGS approach based on Ampliseq libraries and PGM sequencing is a highly efficient, speedy and high-throughput mutation detection method, which may be preferable in lower income countries.

  5. Psychological Distress, Anxiety, and Depression of Cancer-Affected BRCA1/2 Mutation Carriers: a Systematic Review.

    Science.gov (United States)

    Ringwald, Johanna; Wochnowski, Christina; Bosse, Kristin; Giel, Katrin Elisabeth; Schäffeler, Norbert; Zipfel, Stephan; Teufel, Martin

    2016-10-01

    Understanding the intermediate- and long-term psychological consequences of genetic testing for cancer patients has led to encouraging research, but a clear consensus of the psychosocial impact and clinical routine for cancer-affected BRCA1 and BRCA2 mutation carriers is still missing. We performed a systematic review of intermediate- and long-term studies investigating the psychological impact like psychological distress, anxiety, and depression in cancer-affected BRCA mutation carriers compared to unaffected mutation carriers. This review included the screening of 1243 studies. Eight intermediate- and long-term studies focusing on distress, anxiety, and depression symptoms among cancer-affected mutation carriers at least six months after the disclosure of genetic testing results were included. Studies reported a great variety of designs, methods, and patient outcomes. We found evidence indicating that cancer-affected mutation carriers experienced a negative effect in relation to psychological well-being in terms of an increase in symptoms of distress, anxiety, and depression in the first months after test disclosure. In the intermediate- and long-term, no significant clinical relevant symptoms occurred. However, none of the included studies used specific measurements, which can clearly identify psychological burdens of cancer-affected mutation carriers. We concluded that current well-implemented distress screening instruments are not sufficient for precisely identifying the psychological burden of genetic testing. Therefore, future studies should implement coping strategies, specific personality structures, the impact of genetic testing, supportive care needs and disease management behaviour to clearly screen for the possible intermediate- and long-term psychological impact of a positive test disclosure. PMID:27074860

  6. Risk factors for endometrial cancer among women with a BRCA1 or BRCA2 mutation: a case control study.

    Science.gov (United States)

    Segev, Yakir; Rosen, Barry; Lubinski, Jan; Gronwald, Jacek; Lynch, Henry T; Moller, Pal; Kim-Sing, Charmaine; Ghadirian, Parviz; Karlan, Beth; Eng, Charis; Gilchrist, Dawna; Neuhausen, Susan L; Eisen, Andrea; Friedman, Eitan; Euhus, David; Ping, Sun; Narod, Steven A

    2015-09-01

    BRCA mutation carriers may use tamoxifen for breast cancer prevention or treatment. Hormone replacement therapy is often prescribed after surgical menopause and oral contraceptives are recommended for ovarian cancer prevention. The objective of this study was to assess the impact of these medications and other risk factors on endometrial cancer risk in BRCA carriers. Women with a BRCA1 or BRCA2 mutation were identified from a registry of mutation carriers. Cases were 83 women who had a diagnosis of endometrial cancer. Controls were 1027 matched women who did not develop endometrial cancer and who had an intact uterus. All women completed a baseline questionnaire, which included questions about ages at menarche and menopause, oral contraceptive use, hormone replacement therapy use, hysterectomy, oophorectomy, breast cancer history and tamoxifen use. We estimated the odds ratio associated with each risk factor in a multivariate analysis. No differences were found between cases and controls in terms of age at menarche, BMI, smoking, or oral contraceptive use. In a multivariate analysis, for women taking estrogen-only hormone replacement therapy, the odds ratio was 0.23 (95% CI 0.03-1.78, p = 0.16), and for women taking progesterone-only hormone replacement therapy the odds ratio was 6.91 (95% CI 0.99-98.1, p = 0.05). The adjusted odds ratio for endometrial cancer associated with a history of tamoxifen use was 3.50 (95% CI 1.51-8.10, p = 0.003). The observed increased risk of endometrial cancer associated with progesterone-only therapy merits further study. PMID:25838159

  7. Risk of cancer other than breast or ovarian in Chinese Han women with BRCA1/2 mutations%中国汉族BRCA1/2突变的乳腺癌家系中其他肿瘤发病风险分析

    Institute of Scientific and Technical Information of China (English)

    刘静; 张娟; 欧阳涛; 李金峰; 王天峰; 范照青; 范铁; 林本耀; 解云涛

    2013-01-01

    Objective To investigate the risk of cancer other than breast or ovarian in Chinese Han women with family breast cancer who carried a BRCA1 or BRCA2 mutation.Methods Germline mutations in BRCA1/2 genes in the cohort of 465 Chinese Han patients with familial breast cancer were screened using a PCR-sequencing assay.The proportion of cancer other than breast or ovarian was compared in mutantion group and non mutation group.Results Among the 465 familial breast cancer patients,47 (10.1%) were BRCA1/2 mutation carriers and 418 (89.9%) were non-carriers.There was no significant difference in the total proportion of cancers other than breast or ovarian in the family between BRCA1/2 mutation carriers and non-carriers (27.7% ∶29.9%,x2 =0.10,P=0.75).But the tumor spectrum was different between the BRCA1/2 carriers and non-carriers.In the family of BRCA1/2 carriers,the most common cancers were gastric cancer,pancreatic cancer,and prostate cancer; while in the non-carriers,the most common cancers were lung cancer,gastric cancer,and esophageal cancer.The relative risk of gastric cancer,pancreatic cancer and prostate cancer was significantly higher in the families of BRCA1/2 mutation carriers than that of non-carriers (17%∶7.7%,odd ratio:2.47,95% CI:1.07-5.74,P =O.048).Conclusion This study suggests that the relative risk of gastric cancer,pancreatic cancer and prostate cancer in BRCA1/2 carriers is moderate higher than in non-carriers in Chinese Han women.%目的 研究携带BRCA1/2突变的中国汉族家族性乳腺癌家系中非乳腺癌和卵巢癌的其他肿瘤发病风险.方法 采用聚合酶链反应(PCR)-直接测序法检测465个汉族家族性乳腺癌家系中先证者的BRCA1/2基因胚系突变,比较突变组与非突变组有非乳腺癌和卵巢癌的其他肿瘤家族史的比例.结果 在465例汉族家族性乳腺癌先证者中,BRCA1/2突变者47例(10.1%),非突变者418例(89.9%).在BRCA1/2突变组和非突变组中,两者总

  8. High Levels of Nucleolar Spindle-Associated Protein and Reduced Levels of BRCA1 Expression Predict Poor Prognosis in Triple-Negative Breast Cancer.

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    Li Chen

    Full Text Available Nucleolar spindle-associated protein (NuSAP1 is an important mitosis-related protein, and aberrant NuSAP1 expression is associated with abnormal spindles and mitosis. This study investigated the prognostic value of NuSAP1 in breast cancer.Two sets of tissue microarrays (TMAs that included samples from 450 breast cancer patients were constructed, of which 250 patients were training set and the other 200 patients were validation set. Immunohistochemical staining was performed to determine the NuSAP1 levels. A Kaplan-Meier analysis was used to estimate the prognostic value of NuSAP1 in breast cancer. A stepwise Cox analysis was performed to construct a risk-prediction model for triple-negative breast cancer (TNBC. All statistical analysis was performed with SPSS software.There were 108 (43.5% and 88 (44.0% patients expressed NuSAP1 in the training set and validation set respectively. High levels of NuSAP1 expression were related to poor disease-free survival (DFS in both training (P = 0.028 and validation (P = 0.006 cohorts, particularly in TNBC. With combination of two cohorts, both NuSAP1 (HR = 4.136, 95% CI: 1.956-8.747, P < 0.001 and BRCA1 (HR = 0.383, 95% CI: 0.160-0.915, P = 0.031 were independent prognostic indicators of DFS in TNBC. A receiver operating characteristic (ROC analysis revealed that the combination of NuSAP1 and BRCA1 significantly improved the prognostic power compared with the traditional model (0.778 versus 0.612, P < 0.001.Our study confirms the prognostic value of NuSAP1 in breast cancer. The combination of NuSAP1 and BRCA1 could improve the DFS prediction accuracy in TNBC.

  9. Analysis of BRIP1 Variants among Korean Patients with BRCA1/2 Mutation-Negative High-Risk Breast Cancer

    Science.gov (United States)

    Kim, Haeyoung; Cho, Dae-Yeon; Choi, Doo Ho; Jung, Gee Hue; Shin, Inkyung; Park, Won; Huh, Seung Jae; Nam, Seok Jin; Lee, Jeong Eon; Gil, Won Ho; Kim, Seok Won

    2016-01-01

    Purpose The aim of the current study is to assess the spectrum of genetic variation in the BRIP1 gene among Korean high-risk breast cancer patients who tested negative for the BRCA1/2 mutation. Materials and Methods Overall, 235 Korean patientswith BRCA1/2 mutation–negative high-risk breast cancerwere screened for BRIP1 mutations. The entire BRIP1 gene was analyzed using fluorescent-conformation sensitive gel electrophoresis. In silico analysis of BRIP1 variants was performed using PolyPhen-2 and SIFT. Results A total of 20 sequence alterations including 12 exonic and eight intronic variantswere found. Among the 12 exonic variants, 10 were missense and two were silent mutations. No protein-truncating mutation was found among the tested patients. Among the 10 missense variants, four (p.L263F, p.L340F, p.L474P, and p.R848H) were predicted to be pathogenic by both PolyPhen-2 and SIFT, and these variants were found in five patients. Of the four missense variants, p.L263F, p.L474P, and p.R848H localize to regions between the helicase motifs, while p.L340F resides in an iron-sulfur domain of BRIP1. Conclusion No protein-truncating mutation in BRIP1 was found among the tested patients. The contribution of BRIP1 variants is thought to be minor in Korean non-BRCA1/2 high-risk breast cancer. PMID:26790966

  10. A prospective investigation of predictive and modifiable risk factors for breast cancer in unaffected BRCA1 and BRCA2 gene carriers

    International Nuclear Information System (INIS)

    Breast cancer is the most common female cancer worldwide. The lifetime risk of a woman being diagnosed with breast cancer is approximately 12.5%. For women who carry the deleterious mutation in either of the BRCA genes, BRCA1 or BRCA2, the risk of developing breast or ovarian cancer is significantly increased. In recent years there has been increased penetrance of BRCA1 and BRCA2 associated breast cancer, prompting investigation into the role of modifiable risk factors in this group. Previous investigations into this topic have relied on participants recalling lifetime weight changes and subjective methods of recording physical activity. The influence of obesity-related biomarkers, which may explain the link between obesity, physical activity and breast cancer risk, has not been investigated prospectively in this group. This paper describes the design of a prospective cohort study investigating the role of predictive and modifiable risk factors for breast cancer in unaffected BRCA1 and BRCA2 gene mutation carriers. Participants will be recruited from breast cancer family risk clinics and genetics clinics. Lifestyle risk factors that will be investigated will include body composition, metabolic syndrome and its components, physical activity and dietary intake. PBMC telomere length will be measured as a potential predictor of breast cancer occurrence. Measurements will be completed on entry to the study and repeated at two years and five years. Participants will also be followed annually by questionnaire to track changes in risk factor status and to record cancer occurrence. Data will be analysed using multiple regression models. The study has an accrual target of 352 participants. The results from this study will provide valuable information regarding the role of modifiable lifestyle risk factors for breast cancer in women with a deleterious mutation in the BRCA gene. Additionally, the study will attempt to identify potential blood biomarkers which may be predictive

  11. Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2.

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    Tomas Kirchhoff

    Full Text Available Recently, a locus on chromosome 6q22.33 (rs2180341 was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC. In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA. Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR = 1.03, 95% CI 1.00-1.06, p = 0.023. There was evidence for heterogeneity in the ORs among studies (I(2 = 49.3%; p = <0.004. In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048, indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

  12. The CYP1A2 genotype modifies the association between coffee consumption and breast cancer risk among BRCA1 mutation carriers.

    Science.gov (United States)

    Kotsopoulos, Joanne; Ghadirian, Parviz; El-Sohemy, Ahmed; Lynch, Henry T; Snyder, Carrie; Daly, Mary; Domchek, Susan; Randall, Susan; Karlan, Beth; Zhang, Phil; Zhang, Shiyu; Sun, Ping; Narod, Steven A

    2007-05-01

    We have recently reported that, among BRCA1 mutation carriers, the consumption of caffeinated coffee was associated with a significant reduction in breast cancer risk. Because the metabolism of caffeine is primarily by CYP1A2, we examined whether or not the CYP1A2 genotype modifies the association between a history of coffee consumption and the risk of breast cancer. A common A to C polymorphism in the CYP1A2 gene is associated with decreased enzyme inducibility and impaired caffeine metabolism. Information regarding coffee consumption habits and the CYP1A2 genotype was available for 411 BRCA1 mutation carriers (170 cases and 241 controls). We estimated the odds ratios (ORs) and 95% confidence intervals (95% CIs) for breast cancer associated with the CYP1A2 genotype and a history of coffee consumption before age 35, adjusting for potential confounders. The CYP1A2 genotype did not affect breast cancer risk. Among women with at least one variant C allele (AC or CC), those who consumed coffee had a 64% reduction in breast cancer risk, compared with women who never consumed coffee (OR, 0.36; 95% CI, 0.18-0.73). A significant protective effect of coffee consumption was not observed among women with the CYP1A2 AA genotype (OR, 0.93; 95% CI, 0.49-1.77). Similar results were obtained when the analysis was restricted to caffeinated coffee. This study suggests that caffeine protects against breast cancer in women with a BRCA1 mutation and illustrates the importance of integrating individual genetic variability when assessing diet-disease associations. PMID:17507615

  13. Whole exome sequencing suggests much of non-BRCA1/BRCA2 familial breast cancer is due to moderate and low penetrance susceptibility alleles.

    Directory of Open Access Journals (Sweden)

    Francisco Javier Gracia-Aznarez

    Full Text Available The identification of the two most prevalent susceptibility genes in breast cancer, BRCA1 and BRCA2, was the beginning of a sustained effort to uncover new genes explaining the missing heritability in this disease. Today, additional high, moderate and low penetrance genes have been identified in breast cancer, such as P53, PTEN, STK11, PALB2 or ATM, globally accounting for around 35 percent of the familial cases. In the present study we used massively parallel sequencing to analyze 7 BRCA1/BRCA2 negative families, each having at least 6 affected women with breast cancer (between 6 and 10 diagnosed under the age of 60 across generations. After extensive filtering, Sanger sequencing validation and co-segregation studies, variants were prioritized through either control-population studies, including up to 750 healthy individuals, or case-control assays comprising approximately 5300 samples. As a result, a known moderate susceptibility indel variant (CHEK2 1100delC and a catalogue of 11 rare variants presenting signs of association with breast cancer were identified. All the affected genes are involved in important cellular mechanisms like DNA repair, cell proliferation and survival or cell cycle regulation. This study highlights the need to investigate the role of rare variants in familial cancer development by means of novel high throughput analysis strategies optimized for genetically heterogeneous scenarios. Even considering the intrinsic limitations of exome resequencing studies, our findings support the hypothesis that the majority of non-BRCA1/BRCA2 breast cancer families might be explained by the action of moderate and/or low penetrance susceptibility alleles.

  14. DCIS in BRCA1 and BRCA2 mutation carriers: prevalence, phenotype, and expression of oncodrivers C-MET and HER3

    OpenAIRE

    Yang, Rachel L.; Mick, Rosemarie; Lee, Kathreen; Holly L Graves; Nathanson, Katherine L.; Domchek, Susan M.; Kelz, Rachel R; Zhang, Paul J; Czerniecki, Brian J.

    2015-01-01

    Background Studies report conflicting evidence regarding the existence of a DCIS-associated premalignant pathway in BRCA mutation carriers. We aimed to examine the prevalence, phenotype, and expression of oncodrivers in pure DCIS (pDCIS) and invasive breast cancer with concurrent DCIS (IBC + DCIS) in mutation carriers. Methods A cohort of BRCA1 and BRCA2 mutation carriers >18 years old who underwent surgery for breast cancer at an academic hospital (1992–2011) and had pathology available for ...

  15. Experience of BRCA1/2 mutation-negative young women from families with hereditary breast and ovarian cancer: a qualitative study

    OpenAIRE

    Macrae, Lynn; de Souza, Alicia Navarro; Loiselle, Carmen G.; Wong, Nora

    2013-01-01

    Background Little is known about the experience of young women who become aware of their parent’s BRCA1 or BRCA2 (BRCA) mutation status as adolescents or young adults. There is also currently a gap in the literature pertaining to those who are found to be negative for their familial mutation. We aimed to investigate the experience of these mutation-negative young women from hereditary breast and ovarian cancer (HBOC) families. Methods Using a semi-structured questionnaire we interviewed 8 wom...

  16. miR-638 mediated regulation of BRCA1 affects DNA repair and sensitivity to UV and cisplatin in triple-negative breast cancer

    OpenAIRE

    Tan, Xiaohui; Peng, Jin; Fu, Yebo; An, Shejuan; Rezaei, Katayoon; Tabbara, Sana; Teal, Christine B.; Man, Yan-gao; Brem, Rachel F.; Fu, Sidney W.

    2014-01-01

    Introduction Triple-negative breast cancer (TNBC) represents 15 to 20% of all types of breast cancer; however, it accounts for a large number of metastatic cases and deaths, and there is still no effective treatment. The deregulation of microRNAs (miRNAs) in breast cancer has been widely reported. We previously identified that miR-638 was one of the most deregulated miRNAs in breast cancer progression. Bioinformatics analysis revealed that miR-638 directly targets BRCA1. The aim of this study...

  17. 乳腺癌易感基因1在食管鳞癌中的表达及临床意义%Expression and clinical significance of BRCA1 in human esophageal squamous cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    杨怡轩; 薛丽燕; 董立佳; 付明; 詹启敏; 童彤

    2012-01-01

    Objective To investigate the expression of BRCA1 in esophageal squamous cell carcinoma (ESCC) tissues and evaluate its correlation with clinicopathological features as well as the prognosis of ESCC patients.Methods The expression of BRCA1 was detected by immunohistochemistry (IHC) in 201 specimens of T3 stage ESCC tissues and corresponding adjacent normal tissues using tissue microarray.The correlation between BRCA1 expression and clinicopathological features of ESCC was determined by chi-square analysis.The cumulative survival rate was analyzed by Kaplan-Meier method.Results The positive rate of BRCA1 expression in ESCC tissues was significantly higher than that in adjacent normal tissues [88.6% (178/201) vs.36.8% (74/201),P < 0.001].There was a significant correlation between the expression of BRCA1 and lymph node metastasis.In the tumors with positive lymph nodes,strong positive expression of BRCA1 was found in 45.0% (49/109),while only 19.6% (18/92) in tumors without lymph node metastasis,showing a significant difference (P < 0.001).A close relationship was also found between the expression of BRCA1 and gross typing of tumors (P < 0.05).The expression of BRCA1 was not significantly correlated with gender,age,tumor location,differentiation,and tumor thrombus (P > 0.05).The results of Kaplan-Meier analysis indicated that ESCC patients with a higher positive rate of BRCA1 expression have a poorer prognosis (P < 0.05).Conclusions The expression of BRCA1 is related to the occurrence and development of esophageal carcinoma.BRCA1 protein may serve as a new potential biomarker in estimating the biological behavior of ESCC.%目的 研究食管鳞癌组织中乳腺癌易感基因1(BRCA1)的表达与患者临床病理特征及预后之间的关系.方法 采用免疫组织化学染色法检测201例手术切除的T3期食管鳞癌患者癌与癌旁正常组织中BRCA1蛋白的表达.采用x2检验分析BRCA1蛋白的表达与患者临床病理特征间

  18. Breast cancer in women at high risk: the role of rapid genetic testing for BRCA1 and -2 mutations and the consequences for treatment strategies.

    Science.gov (United States)

    Francken, Anne Brecht; Schouten, Philip C; Bleiker, Eveline M A; Linn, Sabine C; Rutgers, Emiel J Th

    2013-10-01

    Specific clinical questions rise when patients, who are diagnosed with breast cancer, are at risk of carrying a mutation in BRCA1 and -2 gene due to a strong family history or young age at diagnosis. These questions concern topics such as 1. Timing of genetic counseling and testing, 2. Choices to be made for BRCA1 or -2 mutation carriers in local treatment, contralateral treatment, (neo)adjuvant systemic therapy, and 3. The psychological effects of rapid testing. The knowledge of the genetic status might have several advantages for the patient in treatment planning, such as the choice whether or not to undergo mastectomy and/or prophylactic contralateral mastectomy. The increased risk of developing a second breast cancer in the ipsilateral breast in mutation carriers, is only slightly higher after primary cancer treatment, than in the general population. Prophylactic contralateral mastectomy provides a substantial reduction of contralateral breast cancer, although only a small breast cancer specific survival benefit. Patients should be enrolled in clinical trials to investigate (neo)-adjuvant drug regimens, that based on preclinical and early clinical evidence might be targeting the homologous recombination defect, such as platinum compounds and PARP inhibitors. If rapid testing is performed, the patient can make a well-balanced decision. Although rapid genetic counseling and testing might cause some distress, most women reported this approach to be worthwhile. In this review the literature regarding these topics is evaluated. Answers and suggestions, useful in clinical practice are discussed.

  19. Reproductive Endocrinologists' Utilization of Genetic Counselors for Oncofertility and Preimplantation Genetic Diagnosis (PGD) Treatment of BRCA1/2 Mutation Carriers.

    Science.gov (United States)

    Goetsch, Allison L; Wicklund, Catherine; Clayman, Marla L; Woodruff, Teresa K

    2016-06-01

    Genetic counselors believe fertility preservation and preimplantation genetic diagnosis (PGD) discussions to be a part of their role when counseling BRCA1/2 mutation-positive patients. This study is the first to explore reproductive endocrinologists' (REI) practices and attitudes regarding involvement of genetic counselors in the care of BRCA1/2 mutation carriers seeking fertility preservation and PGD. A survey was mailed to 1000 REIs from Reproductive Endocrinology & Infertility (SREI), an American Society for Reproductive Medicine (ASRM) affiliate group. A 14.5 % response rate was achieved; data was analyzed using SPSS software. The majority of participating REIs were found to recommend genetic counseling to cancer patients considering fertility preservation (82 %) and consult with a genetic counselor regarding PGD for hereditary cancer syndromes (92 %). Additionally, REIs consult genetic counselors regarding PGD patient counseling (88 %), genetic testing (78 %), and general genetics questions (66 %). Two areas genetic counselors may further aid REIs are: elicitation of family history, which is useful to determine fertility preservation and PGD intervention timing (32 % of REIs utilize a cancer family history to determine intervention timing); and, interpretation of variants of uncertain significance (VOUS) as cancer panel genetic testing becomes more common (36 % of REIs are unfamiliar with VOUS). Given our findings, the Oncofertility Consortium® created an online resource for genetic counselors focused on fertility preservation education and communication strategies.

  20. Reproductive Endocrinologists' Utilization of Genetic Counselors for Oncofertility and Preimplantation Genetic Diagnosis (PGD) Treatment of BRCA1/2 Mutation Carriers.

    Science.gov (United States)

    Goetsch, Allison L; Wicklund, Catherine; Clayman, Marla L; Woodruff, Teresa K

    2016-06-01

    Genetic counselors believe fertility preservation and preimplantation genetic diagnosis (PGD) discussions to be a part of their role when counseling BRCA1/2 mutation-positive patients. This study is the first to explore reproductive endocrinologists' (REI) practices and attitudes regarding involvement of genetic counselors in the care of BRCA1/2 mutation carriers seeking fertility preservation and PGD. A survey was mailed to 1000 REIs from Reproductive Endocrinology & Infertility (SREI), an American Society for Reproductive Medicine (ASRM) affiliate group. A 14.5 % response rate was achieved; data was analyzed using SPSS software. The majority of participating REIs were found to recommend genetic counseling to cancer patients considering fertility preservation (82 %) and consult with a genetic counselor regarding PGD for hereditary cancer syndromes (92 %). Additionally, REIs consult genetic counselors regarding PGD patient counseling (88 %), genetic testing (78 %), and general genetics questions (66 %). Two areas genetic counselors may further aid REIs are: elicitation of family history, which is useful to determine fertility preservation and PGD intervention timing (32 % of REIs utilize a cancer family history to determine intervention timing); and, interpretation of variants of uncertain significance (VOUS) as cancer panel genetic testing becomes more common (36 % of REIs are unfamiliar with VOUS). Given our findings, the Oncofertility Consortium® created an online resource for genetic counselors focused on fertility preservation education and communication strategies. PMID:26567039

  1. Modulation of the BRCA1 Protein and Induction of Apoptosis in Triple Negative Breast Cancer Cell Lines by the Polyphenolic Compound Curcumin

    Directory of Open Access Journals (Sweden)

    Danica L. Rowe

    2009-09-01

    Full Text Available In the current study, we sought to examine the effects of curcumin in a specific type of breast cancer called triple negative breast cancer. These cancers lack expression of the estrogen and progesterone receptors and do not over-express HER2. Current treatment for triple negative breast cancers is limited to cytotoxic chemotherapy, and upon relapse, there are not any therapies currently available. We demonstrate here that the bioactive food compound curcumin induces DNA damage in triple negative breast cancer cells in association with phosphorylation, increased expression, and cytoplasmic retention of the BRCA1 protein. In addition, curcumin promotes apoptosis and prevents anchorage-independent growth and migration of triple negative breast cancer cells. Apoptosis and BRCA1 modulation were not observed in non-transformed mammary epithelial cells, suggesting curcumin may have limited non-specific toxicity. This study suggests that curcumin and potentially curcumin analogues should be tested further in the context of triple negative breast cancer. These results are novel, having never been previously reported, and suggest that curcumin could provide a novel, non-toxic therapy, which could lead to improved survival for patients with triple negative breast cancer. Curcumin should be studied further in this subset of breast cancer patients, for whom treatment options are severely limited.

  2. 复发转移性乳腺癌患者外周血BRCA1、CDH1、DKK1和SFRP1甲基化检测意义的研究%Detection of BRCA1,CDH1,DKK1 and SFRP1 methylation in peripheral blood cells of patients with Metastatic breast cancer

    Institute of Scientific and Technical Information of China (English)

    卢元丽; 梁旭; 林晓琳; 贾军; 袁艳华; 任军

    2011-01-01

    目的 探讨BRCA1、CDH1、DKK1和SFRP1基因甲基化与乳腺癌患者肿瘤激素受体状态、复发转移的关系.方法 利用甲基化特异性PCR法(MSP)检测115例复发转移乳腺癌患者外周血BRCA1、CDH1、DKK1和SFRP1的甲基化情况,与65例健康对照组进行比较.结果 BRCA1、CDH1和SFRP1的甲基化状态在复发转移乳腺癌患者与对照组之间存在差异.ER阳性患者外周血CDH1甲基化阳性率27.5%,ER阴性患者47.8%.ER阳性患者外周血SFRP1甲基化阳性率52.2%,ER阴性患者23.8%.有远处转移者CDH1甲基化阳性率为30.2%,而仅有局部复发转移者为63.2%.结论 复发转移乳腺癌患者外周血BRCA1、CDH1和SFRP1甲基化率显著增加,CDH1和SFRP1甲基化与激素受体状态明显相关,为病情评估、治疗及愈后分析提供了一定的参考.%Objective  To investigate the relationship of BRCA 1 ,CDH1 ,DKK1 and SFRP1 gene methylation with ER status ,relapse and metastasis in patients of Metastatic breast cancer.Methods  Explore the methylation status of four genes BRCA 1 ,CDH 1 ,DKK 1 and SFR P1 in 115 metastasis breast cancer patients' peripheral blood.65 patients with healthy controls with comparison.Results  Percent of BRCA 1.CD H 1 and SFRP1 methylation in patients are significantly higher compared to healthy controls.About27.5% of patients with ER positive tumor were CDH1 methylated in peripheral blood cells ,while 47.8% with ER negative tumor were methylated.In contrast ,ER positive patients had a higher rate of SFRP1 methylation compared to ER negative patients.CDH1 methylation was negatively related to distant metastasis.Conclusion  The four candidate genes methylation in PBC were strongly associated with clinical progress for breast cancer patients.CDH1 and SFRP1 methylation were significantly related with ER status.They provide certain reference for disease assessment ,treatment and prognostic analysis.

  3. BRCA1 1675delA and 1135insA Account for One Third of Norwegian Familial Breast-Ovarian Cancer and Are Associated with Later Disease Onset than Less Frequent Mutations

    Directory of Open Access Journals (Sweden)

    Åke Borg

    1999-01-01

    Full Text Available A total of 845 women from breast-ovarian cancer kindreds were enrolled in a clinical follow-up program for early disease diagnosis; 35 women were prospectively identified with cancer. In order to estimate the role of genetic factors for cancer predisposition in this well-defined set of patients, considered as representative for familial breast-ovarian cancer in the Norwegian population, the BRCA1 gene was investigated for germline mutations. The entire coding region of BRCA1 was analysed using a protein truncation test, direct sequencing and a screen for known large genomic deletions and insertions. Twenty one (60% of the 35 patients were identified as carriers of 11 distinct BRCA1 mutations. Two previously described founder mutations, 1675delA and 1135insA, were found to account for more than half (11/21 of all BRCA1 cases and for almost one third (11/35 of all breast and ovarian cancers. Supported by a previous population-based analysis of these founder mutations in ovarian cancer, our findings suggest that a significant proportion of women at risk for developing inherited breast and ovarian cancer can be identified. This is particularly obvious in certain geographic regions where these founder mutations are prevalent. Women carrying the two founder mutations had a significantly older age of disease onset as compared to women with other BRCA1 mutations. This observation indicates that BRCA mutation penetrance estimates from populations with strong founder effects may be biased. One reason why some deleterious mutations are allowed to prevail in a population may be coupled to penetrance and the fact that they seldom induce disease in women in child-bearing ages. Eleven out of 12 (92% breast cancers in BRCA1 mutation carriers were estrogen receptor negative, versus 4 out of 9 (44% in mutation negative patients (p = 0.03. Histopathological characteristics of the prospectively detected cancers indicated an unfavourable prognosis in mutation

  4. DNA-testing for BRCA1/2 prior to genetic counselling in patients with breast cancer: design of an intervention study, DNA-direct

    Directory of Open Access Journals (Sweden)

    Sie Aisha S

    2012-05-01

    Full Text Available Abstract Background Current practice for patients with breast cancer referred for genetic counseling, includes face-to-face consultations with a genetic counselor prior to and following DNA-testing. This is based on guidelines regarding Huntington’s disease in anticipation of high psychosocial impact of DNA-testing for mutations in BRCA1/2 genes. The initial consultation covers generic information regarding hereditary breast cancer and the (impossibilities of DNA-testing, prior to such testing. Patients with breast cancer may see this information as irrelevant or unnecessary because individual genetic advice depends on DNA-test results. Also, verbal information is not always remembered well by patients. A different format for this information prior to DNA-testing is possible: replacing initial face-to-face genetic counseling (DNA-intake procedure by telephone, written and digital information sent to patients’ homes (DNA-direct procedure. Methods/design In this intervention study, 150 patients with breast cancer referred to the department of Clinical Genetics of the Radboud University Nijmegen Medical Centre are given the choice between two procedures, DNA-direct (intervention group or DNA-intake (usual care, control group. During a triage telephone call, patients are excluded if they have problems with Dutch text, family communication, or of psychological or psychiatric nature. Primary outcome measures are satisfaction and psychological distress. Secondary outcome measures are determinants for the participant’s choice of procedure, waiting and processing times, and family characteristics. Data are collected by self-report questionnaires at baseline and following completion of genetic counseling. A minority of participants will receive an invitation for a 30 min semi-structured telephone interview, e.g. confirmed carriers of a BRCA1/2 mutation, and those who report problems with the procedure. Discussion This study compares current practice

  5. Identification of a novel BRCA1 nucleotide 4803delCC/c.4684delCC mutation and a nucleotide 249T>A/c.130T>A (p.Cys44Ser) mutation in two Greenlandic Inuit families

    DEFF Research Database (Denmark)

    Hansen, Thomas van Overeem; Jønson, Lars; Albrechtsen, Anders;

    2010-01-01

    identified in this population. Here, we describe the identification of a novel disease-causing BRCA1 nucleotide 4803delCC/c.4684delCC mutation in a Greenlandic Inuit with ovarian cancer. The mutation introduces a frameshift and a premature stop at codon 1572. We have also identified a BRCA1 nucleotide 249T...

  6. A screen for germline mutations in the gene encoding CCCTC-binding factor (CTCF) in familial non-BRCA1/BRCA2 breast cancer

    International Nuclear Information System (INIS)

    The CCCTC-binding factor (CTCF), known as a versatile transcription factor and chromatin insulator and to be involved in X inactivation, has also been suggested to be a tumour suppressor on 16q. We investigated 153 patients with familial non-BRCA1/BRCA2 breast cancer for germline mutations in the CTCF gene. Mutation screening of CTCF was performed by denaturing high-performance liquid chromatography followed by cycle sequencing. We found two sequence variants, 240G→A in the 5' untranslated region and 1455C→T (S388S) in exon 4, in five familial breast cancer cases. Three of these five cases had both variants. Cases and controls showed the same prevalence for the two variants, which were found in linkage disequilibrium in most cases and controls. The present study suggests that germline mutations in CTCF are not important as a risk factor for breast cancer

  7. IMPLICATION DE CERTAINES MUTATIONS DANS LES GENES BRCA1 ET BRCA2 SUR LA PRÉDISPOSITION AU CANCER DU SEIN ET AU CANCER OVARIEN

    Directory of Open Access Journals (Sweden)

    Lucian Negura

    2007-08-01

    Full Text Available Le cancer du sein, ainsi que celui ovarien, est une maladie fréquente chez les femmes, ayant un traitement assez difficile et, malheureusement, de sérieuses répercutions sur le physique ; c’est pourquoi il s’avère essentiel que la maladie soit dépistée dès les phases précoces. La prédisposition génétique est responsable de 5% des cancers et de 25% des cas apparus avant l’age de 30 ans [Breast Cancer Linkage Consortium, 1997]. Nous présentons ici l’implication des gènes suppresseurs des tumeurs BRCA1 et BRCA2 sur cette prédisposition.

  8. Genetic variants and haplotype analyses of the ZBRK1/ZNF350 gene in high-risk non BRCA1/2 French Canadian breast and ovarian cancer families.

    Science.gov (United States)

    Desjardins, Sylvie; Belleau, Pascal; Labrie, Yvan; Ouellette, Geneviève; Bessette, Paul; Chiquette, Jocelyne; Laframboise, Rachel; Lépine, Jean; Lespérance, Bernard; Pichette, Roxane; Plante, Marie; Durocher, Francine

    2008-01-01

    Our current understanding of breast cancer susceptibility involves mutations in the 2 major genes BRCA1 and BRCA2, found in about 25% of high-risk families, as well as few other low penetrance genes such as ATM and CHEK2. Approximately two-thirds of the multiple cases families remain to be explained by mutations in still unknown genes. In a candidate gene approach to identify new genes potentially involved in breast cancer susceptibility, we analyzed genomic variants in the ZBRK1 gene, a co-repressor implicated in BRCA1-mediated repression of GADD45. Direct sequencing of ZBRK1 entire coding region in affected breast cancer individuals from 97 high-risk French Canadian breast/ovarian cancer families and 94 healthy controls led to the identification of 18 genomic variants. Haplotype analyses, using PHASE, COCAPHASE and HaploStats programs, put in evidence 3 specific haplotypes which could potentially modulate breast cancer risk, and among which 2 that are associated with a potential protective effect (p = 0.01135 and p = 0.00268), while another haplotype is over-represented in the case group (p = 0.00143). Further analyses of these haplotypes indicated that a strong component of the observed difference between both groups emerge from the first 5 variants (out of 12 used for haplotype determination). The present study also permitted to determine a set of tagging SNPs that could be useful for subsequent analyses in large scale association studies. Additional studies in large cohorts and other populations will however be needed to further evaluate if common and/or rare ZBRK1 sequence variants and haplotypes could be associated with a modest/intermediate breast cancer risk.

  9. Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: Results from three US population-based case-control studies of ovarian cancer

    Energy Technology Data Exchange (ETDEWEB)

    Whittemore, A.S.; Gong, G.; Itnyre, J. [Stanford Univ. School of Medicine, CA (United States)

    1997-03-01

    We investigate the familial risks of cancers of the breast and ovary, using data pooled from three population-based case-control studies of ovarian cancer that were conducted in the United States. We base estimates of the frequency of mutations of BRCA1 (and possibly other genes) on the reported occurrence of breast cancer and ovarian cancer in the mothers and sisters of 922 women with incident ovarian cancer (cases) and in 922 women with no history of ovarian cancer (controls). Segregation analysis and goodness-of-fit testing of genetic models suggest that rare mutations (frequency .0014; 95% confidence interval .0002-.011) account for all the observed aggregation of breast cancer and ovarian cancer in these families. The estimated risk of breast cancer by age 80 years is 73.5% in mutation carriers and 6.8% in noncarriers. The corresponding estimates for ovarian cancer are 27.8% in carriers and 1.8% in noncarriers. For cancer risk in carriers, these estimates are lower than those obtained from families selected for high cancer prevalence. The estimated proportion of all U.S. cancer diagnoses, by age 80 years, that are due to germ-line BRCA1 mutations is 3.0% for breast cancer and 4.4% for ovarian cancer. Aggregation of breast cancer and ovarian cancer was less evident in the families of 169 cases with borderline ovarian cancers than in the families of cases with invasive cancers. Familial aggregation did not differ by the ethnicity of the probands, although the number of non-White and Hispanic cases (N = 99) was sparse. 14 refs., 3 figs., 6 tabs.

  10. Evaluation of an amplicon-based next-generation sequencing panel for detection of BRCA1 and BRCA2 genetic variants.

    Science.gov (United States)

    Shin, Saeam; Hwang, In Sik; Lee, Seung-Tae; Choi, Jong Rak

    2016-08-01

    The recent advances in the next-generation sequencing (NGS) technology have enabled fast, accurate, and cost-effective genetic testing. Here, we evaluated the performance of a targeted NGS panel for BRCA1/2 sequencing and confirmed its applicability in routine clinical diagnostics. We tested samples from 88 patients using the TruSeq custom panel (Illumina Inc, USA) and a MiSeq sequencer (Illumina) and compared the results to the outcomes of conventional Sanger sequencing. All 1015 sequence variations identified by Sanger sequencing were detected by NGS, except for one missense variant that might have been missed due to a rare mutation on a primer-binding site. One deletion variation, c.1909 + 12delT of BRCA2, was falsely called in all samples due to a homopolymer error. In addition, seven different single-nucleotide substitutions with low variant frequencies (range: 16.2-33.3 %) were falsely called by NGS. In a separate batch, 10 different false-positive variations were found in five samples. The overall sensitivity and positive predictive value of NGS were estimated to be 99.9 and 87.5 %, respectively. The false-positive results could be excluded by setting quality and alternative allele ratio filters and/or by visual inspection using the IGV software. Targeted NGS panel for BRCA1 and BRCA2 showed an excellent agreement with Sanger sequencing results. We therefore conclude that this NGS panel can be used for routine diagnostic method in a clinical genetic laboratory. PMID:27383479

  11. 'Cancer doesn't have an age': genetic testing and cancer risk management in BRCA1/2 mutation-positive women aged 18-24.

    Science.gov (United States)

    Werner-Lin, Allison; Hoskins, Lindsey M; Doyle, Maya H; Greene, Mark H

    2012-11-01

    Increasingly, 18-24-year-old women from hereditary breast/ovarian cancer (HBOC) families are pursuing genetic testing, despite their low absolute risks of breast and ovarian cancer and the fact that evidence-based management options used with older high-risk women are not generally available. Difficult clinical decisions in older carriers take on substantially more complexity and value-laden import in very young carriers. As a result, many of the latter receive highly personal and emotionally charged cancer risk information in a life context where management strategies are not well defined. We analyzed 32 in-depth interviews with BRCA1/2 mutation-positive women aged 18-24 using techniques of grounded theory and interpretive description. Participants described feeling vulnerable to a cancer diagnosis but in a quandary regarding their care because evidence-based approaches to management have not been developed and clinical trials have not been undertaken. Our participants demonstrated a wide range of genetic and health literacy. Inconsistent recommendations, surveillance fatigue, and the unpredictability of their having health insurance coverage for surgical risk-reducing procedures led several to contemplate risk-reducing mastectomy before age 25. Parents remained a primary source of emotional and financial support, slowing age-appropriate independence and complicating patient privacy. Our findings suggest that, for 18-24-year-olds, readiness to autonomously elect genetic testing, to fully understand and act on genetic information, and to confidently make decisions with life-long implications are all evolving processes. We comment on the tensions between informed consent, privacy, and the unique developmental needs of BRCA1/2 mutation-positive women just emerging into their adult years. PMID:22547552

  12. 维吾尔民族非小细胞肺癌组织中的ERCC1、BRCA1的表达及预后关系的研究%Expression of ERCC1, BRCA1 and prognosis in non-small cell lung cancer of Uygur patients

    Institute of Scientific and Technical Information of China (English)

    穆清爽; 韩利梅

    2011-01-01

    Objective:To investigate the relationship of expression of ERCC1 and BRCA1 and prognostic in advanced non-small cell lung cancer (NSCLC) of Uygur patients. Methods: The formalin-fixed biopsy speciments of 80 cases of NSCLC Uygur patient from January 2004 to December 2008 are reviewed.We detect the expression of ERCC1 and BRCAl by immunohistochemical method. Then we analyze the relationship of these two genes and prognostic of the patients. Results: In these 80 cases, positive expression rates of ERCC1 was 38.6%(31/80),and this gene is no correlation with age,gender,clinical stage and pathology,but is correlation with smoking and PS score.Positive expression rates of BRCA1 was 88.8%(71/80) ,and this gene is no correlation with age.gender, smoking,clinical stage and pathology,but is correlation with PS score.The expression of ERCC1 and BRCA1 to median survival weeks is analyzed by Univariate analysis in Kaplan-Meier method,which display the difference is no statistically significant (P>0.05).The negative expression of ERCC1 has longer life than the positive ones, and the difference in survival rate of 1 year is statistically significant (P=0.035). But in overall survival the difference is no statistically significant. Conclusion: The negative expression of ERCC1 could help to predict the prognosis and survival time in advanced non-small cell lung cancer of Uygur patients.The expression of BRCA1 was no statistically significant in NSCLC of Uygur patients temporarily .The result of this study may provide new sight for clinical therapy and prognosis to individual NSCLC Uygur patients.%目的:研究探讨维吾尔民族非小细胞肺癌组织中DNA切除修复交叉互补基因1(Excision repair cross-complementing 1,ERCC1)、乳腺癌易感基因1(Brest cancer susceptibility gene 1,BRCA1)的表达与患者预后及生存的关系.方法:收集2004年1月-2008年12月间的80例维吾尔族NSCLC病灶活检的福尔马林固定标本,采用免疫组化方法检测ERCC1、BRCA

  13. Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study.

    NARCIS (Netherlands)

    Jakubowska, A.; Rozkrut, D.; Antoniou, A.; Hamann, U.; Scott, R.J.; McGuffog, L.; Healy, S.; Sinilnikova, O.M.; Rennert, G.; Lejbkowicz, F.; Flugelman, A.; Andrulis, I.L.; Glendon, G.; Ozcelik, H.; Thomassen, M.; Paligo, M.; Aretini, P.; Kantala, J.; Aroer, B.; Wachenfeldt, A. von; Liljegren, A.; Loman, N.; Herbst, K.; Kristoffersson, U.; Rosenquist, R.; Karlsson, P.; Stenmark-Askmalm, M.; Melin, B.; Nathanson, K.L.; Domchek, S.M.; Byrski, T.; Huzarski, T.; Gronwald, J.; Menkiszak, J.; Cybulski, C.; Serrano, P.; Osorio, A.; Cajal, T.R.; Tsitlaidou, M.; Benitez, J.; Gilbert, M.; Rookus, M.; Aalfs, C.M.; Kluijt, I.; Boessenkool-Pape, J.L.; Meijers-Heijboer, H.E.; Oosterwijk, J.C.; Asperen, C.J. van; Blok, M.J.; Nelen, M.R.; Ouweland, A.M. van den; Seynaeve, C.; Luijt, R.B. van der; Devilee, P.; Easton, D.F.; Peock, S.; Frost, D.; Platte, R.; Ellis, S.D.; Fineberg, E.; Evans, D.G.; Lalloo, F.; Eeles, R.; Jacobs, C.; Adlard, J.; Davidson, R.; Eccles, D.; Cole, T.; Cook, J.; Godwin, A.; Bove, B.; Stoppa-Lyonnet, D.; Caux-Moncoutier, V.; Belotti, M.; Tirapo, C.; Mazoyer, S.; Barjhoux, L.; Boutry-Kryza, N.; Pujol, P.; Coupier, I.; Peyrat, J.P.; Vennin, P.; Muller, D.; Fricker, J.P.; Venat-Bouvet, L.; Johannsson, O.T.; Isaacs, C.; Schmutzler, R.; Wappenschmidt, B.; Meindl, A.; Arnold, N.; Varon-Mateeva, R.; Niederacher, D.; Sutter, C.; Deissler, H.; Preisler-Adams, S.; Simard, J.; Soucy, P.; Durocher, F.; Chenevix-Trench, G.; Beesley, J.; Chen, X.; Rebbeck, T.; Couch, F.; Wang, X.; Lindor, N.; Fredericksen, Z.; Pankratz, V.S.; Peterlongo, P.; Bonanni, B.; Fortuzzi, S.; Peissel, B.; Szabo, C.; Mai, P.L.; Loud, J.T.; Lubinski, J.; Ligtenberg, M.J.L.; Hoogerbrugge, N.

    2012-01-01

    BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either di

  14. Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers : results from a multicenter study

    NARCIS (Netherlands)

    Jakubowska, A.; Rozkrut, D.; Antoniou, A.; Hamann, U.; Scott, R. J.; McGuffog, L.; Healy, S.; Sinilnikova, O. M.; Rennert, G.; Lejbkowicz, F.; Flugelman, A.; Andrulis, I. L.; Glendon, G.; Ozcelik, H.; Thomassen, M.; Paligo, M.; Aretini, P.; Kantala, J.; Aroer, B.; Von Wachenfeldt, A.; Liljegren, A.; Loman, N.; Herbst, K.; Kristoffersson, U.; Rosenquist, R.; Karlsson, P.; Stenmark-Askmalm, M.; Melin, B.; Nathanson, K. L.; Domchek, S. M.; Byrski, T.; Huzarski, T.; Gronwald, J.; Menkiszak, J.; Cybulski, C.; Serrano, P.; Osorio, A.; Cajal, T. R.; Tsitlaidou, M.; Benitez, J.; Gilbert, M.; Rookus, M.; Aalfs, C. M.; Kluijt, I.; Boessenkool-Pape, J. L.; Meijers-Heijboer, H. E. J.; Oosterwijk, J. C.; van Asperen, C. J.; Blok, M. J.; Nelen, M. R.; van den Ouweland, A. M. W.; Seynaeve, C.; van der Luijt, R. B.; Devilee, P.; Easton, D. F.; Peock, S.; Frost, D.; Platte, R.; Ellis, S. D.; Fineberg, E.; Evans, D. G.; Lalloo, F.; Eeles, R.; Jacobs, C.; Adlard, J.; Davidson, R.; Eccles, D.; Cole, T.; Cook, J.; Godwin, A.; Bove, B.; Stoppa-Lyonnet, D.; Caux-Moncoutier, V.; Belotti, M.; Tirapo, C.; Mazoyer, S.; Barjhoux, L.; Boutry-Kryza, N.; Pujol, P.; Coupier, I.; Peyrat, J-P; Vennin, P.; Muller, D.; Fricker, J-P; Venat-Bouvet, L.; Johannsson, OTh; Isaacs, C.; Schmutzler, R.; Wappenschmidt, B.; Meindl, A.; Arnold, N.; Varon-Mateeva, R.; Niederacher, D.; Sutter, C.; Deissler, H.; Preisler-Adams, S.; Simard, J.; Soucy, P.; Durocher, F.; Chenevix-Trench, G.; Beesley, J.; Chen, X.; Rebbeck, T.; Couch, F.; Wang, X.; Lindor, N.; Fredericksen, Z.; Pankratz, V. S.; Peterlongo, P.; Bonanni, B.; Fortuzzi, S.; Peissel, B.; Szabo, C.; Mai, P. L.; Loud, J. T.; Lubinski, J.

    2012-01-01

    BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either di

  15. Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    Couch, F.J.; Gaudet, M.M.; Antoniou, A.C.; Ramus, S.J.; Kuchenbaecker, K.B.; Soucy, P.; Beesley, J.; Chen, X.; Wang, X.; Kirchhoff, T.; McGuffog, L.; Barrowdale, D.; Lee, A.; Healey, S.; Sinilnikova, O.M.; Andrulis, I.L.; Ocgn, .; Ozcelik, H.; Mulligan, A.M.; Thomassen, M.; Gerdes, A.M.; Jensen, U.B.; Skytte, A.B.; Kruse, T.A.; Caligo, M.A.; Wachenfeldt, A. von; Barbany-Bustinza, G.; Loman, N.; Soller, M.; Ehrencrona, H.; Karlsson, P.; Swe, B.; Nathanson, K.L.; Rebbeck, T.R.; Domchek, S.M.; Jakubowska, A.; Lubinski, J.; Jaworska, K.; Durda, K.; Zlowocka, E.; Huzarski, T.; Byrski, T.; Gronwald, J.; Cybulski, C.; Gorski, B.; Osorio, A.; Duran, M.; Tejada, M.I.; Benitez, J.; Hamann, U.; Hogervorst, F.B.; Hebon, .; Os, T.A. van; Leeuwen, F.E. van; Meijers-Heijboer, H.E.; Wijnen, J.; Blok, M.J.; Kets, M.; Hooning, M.J.; Oldenburg, R.A.; Ausems, M.G.; Peock, S.; Frost, D.; Ellis, S.D.; Platte, R.; Fineberg, E.; Evans, D.G.; Jacobs, C.; Eeles, R.A.; Adlard, J.; Davidson, R.; Eccles, D.M.; Cole, T.; Cook, J.; Paterson, J.; Brewer, C.; Douglas, F.; Hodgson, S.V.; Morrison, P.J.; Walker, L.; Porteous, M.E.; Kennedy, M.J.; Side, L.E.; Embrace, .; Bove, B.; Godwin, A.K.; Stoppa-Lyonnet, D.; Collaborators, G.S.; Fassy-Colcombet, M.; Castera, L.; Cornelis, F.; Mazoyer, S.; Leone, M.; Boutry-Kryza, N.; Bressac-de Paillerets, B.; Caron, O.; Pujol, P.; Coupier, I.; Delnatte, C.; Akloul, L.; Ligtenberg, M.J.; Hoogerbrugge, N.

    2012-01-01

    BACKGROUND: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these varian

  16. Breast and ovarian cancer screening of non-carriers from BRCA1/2 mutation-positive families: 2-year follow-up of cohorts from France and Quebec.

    Science.gov (United States)

    Dorval, Michel; Noguès, Catherine; Berthet, Pascaline; Chiquette, Jocelyne; Gauthier-Villars, Marion; Lasset, Christine; Picard, Claude; Plante, Marie; Simard, Jacques; Julian-Reynier, Claire

    2011-05-01

    We described and compared breast and ovarian screening practices in the 2-year period following test result disclosure in female non-carriers from BRCA1/2 mutation-positive families living in two countries, France and Quebec, Canada, which provide universal health care. Four hundred and two (France n=293; Quebec n=109) unaffected female non-carriers from BRCA-proven mutation families provided information about the uptake of mammography, clinical breast examination, breast self-examination, and ovarian ultrasounds using self-administered questionnaires. The frequency of screening practices between study cohorts were compared using logistic regression. Annual mammography was conducted in 23 and 43% of French and Quebecer women participants cancer screening practices for female non-carriers from BRCA1/2 mutation-positive families in both France and Quebec exceeded those recommended for similarly aged women in the general population. Our findings highlight the need for clearcut recommendations on the follow-up of women from BRCA1/2 families who are not themselves carriers of a BRCA1/2 mutation.

  17. Individual and Combined Expression of DNA Damage Response Molecules PARP1, γH2AX, BRCA1, and BRCA2 Predict Shorter Survival of Soft Tissue Sarcoma Patients

    Science.gov (United States)

    Park, See-Hyoung; Park, Hye Jeong; Wang, Sung Il; Park, Ho Sung; Lee, Ho; Kwon, Keun Sang; Moon, Woo Sung; Lee, Dong Geun; Kim, Jung Ryul; Jang, Kyu Yun

    2016-01-01

    DNA damage response (DDR) molecules are protective against genotoxic stresses. DDR molecules are also involved in the survival of cancer cells in patients undergoing anti-cancer therapies. Therefore, DDR molecules are potential markers of cancer progression in addition to being potential therapeutic targets. In this study, we evaluated the immunohistochemical expression of PARP1, γH2AX, BRCA1, and BRCA2 and their prognostic significance in 112 cases of soft tissue sarcoma (STS). The expression of PARP1, γH2AX, BRCA1, and BRCA2 were significantly associated with each other and were associated with higher tumor stage and presence of distant metastasis. The expression of PARP1, γH2AX, and BRCA2 were significantly associated with shorter disease-specific survival (DSS) and event-free survival (EFS) by univariate analysis. BRCA1 expression was associated with shorter DSS. Multivariate analysis revealed the expression of PARP1 and γH2AX to be independent indicators of poor prognosis of DSS and EFS. BRCA2 expression was an independent indicator of poor prognosis of DSS. In addition, the combined expressional patterns of PARP1, γH2AX, BRCA1, and BRCA2 (CSddrm) were independent prognostic predictors of DSS (P stratagems for the treatment of STS. PMID:27643881

  18. Comparison of individuals opting for BRCA1/2 or HNPCC genetic susceptibility testing with regard to coping, illness perceptions, illness experiences, family system characteristics and hereditary cancer distress

    NARCIS (Netherlands)

    van Oostrom, Iris; Meijers-Heijboer, Hanne; Duivenvoorden, Hugo J.; Brocker-Vriends, Annette H. J. T.; van Asperen, Christi J.; Sijmons, Rolf H.; Seynaeve, Caroline; Van Gool, Arthur R.; Klijn, Jan G. M.; Tibben, Aad

    2007-01-01

    Objective: To study differences between individuals opting for genetic cancer susceptibility testing of a known familial BRCA1/2 and HNPCC related germline mutation. Methods: Coping, illness perceptions, experiences with cancer in relatives and family system characteristics were assessed in 271 appl

  19. Increased levels of choline metabolites are an early marker of docetaxel treatment response in BRCA1-mutated mouse mammary tumors: an assessment by ex vivo proton magnetic resonance spectroscopy

    NARCIS (Netherlands)

    Asten, J.J.A. van; Vettukattil, R.; Buckle, T.; Rottenberg, S.; Leeuwen, F van; Bathen, T.F.; Heerschap, A.

    2015-01-01

    Docetaxel is one of the most frequently used drugs to treat breast cancer. However, resistance or incomplete response to docetaxel is a major challenge. The aim of this study was to utilize MR metabolomics to identify potential biomarkers of docetaxel resistance in a mouse model for BRCA1-mutated br

  20. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

    NARCIS (Netherlands)

    Antoniou, Antonis C.; Kuchenbaecker, Karoline B.; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Lee, Andrew; Barrowdale, Daniel; Healey, Sue; Sinilnikova, Olga M.; Caligo, Maria A.; Loman, Niklas; Harbst, Katja; Lindblom, Annika; Arver, Brita; Rosenquist, Richard; Karlsson, Per; Nathanson, Kate; Domchek, Susan; Rebbeck, Tim; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Zlowowcka-Perlowska, Elzbieta; Osorio, Ana; Duran, Mercedes; Andres, Raquel; Benitez, Javier; Hamann, Ute; Hogervorst, Frans B.; van Os, Theo A.; Verhoef, Senno; Meijers-Heijboer, Hanne E. J.; Wijnen, Juul; Garcia, Encarna B. Gomez; Ligtenberg, Marjolijn J.; Kriege, Mieke; Collee, Margriet; Ausems, Margreet G. E. M.; Oosterwijk, Jan C.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Walker, Lisa; Rogers, Mark T.; Donaldson, Alan; Dorkins, Huw; Godwin, Andrew K.; Bove, Betsy; Stoppa-Lyonnet, Dominique; Houdayer, Claude; Buecher, Bruno; de Pauw, Antoine; Mazoyer, Sylvie; Calender, Alain; Leone, Melanie; Bressac-de Paillerets, Brigitte; Caron, Olivier; Sobol, Hagay; Frenay, Marc; Prieur, Fabienne; Ferrer, Sandra Fert; Mortemousque, Isabelle; Buys, Saundra; Daly, Mary; Miron, Alexander; Terry, Mary Beth; Hopper, John L.; John, Esther M.; Southey, Melissa; Goldgar, David; Singer, Christian F.; Fink-Retter, Anneliese; Tea, Muy-Kheng; Kaulich, Daphne Geschwantler; Hansen, Thomas V. O.; Nielsen, Finn C.; Barkardottir, Rosa B.; Gaudet, Mia; Kirchhoff, Tomas; Joseph, Vijai; Dutra-Clarke, Ana; Offit, Kenneth; Piedmonte, Marion; Kirk, Judy; Cohn, David; Hurteau, Jean; Byron, John; Fiorica, James; Toland, Amanda E.; Montagna, Marco; Oliani, Cristina; Imyanitov, Evgeny; Isaacs, Claudine; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Teule, Alex; Del Valle, J.; Gayther, Simon A.; Odunsi, Kunle; Gross, Jenny; Karlan, Beth Y.; Olah, Edith; Teo, Soo-Hwang; Ganz, Patricia A.; Beattie, Mary S.; Dorfling, Cecelia M.; van Rensburg, Elizabeth Jansen; 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, Dorothea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schaefer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Muranen, Taru A.; Lesperance, Bernard; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan C.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, Noralane M.; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H.; Loud, Jennifer T.; Andrulis, Irene L.; Ozcelik, Hilmi; Mulligan, Anna Marie; Glendon, Gord; Thomassen, Mads; Gerdes, Anne-Marie; Jensen, Uffe B.; Skytte, Anne-Bine; Kruse, Torben A.; Chenevix-Trench, Georgia; Couch, Fergus J.; Simard, Jacques; Easton, Douglas F.

    2012-01-01

    Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B),

  1. Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Couch, Fergus J; Gaudet, Mia M; Antoniou, Antonis C;

    2012-01-01

    Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mut...

  2. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Kuchenbaecker, Karoline B; Soucy, Penny;

    2012-01-01

    Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 ...

  3. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

    NARCIS (Netherlands)

    Antoniou, A.C.; Kuchenbaecker, K.B.; Soucy, P.; Beesley, J.; Chen, X.; McGuffog, L.; Lee, A.; Barrowdale, D.; Healey, S.; Sinilnikova, O.M.; Caligo, M.A.; Loman, N.; Harbst, K.; Lindblom, A.; Arver, B.; Rosenquist, R.; Karlsson, P.; Nathanson, K.; Domchek, S.; Rebbeck, T.; Jakubowska, A.; Lubinski, J.; Jaworska, K.; Durda, K.; Zlowowcka-Perlowska, E.; Osorio, A.; Duran, M.; Andres, R.; Benitez, J.; Hamann, U.; Hogervorst, F.B.; Os, T.A. van; Verhoef, S.; Meijers-Heijboer, H.E.; Wijnen, J.; Gomez Garcia, E.B.; Ligtenberg, M.J.L.; Kriege, M.; Collee, J.M.; Ausems, M.G.; Oosterwijk, J.C.; Peock, S.; Frost, D.; Ellis, S.D.; Platte, R.; Fineberg, E.; Evans, D.G.; Lalloo, F.; Jacobs, C.; Eeles, R.; Adlard, J.; Davidson, R.; Cole, T.; Cook, J.; Paterson, J.; Douglas, F.; Brewer, C.; Hodgson, S.; Morrison, P.J.; Walker, L.; Rogers, M.T.; Donaldson, A.; Dorkins, H.; Godwin, A.K.; Bove, B.; Stoppa-Lyonnet, D.; Houdayer, C.; Buecher, B.; Pauw, A. de; Mazoyer, S.; Calender, A.; Leone, M.; Bressac-de Paillerets, B.; Caron, O.; Sobol, H.; Frenay, M.; Prieur, F.; Ferrer, S.U.; Mortemousque, I.; Buys, S.; Daly, M.; Miron, A.; Terry, M.U.; Hopper, J.L.; John, E.M.; Southey, M.; Goldgar, D.; Singer, C.F.; Fink-Retter, A.; Tea, M.K.; Kaulich, D.U.; Hansen, T.V.; Nielsen, F.C.; Barkardottir, R.B.; Gaudet, M.; Kirchhoff, T.; Joseph, V.; Dutra-Clarke, A.; Offit, K.; Piedmonte, M., et al.

    2012-01-01

    INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B),

  4. Prevalence of 185delAG and 5382insC mutations in BRCA1, and 6174delT in BRCA2 in women of Ashkenazi Jewish origin in southern Brazil

    Directory of Open Access Journals (Sweden)

    Crisle Vignol Dillenburg

    2012-01-01

    Full Text Available Certain mutations in BRCA1 and BRCA2 genes are frequent in the Ashkenazi Jewish population. Several factors contribute to this increased frequency, including consanguineous marriages and an event known as a "bottleneck', which occurred in the past and caused a drastic reduction in the genetic variability of this population. Several studies were performed over the years in an attempt to elucidate the role of BRCA1 and BRCA2 genes in susceptibility to breast cancer. The aim of this study was to estimate the carrier frequency of certain common mutations in the BRCA1 (185delAG and 5382insC and BRCA2 (6174delT genes in an Ashkenazi Jewish population from Porto Alegre, Brazil. Molecular analyses were done by PCR followed by RFLP (ACRS. The carrier frequencies for BRCA1 185delAG and 5382insC were 0.78 and 0 respectively, and 0.4 for the BRCA2 6174deT mutation. These findings are similar to those of some prior studies but differ from others, possibly due to excluding individuals with a personal or family history of cancer. Our sample was drawn from the community group and included individuals with or without a family or personal history of cancer. Furthermore, increased dispersion among Ashkenazi subpopulations may be the result of strong genetic drift and/or admixture. It is therefore necessary to consider the effects of local admixture on the mismatch distributions of various Jewish populations.

  5. Individual and Combined Expression of DNA Damage Response Molecules PARP1, γH2AX, BRCA1, and BRCA2 Predict Shorter Survival of Soft Tissue Sarcoma Patients

    Science.gov (United States)

    Park, See-Hyoung; Park, Hye Jeong; Wang, Sung Il; Park, Ho Sung; Lee, Ho; Kwon, Keun Sang; Moon, Woo Sung; Lee, Dong Geun; Kim, Jung Ryul; Jang, Kyu Yun

    2016-01-01

    DNA damage response (DDR) molecules are protective against genotoxic stresses. DDR molecules are also involved in the survival of cancer cells in patients undergoing anti-cancer therapies. Therefore, DDR molecules are potential markers of cancer progression in addition to being potential therapeutic targets. In this study, we evaluated the immunohistochemical expression of PARP1, γH2AX, BRCA1, and BRCA2 and their prognostic significance in 112 cases of soft tissue sarcoma (STS). The expression of PARP1, γH2AX, BRCA1, and BRCA2 were significantly associated with each other and were associated with higher tumor stage and presence of distant metastasis. The expression of PARP1, γH2AX, and BRCA2 were significantly associated with shorter disease-specific survival (DSS) and event-free survival (EFS) by univariate analysis. BRCA1 expression was associated with shorter DSS. Multivariate analysis revealed the expression of PARP1 and γH2AX to be independent indicators of poor prognosis of DSS and EFS. BRCA2 expression was an independent indicator of poor prognosis of DSS. In addition, the combined expressional patterns of PARP1, γH2AX, BRCA1, and BRCA2 (CSddrm) were independent prognostic predictors of DSS (P DSS rate of the CSddrm-low, CSddrm-intermediate, and CSddrm-high subgroups were 81%, 26%, and 0%, respectively. In conclusion, this study demonstrates that the individual and combined expression patterns of the DDR molecules PARP1, γH2AX, BRCA1, and BRCA2 could be predictive of the prognosis of STS patients and suggests that controlling the activity of these DDR molecules could be employed in new therapeutic stratagems for the treatment of STS. PMID:27643881

  6. Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes