WorldWideScience

Sample records for cancer epigenetic biomarkers

  1. Diagnostic and prognostic epigenetic biomarkers in cancer.

    Science.gov (United States)

    Costa-Pinheiro, Pedro; Montezuma, Diana; Henrique, Rui; Jerónimo, Carmen

    2015-01-01

    Growing cancer incidence and mortality worldwide demands development of accurate biomarkers to perfect detection, diagnosis, prognostication and monitoring. Urologic (prostate, bladder, kidney), lung, breast and colorectal cancers are the most common and despite major advances in their characterization, this has seldom translated into biomarkers amenable for clinical practice. Epigenetic alterations are innovative cancer biomarkers owing to stability, frequency, reversibility and accessibility in body fluids, entailing great potential of assay development to assist in patient management. Several studies identified putative epigenetic cancer biomarkers, some of which have been commercialized. However, large multicenter validation studies are required to foster translation to the clinics. Herein we review the most promising epigenetic detection, diagnostic, prognostic and predictive biomarkers for the most common cancers.

  2. Epigenetic prognostic biomarkers in colorectal cancer

    NARCIS (Netherlands)

    Benard, Anne

    2015-01-01

    Colorectal cancer is one of the most common diagnosed cancers worldwide, and is the second most important cause of cancer mortality in Europe. The current TNM staging system used at the time of diagnosis is insufficient, as patients with the same tumor stage show wide variations in survival and

  3. Epigenetic Biomarkers of Breast Cancer Risk: Across the Breast Cancer Prevention Continuum.

    Science.gov (United States)

    Terry, Mary Beth; McDonald, Jasmine A; Wu, Hui Chen; Eng, Sybil; Santella, Regina M

    2016-01-01

    Epigenetic biomarkers, such as DNA methylation, can increase cancer risk through altering gene expression. The Cancer Genome Atlas (TCGA) Network has demonstrated breast cancer-specific DNA methylation signatures. DNA methylation signatures measured at the time of diagnosis may prove important for treatment options and in predicting disease-free and overall survival (tertiary prevention). DNA methylation measurement in cell free DNA may also be useful in improving early detection by measuring tumor DNA released into the blood (secondary prevention). Most evidence evaluating the use of DNA methylation markers in tertiary and secondary prevention efforts for breast cancer comes from studies that are cross-sectional or retrospective with limited corresponding epidemiologic data, raising concerns about temporality. Few prospective studies exist that are large enough to address whether DNA methylation markers add to the prediction of tertiary and secondary outcomes over and beyond standard clinical measures. Determining the role of epigenetic biomarkers in primary prevention can help in identifying modifiable pathways for targeting interventions and reducing disease incidence. The potential is great for DNA methylation markers to improve cancer outcomes across the prevention continuum. Large, prospective epidemiological studies will provide essential evidence of the overall utility of adding these markers to primary prevention efforts, screening, and clinical care.

  4. The increasing roles of epigenetics in breast cancer: Implications for pathogenicity, biomarkers, prevention and treatment.

    Science.gov (United States)

    Basse, Clémence; Arock, Michel

    2015-12-15

    Nowadays, the mechanisms governing the occurrence of cancer are thought to be the consequence not only of genetic defects but also of epigenetic modifications. Therefore, epigenetic has become a very attractive and increasingly investigated field of research in order to find new ways of prevention and treatment of neoplasia, and this is particularly the case for breast cancer (BC). Thus, this review will first develop the main known epigenetic modifications that can occur in cancer and then expose the future role that control of epigenetic modifications might play in prevention, prognostication, follow-up and treatment of BC. Indeed, epigenetic biomarkers found in peripheral blood might become new tools to detect BC, to define its prognostic and to predict its outcome, whereas epi-drugs might have an increasing potential of development in the next future. However, if DNA methyltransferase inhibitors and histone desacetylase inhibitors have shown encouraging results in BC, their action remains nonspecific. Thus, additional clinical studies are needed to evaluate more precisely the effects of these molecules, even if they have provided encouraging results in cotreatment and combined therapies. This review will also deal with the potential of RNA interference (RNAi) as epi-drugs. Finally, we will focus on the potential prevention of BC through epigenetic based on diet and we will particularly develop the possible place of isothiocyanates from cruciferous vegetables or of Genistein from soybean in a dietary program that might potentially reduce the risk of BC in large populations. © 2014 UICC.

  5. Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas

    Directory of Open Access Journals (Sweden)

    Lind Guro E

    2011-07-01

    Full Text Available Abstract Background The presence of cancer-specific DNA methylation patterns in epithelial colorectal cells in human feces provides the prospect of a simple, non-invasive screening test for colorectal cancer and its precursor, the adenoma. This study investigates a panel of epigenetic markers for the detection of colorectal cancer and adenomas. Methods Candidate biomarkers were subjected to quantitative methylation analysis in test sets of tissue samples from colorectal cancers, adenomas, and normal colonic mucosa. All findings were verified in independent clinical validation series. A total of 523 human samples were included in the study. Receiver operating characteristic (ROC curve analysis was used to evaluate the performance of the biomarker panel. Results Promoter hypermethylation of the genes CNRIP1, FBN1, INA, MAL, SNCA, and SPG20 was frequent in both colorectal cancers (65-94% and adenomas (35-91%, whereas normal mucosa samples were rarely (0-5% methylated. The combined sensitivity of at least two positives among the six markers was 94% for colorectal cancers and 93% for adenoma samples, with a specificity of 98%. The resulting areas under the ROC curve were 0.984 for cancers and 0.968 for adenomas versus normal mucosa. Conclusions The novel epigenetic marker panel shows very high sensitivity and specificity for both colorectal cancers and adenomas. Our findings suggest this biomarker panel to be highly suitable for early tumor detection.

  6. Modern molecular biomarkers of head and neck cancer. Part I. Epigenetic diagnostics and prognostics: Systematic review.

    Science.gov (United States)

    Juodzbalys, Gintaras; Kasradze, David; Cicciù, Marco; Sudeikis, Aurimas; Banys, Laurynas; Galindo-Moreno, Pablo; Guobis, Zygimantas

    2016-01-01

    Nearly half of the head and neck cancer cases are diagnosed in late stages. Traditional screening modalities have many disadvantages. The aim of the present article was to review the scientific literature about novel head and neck cancer diagnostics - epigenetic biomarkers. A comprehensive review of the current literature was conducted according to the PRISMA guidelines by accessing the NCBI PubMed database. Authors conducted the search of articles in English language published from 2004 to 2015. A total of thirty three relevant studies were included in the review. Fifteen of them concerned DNA methylation alterations, nine evaluation of abundancies in histone expressions and nine miRNA expression changes in HNC. Considerable number of epigenetic biomarkers have been identified in both tumor tissue and salivary samples. Genes with best diagnostic effectiveness rates and further studying prospects were: TIMP3, DCC, DAPK, CDH1, CCNA1, AIM1, MGMT, HIC1, PAX1, PAX5, ZIC4, p16, EDNRB, KIF1A, MINT31, CD44, RARβ , ECAD. Individual histone and miRNA alterations tend to be hnc specific. Prognostic values of separate biomarkers are ambiguous. No established standards for molecular assay of head and neck cancer was found in order to elude the paradoxical results and discrepancies in separate trials.

  7. Genetic and Epigenetic Biomarkers for Recurrent Prostate Cancer After Radiotherapy

    Science.gov (United States)

    2015-07-01

    several distinct advantages over surgical treatment, such as no complications from surgery, and a low risk of urinary incontinence , RT treatment takes...Khorana, Tissue factor and VEGF expression in prostate carcinoma: a tissue microarray study. Cancer Invest, 2009. 27(4): p. 430-4. 7. Crawford, E.D

  8. Epigenetics and Colorectal Cancer

    Science.gov (United States)

    Lao, Victoria Valinluck; Grady, William M.

    2012-01-01

    Colorectal cancer is a leading cause of cancer deaths in the world. It results from an accumulation of genetic and epigenetic changes in colon epithelial cells that transforms them into adenocarcinomas. There have been major advances in our understanding of cancer epigenetics over the last decade, particularly regarding aberrant DNA methylation. Assessment of the colon cancer epigenome has revealed that virtually all colorectal cancers have aberrantly methylated genes and the average colorectal cancer methylome has hundreds to thousands of abnormally methylated genes. As with gene mutations in the cancer genome, a subset of these methylated genes, called driver genes, is presumed to play a functional role in colorectal cancer. The assessment of methylated genes in colorectal cancers has also revealed a unique molecular subgroup of colorectal cancers called CpG Island Methylator Phenotype (CIMP) cancers; these tumors have a particularly high frequency of methylated genes. The advances in our understanding of aberrant methylation in colorectal cancer has led to epigenetic alterations being developed as clinical biomarkers for diagnostic, prognostic, and therapeutic applications. Progress in the assessment of epigenetic alterations in colorectal cancer and their clinical applications has shown that these alterations will be commonly used in the near future as molecular markers to direct the prevention and treatment of colorectal cancer. PMID:22009203

  9. Biomarkers in Prostate Cancer Epidemiology

    Directory of Open Access Journals (Sweden)

    Mudit Verma

    2011-09-01

    Full Text Available Understanding the etiology of a disease such as prostate cancer may help in identifying populations at high risk, timely intervention of the disease, and proper treatment. Biomarkers, along with exposure history and clinical data, are useful tools to achieve these goals. Individual risk and population incidence of prostate cancer result from the intervention of genetic susceptibility and exposure. Biochemical, epigenetic, genetic, and imaging biomarkers are used to identify people at high risk for developing prostate cancer. In cancer epidemiology, epigenetic biomarkers offer advantages over other types of biomarkers because they are expressed against a person’s genetic background and environmental exposure, and because abnormal events occur early in cancer development, which includes several epigenetic alterations in cancer cells. This article describes different biomarkers that have potential use in studying the epidemiology of prostate cancer. We also discuss the characteristics of an ideal biomarker for prostate cancer, and technologies utilized for biomarker assays. Among epigenetic biomarkers, most reports indicate GSTP1 hypermethylation as the diagnostic marker for prostate cancer; however, NKX2-5, CLSTN1, SPOCK2, SLC16A12, DPYS, and NSE1 also have been reported to be regulated by methylation mechanisms in prostate cancer. Current challenges in utilization of biomarkers in prostate cancer diagnosis and epidemiologic studies and potential solutions also are discussed.

  10. Epigenetics in Prostate Cancer

    OpenAIRE

    Albany, Costantine; Alva, Ajjai S.; Aparicio, Ana M.; Singal, Rakesh; Yellapragada, Sarvari; Sonpavde, Guru; Hahn, Noah M.

    2011-01-01

    Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequ...

  11. Epigenetics and cancer

    DEFF Research Database (Denmark)

    Lund, Anders H; van Lohuizen, Maarten

    2004-01-01

    Epigenetic mechanisms act to change the accessibility of chromatin to transcriptional regulation locally and globally via modifications of the DNA and by modification or rearrangement of nucleosomes. Epigenetic gene regulation collaborates with genetic alterations in cancer development. This is e......Epigenetic mechanisms act to change the accessibility of chromatin to transcriptional regulation locally and globally via modifications of the DNA and by modification or rearrangement of nucleosomes. Epigenetic gene regulation collaborates with genetic alterations in cancer development....... This is evident from every aspect of tumor biology including cell growth and differentiation, cell cycle control, DNA repair, angiogenesis, migration, and evasion of host immunosurveillance. In contrast to genetic cancer causes, the possibility of reversing epigenetic codes may provide new targets for therapeutic...

  12. An epigenetic biomarker of aging for lifespan and healthspan

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    Levine, Morgan E.; Lu, Ake T.; Quach, Austin; Chen, Brian H.; Assimes, Themistocles L.; Bandinelli, Stefania; Hou, Lifang; Baccarelli, Andrea A.; Stewart, James D.; Li, Yun; Whitsel, Eric A.; Wilson, James G; Reiner, Alex P; Aviv, Abraham; Lohman, Kurt; Liu, Yongmei; Ferrucci, Luigi

    2018-01-01

    Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using an innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer's disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated with increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging. PMID:29676998

  13. Prostate cancer epigenetics and its clinical implications.

    Science.gov (United States)

    Yegnasubramanian, Srinivasan

    2016-01-01

    Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy.

  14. Prostate cancer epigenetics and its clinical implications

    Directory of Open Access Journals (Sweden)

    Srinivasan Yegnasubramanian

    2016-01-01

    Full Text Available Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy.

  15. Epigenetics and Colorectal Cancer Pathogenesis

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    Bardhan, Kankana; Liu, Kebin, E-mail: Kliu@gru.edu [Department of Biochemistry and Molecular Biology, Medical College of Georgia, and Cancer Center, Georgia Regents University, Augusta, GA 30912 (United States)

    2013-06-05

    Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

  16. Epigenetics and colorectal cancer pathogenesis.

    Science.gov (United States)

    Bardhan, Kankana; Liu, Kebin

    2013-06-05

    Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

  17. Epigenetics and Colorectal Cancer Pathogenesis

    International Nuclear Information System (INIS)

    Bardhan, Kankana; Liu, Kebin

    2013-01-01

    Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy

  18. Epigenetics and Colorectal Cancer Pathogenesis

    Directory of Open Access Journals (Sweden)

    Kebin Liu

    2013-06-01

    Full Text Available Colorectal cancer (CRC develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

  19. Epigenetic Regulation in Prostate Cancer Progression.

    Science.gov (United States)

    Ruggero, Katia; Farran-Matas, Sonia; Martinez-Tebar, Adrian; Aytes, Alvaro

    2018-01-01

    An important number of newly identified molecular alterations in prostate cancer affect gene encoding master regulators of chromatin biology epigenetic regulation. This review will provide an updated view of the key epigenetic mechanisms underlying prostate cancer progression, therapy resistance, and potential actionable mechanisms and biomarkers. Key players in chromatin biology and epigenetic master regulators has been recently described to be crucially altered in metastatic CRPC and tumors that progress to AR independency. As such, epigenetic dysregulation represents a driving mechanism in the reprograming of prostate cancer cells as they lose AR-imposed identity. Chromatin integrity and accessibility for transcriptional regulation are key features altered in cancer progression, and particularly relevant in nuclear hormone receptor-driven tumors like prostate cancer. Understanding how chromatin remodeling dictates prostate development and how its deregulation contributes to prostate cancer onset and progression may improve risk stratification and treatment selection for prostate cancer patients.

  20. Network Biomarkers of Bladder Cancer Based on a Genome-Wide Genetic and Epigenetic Network Derived from Next-Generation Sequencing Data.

    Science.gov (United States)

    Li, Cheng-Wei; Chen, Bor-Sen

    2016-01-01

    Epigenetic and microRNA (miRNA) regulation are associated with carcinogenesis and the development of cancer. By using the available omics data, including those from next-generation sequencing (NGS), genome-wide methylation profiling, candidate integrated genetic and epigenetic network (IGEN) analysis, and drug response genome-wide microarray analysis, we constructed an IGEN system based on three coupling regression models that characterize protein-protein interaction networks (PPINs), gene regulatory networks (GRNs), miRNA regulatory networks (MRNs), and epigenetic regulatory networks (ERNs). By applying system identification method and principal genome-wide network projection (PGNP) to IGEN analysis, we identified the core network biomarkers to investigate bladder carcinogenic mechanisms and design multiple drug combinations for treating bladder cancer with minimal side-effects. The progression of DNA repair and cell proliferation in stage 1 bladder cancer ultimately results not only in the derepression of miR-200a and miR-200b but also in the regulation of the TNF pathway to metastasis-related genes or proteins, cell proliferation, and DNA repair in stage 4 bladder cancer. We designed a multiple drug combination comprising gefitinib, estradiol, yohimbine, and fulvestrant for treating stage 1 bladder cancer with minimal side-effects, and another multiple drug combination comprising gefitinib, estradiol, chlorpromazine, and LY294002 for treating stage 4 bladder cancer with minimal side-effects.

  1. Epigenetics in prostate cancer.

    Science.gov (United States)

    Albany, Costantine; Alva, Ajjai S; Aparicio, Ana M; Singal, Rakesh; Yellapragada, Sarvari; Sonpavde, Guru; Hahn, Noah M

    2011-01-01

    Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a "normal" epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

  2. Epigenetics in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Costantine Albany

    2011-01-01

    Full Text Available Prostate cancer (PC is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a “normal” epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

  3. Epigenetics in breast and prostate cancer.

    Science.gov (United States)

    Wu, Yanyuan; Sarkissyan, Marianna; Vadgama, Jaydutt V

    2015-01-01

    Most recent investigations into cancer etiology have identified a key role played by epigenetics. Specifically, aberrant DNA and histone modifications which silence tumor suppressor genes or promote oncogenes have been demonstrated in multiple cancer models. While the role of epigenetics in several solid tumor cancers such as colorectal cancer are well established, there is emerging evidence that epigenetics also plays a critical role in breast and prostate cancer. In breast cancer, DNA methylation profiles have been linked to hormone receptor status and tumor progression. Similarly in prostate cancer, epigenetic patterns have been associated with androgen receptor status and response to therapy. The regulation of key receptor pathways and activities which affect clinical therapy treatment options by epigenetics renders this field high priority for elucidating mechanisms and potential targets. A new set of methylation arrays are now available to screen epigenetic changes and provide the cutting-edge tools needed to perform such investigations. The role of nutritional interventions affecting epigenetic changes particularly holds promise. Ultimately, determining the causes and outcomes from epigenetic changes will inform translational applications for utilization as biomarkers for risk and prognosis as well as candidates for therapy.

  4. [Epigenetics of prostate cancer].

    Science.gov (United States)

    Yi, Xiao-Ming; Zhou, Wen-Quan

    2010-07-01

    Prostate cancer is one of the most common malignant tumors in males, and its etiology and pathogenesis remain unclear. Epigenesis is involved in prostate cancer at all stages of the process, and closely related with its growth and metastasis. DNA methylation and histone modification are the most important manifestations of epigenetics in prostate cancer. The mechanisms of carcinogenesis of DNA methylation include whole-genome hypomethylation, aberrant local hypermethylation of promoters and genomic instability. DNA methylation is closely related to the process of prostate cancer, as in DNA damage repair, hormone response, tumor cell invasion/metastasis, cell cycle regulation, and so on. Histone modification causes corresponding changes in chromosome structure and the level of gene transcription, and it may affect the cycle, differentiation and apoptosis of cells, resulting in prostate cancer. Some therapies have been developed targeting the epigenetic changes in prostate cancer, including DNA methyltransferases and histone deacetylase inhibitors, and have achieved certain desirable results.

  5. Epigenetic modifications in prostate cancer.

    Science.gov (United States)

    Ngollo, Marjolaine; Dagdemir, Aslihan; Karsli-Ceppioglu, Seher; Judes, Gaelle; Pajon, Amaury; Penault-Llorca, Frederique; Boiteux, Jean-Paul; Bignon, Yves-Jean; Guy, Laurent; Bernard-Gallon, Dominique J

    2014-01-01

    Prostate cancer is the most common cancer in men and the second leading cause of cancer deaths in men in France. Apart from the genetic alterations in prostate cancer, epigenetics modifications are involved in the development and progression of this disease. Epigenetic events are the main cause in gene regulation and the three most epigenetic mechanisms studied include DNA methylation, histone modifications and microRNA expression. In this review, we summarized epigenetic mechanisms in prostate cancer. Epigenetic drugs that inhibit DNA methylation, histone methylation and histone acetylation might be able to reactivate silenced gene expression in prostate cancer. However, further understanding of interactions of these enzymes and their effects on transcription regulation in prostate cancer is needed and has become a priority in biomedical research. In this study, we summed up epigenetic changes with emphasis on pharmacologic epigenetic target agents.

  6. Epigenetic Therapy in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Stephen V Liu

    2013-05-01

    Full Text Available Epigenetic dysregulation of gene function has been strongly implicated in carcinogenesis and is one of the mechanisms contributing to the development of lung cancer. The inherent reversibility of epigenetic alterations makes them viable therapeutic targets. Here, we review the therapeutic implications of epigenetic changes in lung cancer, and recent advances in therapeutic strategies targeting DNA methylation and histone acetylation.

  7. THE EPIGENETICS OF RENAL CELL TUMORS: FROM BIOLOGY TO BIOMARKERS

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    Rui eHenrique

    2012-05-01

    Full Text Available Renal cell tumors (RCT collectively constitute the third most common type of genitourinary neoplasms, only surpassed by prostate and bladder cancer. They comprise a heterogeneous group of neoplasms with distinctive clinical, morphological and genetic features. Epigenetic alterations are a hallmark of cancer cells and their role in renal tumorigenesis is starting to emerge. Aberrant DNA methylation, altered chromatin remodeling / histone onco-modifications and deregulated microRNA expression not only contribute to the emergence and progression of RCTs, but owing to their ubiquity, they also constitute a promising class of biomarkers tailored for disease detection, diagnosis, assessment of prognosis and prediction of response to therapy. Moreover, due to their dynamic and reversible properties, those alterations represent a target for epigenetic-directed therapies. In this review, the current knowledge about epigenetic mechanisms and their altered status in RCT is summarized and their envisaged use in a clinical setting is also provided.

  8. Exploiting Epigenetic Alterations in Prostate Cancer.

    Science.gov (United States)

    Baumgart, Simon J; Haendler, Bernard

    2017-05-09

    Prostate cancer affects an increasing number of men worldwide and is a leading cause of cancer-associated deaths. Beside genetic mutations, many epigenetic alterations including DNA and histone modifications have been identified in clinical prostate tumor samples. They have been linked to aberrant activity of enzymes and reader proteins involved in these epigenetic processes, leading to the search for dedicated inhibitory compounds. In the wake of encouraging anti-tumor efficacy results in preclinical models, epigenetic modulators addressing different targets are now being tested in prostate cancer patients. In addition, the assessment of microRNAs as stratification biomarkers, and early clinical trials evaluating suppressor microRNAs as potential prostate cancer treatment are being discussed.

  9. Exploiting Epigenetic Alterations in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Simon J. Baumgart

    2017-05-01

    Full Text Available Prostate cancer affects an increasing number of men worldwide and is a leading cause of cancer-associated deaths. Beside genetic mutations, many epigenetic alterations including DNA and histone modifications have been identified in clinical prostate tumor samples. They have been linked to aberrant activity of enzymes and reader proteins involved in these epigenetic processes, leading to the search for dedicated inhibitory compounds. In the wake of encouraging anti-tumor efficacy results in preclinical models, epigenetic modulators addressing different targets are now being tested in prostate cancer patients. In addition, the assessment of microRNAs as stratification biomarkers, and early clinical trials evaluating suppressor microRNAs as potential prostate cancer treatment are being discussed.

  10. First Barcelona Conference on Epigenetics and Cancer

    Science.gov (United States)

    Palau, Anna; Perucho, Manuel; Esteller, Manel; Buschbeck, Marcus

    2014-01-01

    The Barcelona Conference on Epigenetics and Cancer (BCEC) entitled “Challenges, opportunities and perspectives” took place November 21–22, 2013 in Barcelona. The 2013 BCEC is the first edition of a series of annual conferences jointly organized by five leading research centers in Barcelona. These centers are the Institute of Predictive and Personalized Medicine of Cancer (IMPPC), the Biomedical Campus Bellvitge with its Program of Epigenetics and Cancer Biology (PEBC), the Centre for Genomic Regulation (CRG), the Institute for Biomedical Research (IRB), and the Molecular Biology Institute of Barcelona (IBMB). Manuel Perucho and Marcus Buschbeck from the Institute of Predictive and Personalized Medicine of Cancer put together the scientific program of the first conference broadly covering all aspects of epigenetic research ranging from fundamental molecular research to drug and biomarker development and clinical application. In one and a half days, 23 talks and 50 posters were presented to a completely booked out audience counting 270 participants. PMID:24413145

  11. Concepts of epigenetics in prostate cancer development.

    Science.gov (United States)

    Cooper, C S; Foster, C S

    2009-01-27

    Substantial evidence now supports the view that epigenetic changes have a role in the development of human prostate cancer. Analyses of the patterns of epigenetic alteration are providing important insights into the origin of this disease and have identified specific alterations that may serve as useful diagnostic and prognostic biomarkers. Examination of cancer methylation patterns supports a stem cell origin of prostate cancer. It is well established that methylation of GSTpi is a marker of prostate cancer, and global patterns of histone marking appear to be linked to cancer prognosis with levels of acetylated histones H3K9, H3K18, and H4K12, and of dimethylated H4R3 and H3K4, dividing low-grade prostate cancer (Gleason 6 or less) into two prognostically separate groups. Elevated levels of several components of the polycomb group protein complex, EZH2, BMI1, and RING1, can also act as biomarkers of poor clinical outcome. Many components of the epigenetic machinery, including histone deacetylase (whose expression level is linked to the TMPRSS2:ERG translocation) and the histone methylase EZH2, are potential therapeutic targets. The recent discovery of the role of small RNAs in governing the epigenetic status of individual genes offers exciting new possibilities in therapeutics and chemoprevention.

  12. Epigenetics in cancer stem cells.

    Science.gov (United States)

    Toh, Tan Boon; Lim, Jhin Jieh; Chow, Edward Kai-Hua

    2017-02-01

    Compelling evidence have demonstrated that bulk tumors can arise from a unique subset of cells commonly termed "cancer stem cells" that has been proposed to be a strong driving force of tumorigenesis and a key mechanism of therapeutic resistance. Recent advances in epigenomics have illuminated key mechanisms by which epigenetic regulation contribute to cancer progression. In this review, we present a discussion of how deregulation of various epigenetic pathways can contribute to cancer initiation and tumorigenesis, particularly with respect to maintenance and survival of cancer stem cells. This information, together with several promising clinical and preclinical trials of epigenetic modulating drugs, offer new possibilities for targeting cancer stem cells as well as improving cancer therapy overall.

  13. Clinical implications of epigenetic regulation in oral cancer.

    Science.gov (United States)

    D'Souza, Wendy; Saranath, Dhananjaya

    2015-12-01

    Oral cancer is a high incidence cancer which is of major public health concern in India being the most common cancer in males and fifth most common cancer in females in India, contributing to 26% of the global oral cancer burden. The major risk factors of oral cancer are tobacco, alcohol and high risk Human Papilloma Virus type 16/18. However, only 3-12% of the high risk individuals with dysplasia develop oral cancer. Thus, individual genomic variants representing the genomic constitution and epigenetic alterations play a critical role in the development of oral cancer. Extensive epigenetic studies on the molecular lesions including oncogenes, tumor suppressor genes, genes associated with apoptosis, DNA damage repair have been reported. The current review highlights epigenetic regulation with a focus on molecular biomarkers and epidrug therapy in oral cancer. Epigenetic regulation by hypermethylation, histone modifications and specific microRNAs are often associated with early events and advanced stages in oral cancer, and thus indicate epidrug therapy for intervention. The presence of epigenetic marks in oral lesions, cancers and tumor associated mucosa emphasizes indications as biomarkers and epidrugs with therapeutic potential for better patient management. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Circadian clocks, epigenetics, and cancer

    KAUST Repository

    Masri, Selma; Kinouchi, Kenichiro; Sassone-Corsi, Paolo

    2015-01-01

    The interplay between circadian rhythm and cancer has been suggested for more than a decade based on the observations that shift work and cancer incidence are linked. Accumulating evidence implicates the circadian clock in cancer survival and proliferation pathways. At the molecular level, multiple control mechanisms have been proposed to link circadian transcription and cell-cycle control to tumorigenesis.The circadian gating of the cell cycle and subsequent control of cell proliferation is an area of active investigation. Moreover, the circadian clock is a transcriptional system that is intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape at the level of histone modifications, DNA methylation, and small regulatory RNAs are differentially controlled in cancer cells. This concept raises the possibility that epigenetic control is a common thread linking the clock with cancer, though little scientific evidence is known to date.This review focuses on the link between circadian clock and cancer, and speculates on the possible connections at the epigenetic level that could further link the circadian clock to tumor initiation or progression.

  15. Cancer Development, Progression, and Therapy: An Epigenetic Overview

    Science.gov (United States)

    Sarkar, Sibaji; Horn, Garrick; Moulton, Kimberly; Oza, Anuja; Byler, Shannon; Kokolus, Shannon; Longacre, McKenna

    2013-01-01

    Carcinogenesis involves uncontrolled cell growth, which follows the activation of oncogenes and/or the deactivation of tumor suppression genes. Metastasis requires down-regulation of cell adhesion receptors necessary for tissue-specific, cell–cell attachment, as well as up-regulation of receptors that enhance cell motility. Epigenetic changes, including histone modifications, DNA methylation, and DNA hydroxymethylation, can modify these characteristics. Targets for these epigenetic changes include signaling pathways that regulate apoptosis and autophagy, as well as microRNA. We propose that predisposed normal cells convert to cancer progenitor cells that, after growing, undergo an epithelial-mesenchymal transition. This process, which is partially under epigenetic control, can create a metastatic form of both progenitor and full-fledged cancer cells, after which metastasis to a distant location may occur. Identification of epigenetic regulatory mechanisms has provided potential therapeutic avenues. In particular, epigenetic drugs appear to potentiate the action of traditional therapeutics, often by demethylating and re-expressing tumor suppressor genes to inhibit tumorigenesis. Epigenetic drugs may inhibit both the formation and growth of cancer progenitor cells, thus reducing the recurrence of cancer. Adopting epigenetic alteration as a new hallmark of cancer is a logical and necessary step that will further encourage the development of novel epigenetic biomarkers and therapeutics. PMID:24152442

  16. Cancer Development, Progression, and Therapy: An Epigenetic Overview

    Directory of Open Access Journals (Sweden)

    McKenna Longacre

    2013-10-01

    Full Text Available Carcinogenesis involves uncontrolled cell growth, which follows the activation of oncogenes and/or the deactivation of tumor suppression genes. Metastasis requires down-regulation of cell adhesion receptors necessary for tissue-specific, cell–cell attachment, as well as up-regulation of receptors that enhance cell motility. Epigenetic changes, including histone modifications, DNA methylation, and DNA hydroxymethylation, can modify these characteristics. Targets for these epigenetic changes include signaling pathways that regulate apoptosis and autophagy, as well as microRNA. We propose that predisposed normal cells convert to cancer progenitor cells that, after growing, undergo an epithelial-mesenchymal transition. This process, which is partially under epigenetic control, can create a metastatic form of both progenitor and full-fledged cancer cells, after which metastasis to a distant location may occur. Identification of epigenetic regulatory mechanisms has provided potential therapeutic avenues. In particular, epigenetic drugs appear to potentiate the action of traditional therapeutics, often by demethylating and re-expressing tumor suppressor genes to inhibit tumorigenesis. Epigenetic drugs may inhibit both the formation and growth of cancer progenitor cells, thus reducing the recurrence of cancer. Adopting epigenetic alteration as a new hallmark of cancer is a logical and necessary step that will further encourage the development of novel epigenetic biomarkers and therapeutics.

  17. Circulating epigenetic biomarkers in lung malignancies: From early diagnosis to therapy

    Czech Academy of Sciences Publication Activity Database

    Tomasetti, M.; Amati, M.; Neužil, Jiří; Santarelli, L.

    2017-01-01

    Roč. 107, May 2017 (2017), s. 65-72 ISSN 0169-5002 R&D Projects: GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:86652036 Keywords : Malignant mesothelioma * Epigenetic biomarkers * Lung cancer * Circulating methylated DNA Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Cell biology Impact factor: 4.294, year: 2016

  18. Epigenetic Regulation of Epidermal Stem Cell Biomarkers and Their Role in Wound Healing

    Directory of Open Access Journals (Sweden)

    Sabita N. Saldanha

    2015-12-01

    Full Text Available As an actively renewable tissue, changes in skin architecture are subjected to the regulation of stem cells that maintain the population of cells responsible for the formation of epidermal layers. Stems cells retain their self-renewal property and express biomarkers that are unique to this population. However, differential regulation of the biomarkers can initiate the pathway of terminal cell differentiation. Although, pockets of non-clarity in stem cell maintenance and differentiation in skin still exist, the influence of epigenetics in epidermal stem cell functions and differentiation in skin homeostasis and wound healing is clearly evident. The focus of this review is to discuss the epigenetic regulation of confirmed and probable epidermal stem cell biomarkers in epidermal stratification of normal skin and in diseased states. The role of epigenetics in wound healing, especially in diseased states of diabetes and cancer, will also be conveyed.

  19. Epigenetics in Breast and Prostate Cancer

    OpenAIRE

    Wu, Yanyuan; Sarkissyan, Marianna; Vadgama, Jaydutt V.

    2015-01-01

    Most recent investigations into cancer etiology have identified a key role played by epigenetics. Specifically, aberrant DNA and histone modifications which silence tumor suppressor genes or promote oncogenes have been demonstrated in multiple cancer models. While the role of epigenetics in several solid tumor cancers such as colorectal cancer are well established, there is emerging evidence that epigenetics also plays a critical role in breast and prostate cancer. In breast cancer, DNA methy...

  20. DNA Methylation Biomarkers: Cancer and Beyond

    Directory of Open Access Journals (Sweden)

    Thomas Mikeska

    2014-09-01

    Full Text Available Biomarkers are naturally-occurring characteristics by which a particular pathological process or disease can be identified or monitored. They can reflect past environmental exposures, predict disease onset or course, or determine a patient’s response to therapy. Epigenetic changes are such characteristics, with most epigenetic biomarkers discovered to date based on the epigenetic mark of DNA methylation. Many tissue types are suitable for the discovery of DNA methylation biomarkers including cell-based samples such as blood and tumor material and cell-free DNA samples such as plasma. DNA methylation biomarkers with diagnostic, prognostic and predictive power are already in clinical trials or in a clinical setting for cancer. Outside cancer, strong evidence that complex disease originates in early life is opening up exciting new avenues for the detection of DNA methylation biomarkers for adverse early life environment and for estimation of future disease risk. However, there are a number of limitations to overcome before such biomarkers reach the clinic. Nevertheless, DNA methylation biomarkers have great potential to contribute to personalized medicine throughout life. We review the current state of play for DNA methylation biomarkers, discuss the barriers that must be crossed on the way to implementation in a clinical setting, and predict their future use for human disease.

  1. The epigenetic promise for prostate cancer diagnosis.

    Science.gov (United States)

    Van Neste, Leander; Herman, James G; Otto, Gaëtan; Bigley, Joseph W; Epstein, Jonathan I; Van Criekinge, Wim

    2012-08-01

    Prostate cancer is the most common cancer diagnosis in men and a leading cause of death. Improvements in disease management would have a significant impact and could be facilitated by the development of biomarkers, whether for diagnostic, prognostic, or predictive purposes. The blood-based prostate biomarker PSA has been part of clinical practice for over two decades, although it is surrounded by controversy. While debates of usefulness are ongoing, alternatives should be explored. Particularly with recent recommendations against routine PSA-testing, the time is ripe to explore promising biomarkers to yield a more efficient and accurate screening for detection and management of prostate cancer. Epigenetic changes, more specifically DNA methylation, are amongst the most common alterations in human cancer. These changes are associated with transcriptional silencing of genes, leading to an altered cellular biology. One gene in particular, GSTP1, has been widely studied in prostate cancer. Therefore a meta-analysis has been conducted to examine the role of this and other genes and the potential contribution to prostate cancer management and screening refinement. More than 30 independent, peer reviewed studies have reported a consistently high sensitivity and specificity of GSTP1 hypermethylation in prostatectomy or biopsy tissue. The meta-analysis combined and compared these results. GSTP1 methylation detection can serve an important role in prostate cancer managment. The meta-analysis clearly confirmed a link between tissue DNA hypermethylation of this and other genes and prostate cancer. Detection of DNA methylation in genes, including GSTP1, could serve an important role in clinical practice. Copyright © 2011 Wiley Periodicals, Inc.

  2. Promoter Hypermethylation of the Eyes Absent 4 Gene is a Tumor-Specific Epigenetic Biomarker in Iranian Colorectal Cancer Patients

    Directory of Open Access Journals (Sweden)

    Matineh Barati Bagerabad

    2018-02-01

    Full Text Available The aim of this study was to investigate whether hypermethylation of Eyes Absent 4 (EYA4 is also implicated in Iranian Colorectal Cancer (CRC patients or not. From fresh frozen tissues, samples from 38 paired (cancer and normal CRC tissue specimens were used in this study, the DNA was isolated, sodium bisulfite treated and analyzed by methylation-specific polymerase (MSP chain reaction using primers specific for unmethylated or methylated promoter sequences of the EYA4 gene. We also analyzed EYA4 mRNA expression using real time RT-PCR. Demographic characteristics of these patients including age, sex, tumor grade, location, stage, and TNM classification were evaluated and the relationship between methylation status of the gene and clinicopathological features was analyzed. Current study indicated that EYA4 promoter hypermethylation has a sensitivity of 81.57% and specificity of 78.94%. Findings showed lower expression of EYA-4 in methylated samples in comparison with its normal adjacent tissue, although it was not significant (P>0.05. No significant associations were observed between EYA4 hypermethylation and the clinicopathological characteristics. Although the clinical patient outcome of our 38 CRC patients was not associated with EYA4 promoter hypermethylation, the high frequency of this methylation and its high sensitivity and specificity to neoplastic cells may qualify EYA4 promoter methylation as a potential candidate screening marker in Iranian population and may help to improve early detection of CRC.

  3. Testicular cancer from diagnosis to epigenetic factors

    Science.gov (United States)

    Boccellino, Mariarosaria; Vanacore, Daniela; Zappavigna, Silvia; Cavaliere, Carla; Rossetti, Sabrina; D’Aniello, Carmine; Chieffi, Paolo; Amler, Evzen; Buonerba, Carlo; Di Lorenzo, Giuseppe; Di Franco, Rossella; Izzo, Alessandro; Piscitelli, Raffaele; Iovane, Gelsomina; Muto, Paolo; Botti, Gerardo; Perdonà, Sisto; Caraglia, Michele; Facchini, Gaetano

    2017-01-01

    Testicular cancer (TC) is one of the most common neoplasms that occurs in male and includes germ cell tumors (GCT), sex cord-gonadal stromal tumors and secondary testicular tumors. Diagnosis of TC involves the evaluation of serum tumor markers alpha-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase, but clinically several types of immunohistochemical markers are more useful and more sensitive in GCT, but not in teratoma. These new biomarkers are genes expressed in primordial germ cells/gonocytes and embryonic pluripotency-related cells but not in normal adult germ cells and they include PLAP, OCT3/4 (POU5F1), NANOG, SOX2, REX1, AP-2γ (TFAP2C) and LIN28. Gene expression in GCT is regulated, at least in part, by DNA and histone modifications, and the epigenetic profile of these tumours is characterised by genome-wide demethylation. There are different epigenetic modifications in TG-subtypes that reflect the normal developmental switch in primordial germ cells from an under- to normally methylated genome. The main purpose of this review is to illustrate the findings of recent investigations in the classification of male genital organs, the discoveries in the use of prognostic and diagnostic markers and the epigenetic aberrations mainly affecting the patterns of DNA methylation/histone modifications of genes (especially tumor suppressors) and microRNAs (miRNAs). PMID:29262668

  4. Epigenetics in Cancer: A Hematological Perspective.

    Directory of Open Access Journals (Sweden)

    Maximilian Stahl

    2016-10-01

    Full Text Available For several decades, we have known that epigenetic regulation is disrupted in cancer. Recently, an increasing body of data suggests epigenetics might be an intersection of current cancer research trends: next generation sequencing, immunology, metabolomics, and cell aging. The new emphasis on epigenetics is also related to the increasing production of drugs capable of interfering with epigenetic mechanisms and able to trigger clinical responses in even advanced phase patients. In this review, we will use myeloid malignancies as proof of concept examples of how epigenetic mechanisms can trigger or promote oncogenesis. We will also show how epigenetic mechanisms are related to genetic aberrations, and how they affect other systems, like immune response. Finally, we will show how we can try to influence the fate of cancer cells with epigenetic therapy.

  5. Epigenetics of prostate cancer.

    Science.gov (United States)

    McKee, Tawnya C; Tricoli, James V

    2015-01-01

    The introduction of novel technologies that can be applied to the investigation of the molecular underpinnings of human cancer has allowed for new insights into the mechanisms associated with tumor development and progression. They have also advanced the diagnosis, prognosis and treatment of cancer. These technologies include microarray and other analysis methods for the generation of large-scale gene expression data on both mRNA and miRNA, next-generation DNA sequencing technologies utilizing a number of platforms to perform whole genome, whole exome, or targeted DNA sequencing to determine somatic mutational differences and gene rearrangements, and a variety of proteomic analysis platforms including liquid chromatography/mass spectrometry (LC/MS) analysis to survey alterations in protein profiles in tumors. One other important advancement has been our current ability to survey the methylome of human tumors in a comprehensive fashion through the use of sequence-based and array-based methylation analysis (Bock et al., Nat Biotechnol 28:1106-1114, 2010; Harris et al., Nat Biotechnol 28:1097-1105, 2010). The focus of this chapter is to present and discuss the evidence for key genes involved in prostate tumor development, progression, or resistance to therapy that are regulated by methylation-induced silencing.

  6. Enduring epigenetic landmarks define the cancer microenvironment

    Science.gov (United States)

    Pidsley, Ruth; Lawrence, Mitchell G.; Zotenko, Elena; Niranjan, Birunthi; Statham, Aaron; Song, Jenny; Chabanon, Roman M.; Qu, Wenjia; Wang, Hong; Richards, Michelle; Nair, Shalima S.; Armstrong, Nicola J.; Nim, Hieu T.; Papargiris, Melissa; Balanathan, Preetika; French, Hugh; Peters, Timothy; Norden, Sam; Ryan, Andrew; Pedersen, John; Kench, James; Daly, Roger J.; Horvath, Lisa G.; Stricker, Phillip; Frydenberg, Mark; Taylor, Renea A.; Stirzaker, Clare; Risbridger, Gail P.; Clark, Susan J.

    2018-01-01

    The growth and progression of solid tumors involves dynamic cross-talk between cancer epithelium and the surrounding microenvironment. To date, molecular profiling has largely been restricted to the epithelial component of tumors; therefore, features underpinning the persistent protumorigenic phenotype of the tumor microenvironment are unknown. Using whole-genome bisulfite sequencing, we show for the first time that cancer-associated fibroblasts (CAFs) from localized prostate cancer display remarkably distinct and enduring genome-wide changes in DNA methylation, significantly at enhancers and promoters, compared to nonmalignant prostate fibroblasts (NPFs). Differentially methylated regions associated with changes in gene expression have cancer-related functions and accurately distinguish CAFs from NPFs. Remarkably, a subset of changes is shared with prostate cancer epithelial cells, revealing the new concept of tumor-specific epigenome modifications in the tumor and its microenvironment. The distinct methylome of CAFs provides a novel epigenetic hallmark of the cancer microenvironment and promises new biomarkers to improve interpretation of diagnostic samples. PMID:29650553

  7. Epigenetic modulators of thyroid cancer.

    Science.gov (United States)

    Rodríguez-Rodero, Sandra; Delgado-Álvarez, Elías; Díaz-Naya, Lucía; Martín Nieto, Alicia; Menéndez Torre, Edelmiro

    2017-01-01

    There are some well known factors involved in the etiology of thyroid cancer, including iodine deficiency, radiation exposure at early ages, or some genetic changes. However, epigenetic modulators that may contribute to development of these tumors and be helpful to for both their diagnosis and treatment have recently been discovered. The currently known changes in DNA methylation, histone modifications, and non-coding RNAs in each type of thyroid carcinoma are reviewed here. Copyright © 2016 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.

  8. Epigenetic Modifications: Therapeutic Potential in Cancer

    Directory of Open Access Journals (Sweden)

    Manisha Sachan

    2015-08-01

    Full Text Available Epigenetic modifications and alterations in chromatin structure and function contribute to the cumulative changes observed as normal cells undergo malignant transformation. These modifications and enzymes (DNA methyltransferases, histone deacetylases, histone methyltransferases, and demethylases related to them have been deeply studied to develop new drugs, epigenome-targeted therapies and new diagnostic tools. Epigenetic modifiers aim to restore normal epigenetic modification patterns through the inhibition of epigenetic modifier enzymes. Four of them (azacitidine, decitabine, vorinostat and romidepsin are approved by the U.S. Food and Drug Administration. This article provides an overview about the known functional roles of epigenetic enzymes in cancer development.

  9. Inflammatory biomarkers and cancer

    DEFF Research Database (Denmark)

    Rasmussen, Line Jee Hartmann; Schultz, Martin; Gaardsting, Anne

    2017-01-01

    and previous cancer diagnoses compared to patients who were not diagnosed with cancer. Previous cancer, C-reactive protein (CRP) and suPAR were significantly associated with newly diagnosed cancer during follow-up in multiple logistic regression analyses adjusted for age, sex and CRP. Neither any of the PRRs......In Denmark, patients with serious nonspecific symptoms and signs of cancer (NSSC) are referred to the diagnostic outpatient clinics (DOCs) where an accelerated cancer diagnostic program is initiated. Various immunological and inflammatory biomarkers have been associated with cancer, including...... soluble urokinase plasminogen activator receptor (suPAR) and the pattern recognition receptors (PRRs) pentraxin-3, mannose-binding lectin, ficolin-1, ficolin-2 and ficolin-3. We aimed to evaluate these biomarkers and compare their diagnostic ability to classical biomarkers for diagnosing cancer...

  10. Nanomaterials based biosensors for cancer biomarker detection

    International Nuclear Information System (INIS)

    Malhotra, Bansi D; Kumar, Saurabh; Pandey, Chandra Mouli

    2016-01-01

    Biosensors have enormous potential to contribute to the evolution of new molecular diagnostic techniques for patients suffering with cancerous diseases. A major obstacle preventing faster development of biosensors pertains to the fact that cancer is a highly complex set of diseases. The oncologists currently rely on a few biomarkers and histological characterization of tumors. Some of the signatures include epigenetic and genetic markers, protein profiles, changes in gene expression, and post-translational modifications of proteins. These molecular signatures offer new opportunities for development of biosensors for cancer detection. In this context, conducting paper has recently been found to play an important role towards the fabrication of a biosensor for cancer biomarker detection. In this paper we will focus on results of some of the recent studies obtained in our laboratories relating to fabrication and application of nanomaterial modified paper based biosensors for cancer biomarker detection. (paper)

  11. Epigenetic suppression of neprilysin regulates breast cancer invasion.

    Science.gov (United States)

    Stephen, H M; Khoury, R J; Majmudar, P R; Blaylock, T; Hawkins, K; Salama, M S; Scott, M D; Cosminsky, B; Utreja, N K; Britt, J; Conway, R E

    2016-03-07

    In women, invasive breast cancer is the second most common cancer and the second cause of cancer-related death. Therefore, identifying novel regulators of breast cancer invasion could lead to additional biomarkers and therapeutic targets. Neprilysin, a cell-surface enzyme that cleaves and inactivates a number of substrates including endothelin-1 (ET1), has been implicated in breast cancer, but whether neprilysin promotes or inhibits breast cancer cell progression and metastasis is unclear. Here, we asked whether neprilysin expression predicts and functionally regulates breast cancer cell invasion. RT-PCR and flow cytometry analysis of MDA-MB-231 and MCF-7 breast cancer cell lines revealed decreased neprilysin expression compared with normal epithelial cells. Expression was also suppressed in invasive ductal carcinoma (IDC) compared with normal tissue. In addition, in vtro invasion assays demonstrated that neprilysin overexpression decreased breast cancer cell invasion, whereas neprilysin suppression augmented invasion. Furthermore, inhibiting neprilysin in MCF-7 breast cancer cells increased ET1 levels significantly, whereas overexpressing neprilysin decreased extracellular-signal related kinase (ERK) activation, indicating that neprilysin negatively regulates ET1-induced activation of mitogen-activated protein kinase (MAPK) signaling. To determine whether neprilysin was epigenetically suppressed in breast cancer, we performed bisulfite conversion analysis of breast cancer cells and clinical tumor samples. We found that the neprilysin promoter was hypermethylated in breast cancer; chemical reversal of methylation in MDA-MB-231 cells reactivated neprilysin expression and inhibited cancer cell invasion. Analysis of cancer databases revealed that neprilysin methylation significantly associates with survival in stage I IDC and estrogen receptor-negative breast cancer subtypes. These results demonstrate that neprilysin negatively regulates the ET axis in breast cancer

  12. Biomarkers of cancer cachexia.

    Science.gov (United States)

    Loumaye, Audrey; Thissen, Jean-Paul

    2017-12-01

    Cachexia is a complex multifactorial syndrome, characterized by loss of skeletal muscle and fat mass, which affects the majority of advanced cancer patients and is associated with poor prognosis. Interestingly, reversing muscle loss in animal models of cancer cachexia leads to prolong survival. Therefore, detecting cachexia and maintaining muscle mass represent a major goal in the care of cancer patients. However, early diagnosis of cancer cachexia is currently limited for several reasons. Indeed, cachexia development is variable according to tumor and host characteristics. In addition, safe, accessible and non-invasive tools to detect skeletal muscle atrophy are desperately lacking in clinical practice. Finally, the precise molecular mechanisms and the key players involved in cancer cachexia remain poorly characterized. The need for an early diagnosis of cancer cachexia supports therefore the quest for a biomarker that might reflect skeletal muscle atrophy process. Current research offers different promising ways to identify such a biomarker. Initially, the quest for a biomarker of cancer cachexia has mostly focused on mediators of muscle atrophy, produced by both tumor and host, in an attempt to define new therapeutic approaches. In another hand, molecules released by the muscle into the circulation during the atrophy process have been also considered as potential biomarkers. More recently, several "omics" studies are emerging to identify new muscular or circulating markers of cancer cachexia. Some genetic markers could also contribute to identify patients more susceptible to develop cachexia. This article reviews our current knowledge regarding potential biomarkers of cancer cachexia. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  13. Targeting Epigenetics to Prevent Obesity Promoted Cancers.

    Science.gov (United States)

    Berger, Nathan A; Scacheri, Peter C

    2018-03-01

    Epigenetic changes in DNA and associated chromatin proteins are increasingly being considered as important mediators of the linkage between obesity and cancer. Although multiple agents, targeted at epigenetic changes, are being tested for therapy of established cancers, this issue of Cancer Prevention Research carries two articles demonstrating that the bromodomain inhibitor I-BET-762 can attenuate adipose tissue-promoted cancers. Although I-BET-762 significantly delayed, rather than completely prevented, the onset of adiposity-promoted transformation and malignancy, these experiments provide important proof of principle for the strategies of targeting epigenetic changes to disrupt the obesity-cancer linkage. Because bromodomain proteins represent only one of multiple epigenetic mediators, it is probable that targeting other epigenetic processes, alone or in combination, may serve to even more effectively disrupt the obesity promotion of cancer. Given the magnitude of the current obesity pandemic and its impact on cancer, preventive measures to disrupt this linkage are critically important. Cancer Prev Res; 11(3); 125-8. ©2018 AACR See related article by Chakraborty et al., p. 129 . ©2018 American Association for Cancer Research.

  14. Epigenetics in prostate cancer: biologic and clinical relevance.

    Science.gov (United States)

    Jerónimo, Carmen; Bastian, Patrick J; Bjartell, Anders; Carbone, Giuseppina M; Catto, James W F; Clark, Susan J; Henrique, Rui; Nelson, William G; Shariat, Shahrokh F

    2011-10-01

    Prostate cancer (PCa) is one of the most common human malignancies and arises through genetic and epigenetic alterations. Epigenetic modifications include DNA methylation, histone modifications, and microRNAs (miRNA) and produce heritable changes in gene expression without altering the DNA coding sequence. To review progress in the understanding of PCa epigenetics and to focus upon translational applications of this knowledge. PubMed was searched for publications regarding PCa and DNA methylation, histone modifications, and miRNAs. Reports were selected based on the detail of analysis, mechanistic support of data, novelty, and potential clinical applications. Aberrant DNA methylation (hypo- and hypermethylation) is the best-characterized alteration in PCa and leads to genomic instability and inappropriate gene expression. Global and locus-specific changes in chromatin remodeling are implicated in PCa, with evidence suggesting a causative dysfunction of histone-modifying enzymes. MicroRNA deregulation also contributes to prostate carcinogenesis, including interference with androgen receptor signaling and apoptosis. There are important connections between common genetic alterations (eg, E twenty-six fusion genes) and the altered epigenetic landscape. Owing to the ubiquitous nature of epigenetic alterations, they provide potential biomarkers for PCa detection, diagnosis, assessment of prognosis, and post-treatment surveillance. Altered epigenetic gene regulation is involved in the genesis and progression of PCa. Epigenetic alterations may provide valuable tools for the management of PCa patients and be targeted by pharmacologic compounds that reverse their nature. The potential for epigenetic changes in PCa requires further exploration and validation to enable translation to the clinic. Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  15. Validation of New Cancer Biomarkers

    DEFF Research Database (Denmark)

    Duffy, Michael J; Sturgeon, Catherine M; Söletormos, Georg

    2015-01-01

    BACKGROUND: Biomarkers are playing increasingly important roles in the detection and management of patients with cancer. Despite an enormous number of publications on cancer biomarkers, few of these biomarkers are in widespread clinical use. CONTENT: In this review, we discuss the key steps...... in advancing a newly discovered cancer candidate biomarker from pilot studies to clinical application. Four main steps are necessary for a biomarker to reach the clinic: analytical validation of the biomarker assay, clinical validation of the biomarker test, demonstration of clinical value from performance...... of the biomarker test, and regulatory approval. In addition to these 4 steps, all biomarker studies should be reported in a detailed and transparent manner, using previously published checklists and guidelines. Finally, all biomarker studies relating to demonstration of clinical value should be registered before...

  16. Interactions between epigenetics and metabolism in cancers

    International Nuclear Information System (INIS)

    Yun, Jihye; Johnson, Jared L.; Hanigan, Christin L.; Locasale, Jason W.

    2012-01-01

    Cancer progression is accompanied by widespread transcriptional changes and metabolic alterations. While it is widely accepted that the origin of cancer can be traced to the mutations that accumulate over time, relatively recent evidence favors a similarly fundamental role for alterations in the epigenome during tumorigenesis. Changes in epigenetics that arise from post-translational modifications of histones and DNA are exploited by cancer cells to upregulate and/or downregulate the expression levels of oncogenes and tumor suppressors, respectively. Although the mechanisms behind these modifications, in particular how they lead to gene silencing and activation, are still being understood, most of the enzymatic machinery of epigenetics require metabolites as substrates or cofactors. As a result, their activities can be influenced by the metabolic state of the cell. The purpose of this review is to give an overview of cancer epigenetics and metabolism and provide examples of where they converge.

  17. Interactions between epigenetics and metabolism in cancers

    Directory of Open Access Journals (Sweden)

    Jihye eYun

    2012-11-01

    Full Text Available Cancer progression is accompanied by widespread transcriptional changes and metabolic alterations. Although it is widely accepted that the origin of cancer can be traced to the mutations that accumulate over time, relatively recent evidence favors a similarly fundamental role for alterations in the epigenome during tumorigenesis. Changes in epigenetics that arise from post-translational modifications of histones and DNA, are exploited by cancer cells to upregulate and/or downregulate the expression levels of oncogenes and tumor suppressors, respectively. Although the mechanisms behind these modifications, in particular how they lead to gene silencing and activation, are still being understood, many enzymes that carry out post-translational modifications that alter epigenetics require metabolites as substrates or cofactors. As a result, their activities can be influenced by the metabolic state of the cell. The purpose of this review is to give an overview of cancer epigenetics and metabolism and provide examples of where they converge.

  18. Cancer Control and Prevention by Nutrition and Epigenetic Approaches

    OpenAIRE

    Verma, Mukesh

    2012-01-01

    Significance: Epigenetics involves alterations in gene expression without changing the nucleotide sequence. Because some epigenetic changes can be reversed chemically, epigenetics has tremendous implications for disease intervention and treatment. Recent Advances: After epigenetic components in cancer were characterized, genes and pathways are being characterized in other diseases such as diabetes, obesity, and neurological disorders. Observational, experimental, and clinical studies in diffe...

  19. Prediction of epigenetically regulated genes in breast cancer cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Loss, Leandro A; Sadanandam, Anguraj; Durinck, Steffen; Nautiyal, Shivani; Flaucher, Diane; Carlton, Victoria EH; Moorhead, Martin; Lu, Yontao; Gray, Joe W; Faham, Malek; Spellman, Paul; Parvin, Bahram

    2010-05-04

    Methylation of CpG islands within the DNA promoter regions is one mechanism that leads to aberrant gene expression in cancer. In particular, the abnormal methylation of CpG islands may silence associated genes. Therefore, using high-throughput microarrays to measure CpG island methylation will lead to better understanding of tumor pathobiology and progression, while revealing potentially new biomarkers. We have examined a recently developed high-throughput technology for measuring genome-wide methylation patterns called mTACL. Here, we propose a computational pipeline for integrating gene expression and CpG island methylation profles to identify epigenetically regulated genes for a panel of 45 breast cancer cell lines, which is widely used in the Integrative Cancer Biology Program (ICBP). The pipeline (i) reduces the dimensionality of the methylation data, (ii) associates the reduced methylation data with gene expression data, and (iii) ranks methylation-expression associations according to their epigenetic regulation. Dimensionality reduction is performed in two steps: (i) methylation sites are grouped across the genome to identify regions of interest, and (ii) methylation profles are clustered within each region. Associations between the clustered methylation and the gene expression data sets generate candidate matches within a fxed neighborhood around each gene. Finally, the methylation-expression associations are ranked through a logistic regression, and their significance is quantified through permutation analysis. Our two-step dimensionality reduction compressed 90% of the original data, reducing 137,688 methylation sites to 14,505 clusters. Methylation-expression associations produced 18,312 correspondences, which were used to further analyze epigenetic regulation. Logistic regression was used to identify 58 genes from these correspondences that showed a statistically signifcant negative correlation between methylation profles and gene expression in the

  20. Epigenetic targets in the diagnosis and treatment of prostate cancer

    Directory of Open Access Journals (Sweden)

    Murugesan Manoharan

    2007-02-01

    Full Text Available Prostate cancer (PC is one of leading cause of cancer related deaths in men. Various aspects of cancer epigenetics are rapidly evolving and the role of 2 major epigenetic changes including DNA methylation and histone modifications in prostate cancer is being studied widely. The epigenetic changes are early event in the cancer development and are reversible. Novel epigenetic markers are being studied, which have the potential as sensitive diagnostic and prognostic marker. Variety of drugs targeting epigenetic changes are being studied, which can be effective individually or in combination with other conventional drugs in PC treatment. In this review, we discuss epigenetic changes associated with PC and their potential diagnostic and therapeutic applications including future areas of research.

  1. Epigenetics application in the diagnosis and treatment of bladder cancer.

    Science.gov (United States)

    Harb-de la Rosa, Alfredo; Acker, Matthew; Kumar, Raj A; Manoharan, Murugesan

    2015-10-01

    Bladder cancer is the sixth most common cancer in the Western world. Patients with bladder cancer require close monitoring, which may include frequent cystoscopy and urine cytology. Such monitoring results in significant health care cost. The application of epigenetics may allow for a risk adapted approach and more cost-effective method of monitoring. A number of epigenetic changes have been described for many cancer sites, including the urinary bladder. In this review, we discuss the use of epigenetics in bladder cancer and the potential diagnostic and therapeutic applications. A comprehensive search of the English medical literature was conducted in PubMed using the terms microRNA regulation, DNA methylation, histone modification and bladder cancer. The most important epigenetic changes include DNA methylation, histone modification and microRNA regulation. Both DNA hypomethylation and hypermethylation have been associated with higher rate of cancer. The association of epigenetic changes with bladder cancer has led to the research of its diagnostic and prognostic implications as well as to the development of novel drugs to target these changes with the aim of achieving a survival benefit. Recently, epigenetics has been shown to play a much greater role than previously anticipated in the initiation and propagation of many tumors. The use of epigenetics for the diagnosis and treatment of bladder cancer is an evolving and promising field. The possibility of reversing epigenetic changes may facilitate additional cancer treatment options in the future.

  2. The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer.

    Science.gov (United States)

    Chaligné, Ronan; Popova, Tatiana; Mendoza-Parra, Marco-Antonio; Saleem, Mohamed-Ashick M; Gentien, David; Ban, Kristen; Piolot, Tristan; Leroy, Olivier; Mariani, Odette; Gronemeyer, Hinrich; Vincent-Salomon, Anne; Stern, Marc-Henri; Heard, Edith

    2015-04-01

    Disappearance of the Barr body is considered a hallmark of cancer, although whether this corresponds to genetic loss or to epigenetic instability and transcriptional reactivation is unclear. Here we show that breast tumors and cell lines frequently display major epigenetic instability of the inactive X chromosome, with highly abnormal 3D nuclear organization and global perturbations of heterochromatin, including gain of euchromatic marks and aberrant distributions of repressive marks such as H3K27me3 and promoter DNA methylation. Genome-wide profiling of chromatin and transcription reveal modified epigenomic landscapes in cancer cells and a significant degree of aberrant gene activity from the inactive X chromosome, including several genes involved in cancer promotion. We demonstrate that many of these genes are aberrantly reactivated in primary breast tumors, and we further demonstrate that epigenetic instability of the inactive X can lead to perturbed dosage of X-linked factors. Taken together, our study provides the first integrated analysis of the inactive X chromosome in the context of breast cancer and establishes that epigenetic erosion of the inactive X can lead to the disappearance of the Barr body in breast cancer cells. This work offers new insights and opens up the possibility of exploiting the inactive X chromosome as an epigenetic biomarker at the molecular and cytological levels in cancer. © 2015 Chaligné et al.; Published by Cold Spring Harbor Laboratory Press.

  3. Environmental Epigenetics: Crossroad between Public Health, Lifestyle, and Cancer Prevention

    Science.gov (United States)

    Romani, Massimo; Pistillo, Maria Pia; Banelli, Barbara

    2015-01-01

    Epigenetics provides the key to transform the genetic information into phenotype and because of its reversibility it is considered an ideal target for therapeutic interventions. This paper reviews the basic mechanisms of epigenetic control: DNA methylation, histone modifications, chromatin remodeling, and ncRNA expression and their role in disease development. We describe also the influence of the environment, lifestyle, nutritional habits, and the psychological influence on epigenetic marks and how these factors are related to cancer and other diseases development. Finally we discuss the potential use of natural epigenetic modifiers in the chemoprevention of cancer to link together public health, environment, and lifestyle. PMID:26339624

  4. The epigenetics of prostate cancer diagnosis and prognosis: update on clinical applications.

    Science.gov (United States)

    Blute, Michael L; Damaschke, Nathan A; Jarrard, David F

    2015-01-01

    There is a major deficit in our ability to detect and predict the clinical behavior of prostate cancer (PCa). Epigenetic changes are associated with PCa development and progression. This review will focus on recent results in the clinical application of diagnostic and prognostic epigenetic markers. The development of high throughput technology has seen an enormous increase in the discovery of new markers that encompass epigenetic changes including those in DNA methylation and histone modifications. Application of these findings to urine and other biofluids, but also cancer and noncancerous prostate tissue, has resulted in new biomarkers. There has been a recent commercial development of a DNA methylation-based assay for identifying PCa risk from normal biopsy tissue. Other biomarkers are currently in the validation phase and encompass combinations of multiple genes. Epigenetic changes improve the specificity and sensitivity of PCa diagnosis and have the potential to help determine clinical prognosis. Additional studies will not only provide new and better biomarker candidates, but also have the potential to inform new therapeutic strategies given the reversibility of these processes.

  5. SFRP Tumour Suppressor Genes Are Potential Plasma-Based Epigenetic Biomarkers for Malignant Pleural Mesothelioma

    Directory of Open Access Journals (Sweden)

    Yuen Yee Cheng

    2017-01-01

    Full Text Available Malignant pleural mesothelioma (MPM is associated with asbestos exposure. Asbestos can induce chronic inflammation which in turn can lead to silencing of tumour suppressor genes. Wnt signaling pathway can be affected by chronic inflammation and is aberrantly activated in many cancers including colon and MPM. SFRP genes are antagonists of Wnt pathway, and SFRPs are potential tumour suppressors in colon, gastric, breast, ovarian, and lung cancers and mesothelioma. This study investigated the expression and DNA methylation of SFRP genes in MPM cells lines with and without demethylation treatment. Sixty-six patient FFPE samples were analysed and have showed methylation of SFRP2 (56% and SFRP5 (70% in MPM. SFRP2 and SFRP5 tumour-suppressive activity in eleven MPM lines was confirmed, and long-term asbestos exposure led to reduced expression of the SFRP1 and SFRP2 genes in the mesothelium (MeT-5A via epigenetic alterations. Finally, DNA methylation of SFRPs is detectable in MPM patient plasma samples, with methylated SFRP2 and SFRP5 showing a tendency towards greater abundance in patients. These data suggested that SFRP genes have tumour-suppresive activity in MPM and that methylated DNA from SFRP gene promoters has the potential to serve as a biomarker for MPM patient plasma.

  6. The Art of Interpreting Epigenetic Activity | Center for Cancer Research

    Science.gov (United States)

    Even though all the cells of the human body share a common genomic blueprint, epigenetic activity such as DNA methylation, introduces molecular diversity that results in functionally and biologically different cellular constituents. In cancers, this ability of epigenetic activity to introduce molecular diversity is emerging as a powerful classifier of biological aggressiveness.

  7. Prostate Cancer Epigenetics: A Review on Gene Regulation

    Directory of Open Access Journals (Sweden)

    Lena Diaw

    2007-01-01

    Full Text Available Prostate cancer is the most common cancer in men in western countries, and its incidence is increasing steadily worldwide. Molecular changes including both genetic and epigenetic events underlying the development and progression of this disease are still not well understood. Epigenetic events are involved in gene regulation and occur through different mechanisms such as DNA methylation and histone modifi cations. Both DNA methylation and histone modifi cations affect gene regulation and play important roles either independently or by interaction in tumor initiation and progression. This review will discuss the genes associated with epigenetic alterations in prostate cancer progression: their regulation and importance as possible markers for the disease.

  8. The developmental environment, epigenetic biomarkers and long-term health.

    Science.gov (United States)

    Godfrey, K M; Costello, P M; Lillycrop, K A

    2015-10-01

    Evidence from both human and animal studies has shown that the prenatal and early postnatal environments influence susceptibility to chronic disease in later life and suggests that epigenetic processes are an important mechanism by which the environment alters long-term disease risk. Epigenetic processes, including DNA methylation, histone modification and non-coding RNAs, play a central role in regulating gene expression. The epigenome is highly sensitive to environmental factors in early life, such as nutrition, stress, endocrine disruption and pollution, and changes in the epigenome can induce long-term changes in gene expression and phenotype. In this review we focus on how the early life nutritional environment can alter the epigenome leading to an altered susceptibility to disease in later life.

  9. The Role of Epigenomics in the Study of Cancer Biomarkers and in the Development of Diagnostic Tools.

    Science.gov (United States)

    Verma, Mukesh

    2015-01-01

    Epigenetics plays a key role in cancer development. Genetics alone cannot explain sporadic cancer and cancer development in individuals with no family history or a weak family history of cancer. Epigenetics provides a mechanism to explain the development of cancer in such situations. Alterations in epigenetic profiling may provide important insights into the etiology and natural history of cancer. Because several epigenetic changes occur before histopathological changes, they can serve as biomarkers for cancer diagnosis and risk assessment. Many cancers may remain asymptomatic until relatively late stages; in managing the disease, efforts should be focused on early detection, accurate prediction of disease progression, and frequent monitoring. This chapter describes epigenetic biomarkers as they are expressed during cancer development and their potential use in cancer diagnosis and prognosis. Based on epigenomic information, biomarkers have been identified that may serve as diagnostic tools; some such biomarkers also may be useful in identifying individuals who will respond to therapy and survive longer. The importance of analytical and clinical validation of biomarkers is discussed, along with challenges and opportunities in this field.

  10. The Interactions of microRNA and Epigenetic Modifications in Prostate Cancer

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    Prashant Kumar Singh

    2013-08-01

    Full Text Available Epigenetic modifiers play important roles in fine-tuning the cellular transcriptome. Any imbalance in these processes may lead to abnormal transcriptional activity and thus result in disease state. Distortions of the epigenome have been reported in cancer initiation and progression. DNA methylation and histone modifications are principle components of this epigenome, but more recently it has become clear that microRNAs (miRNAs are another major component of the epigenome. Interactions of these components are apparent in prostate cancer (CaP, which is the most common non-cutaneous cancer and second leading cause of death from cancer in the USA. Changes in DNA methylation, altered histone modifications and miRNA expression are functionally associated with CaP initiation and progression. Various aspects of the epigenome have also been investigated as biomarkers for different stages of CaP detection, though with limited success. This review aims to summarize key aspects of these mechanistic interactions within the epigenome and to highlight their translational potential as functional biomarkers. To this end, exploration of TCGA prostate cancer data revealed that expression of key CaP miRNAs inversely associate with DNA methylation. Given the importance and prevalence of these epigenetic events in CaP biology it is timely to understand further how different epigenetic components interact and influence each other.

  11. Potential of Epigenetic Therapies in Non-cancerous Conditions

    Directory of Open Access Journals (Sweden)

    Raymond eYung

    2014-12-01

    Full Text Available There has been an explosion of knowledge in the epigenetics field in the past 20 years. The first epigenetic therapies have arrived in the clinic for cancer treatments. In contrast, much of the promise of epigenetic therapies for non-cancerous conditions remains in the laboratories. The current review will focus on the recent progress that has been made in understanding the pathogenic role of epigenetics in immune and inflammatory conditions, and how the knowledge may provide much needed new therapeutic targets for many autoimmune diseases. Dietary factors are increasingly recognized as potential modifiers of epigenetic marks that can influence health and diseases across generations. The current epigenomics revolution will almost certainly complement the explosion of personal genetics medicine to help guide treatment decisions and disease risk stratification.

  12. The Interaction between Epigenetics, Nutrition and the Development of Cancer

    Directory of Open Access Journals (Sweden)

    Karen S. Bishop

    2015-01-01

    Full Text Available Unlike the genome, the epigenome can be modified and hence some epigenetic risk markers have the potential to be reversed. Such modifications take place by means of drugs, diet or environmental exposures. It is widely accepted that epigenetic modifications take place during early embryonic and primordial cell development, but it is also important that we gain an understanding of the potential for such changes later in life. These “later life” epigenetic modifications in response to dietary intervention are the focus of this paper. The epigenetic modifications investigated include DNA methylation, histone modifications and the influence of microRNAs. The epigenotype could be used not only to predict susceptibility to certain cancers but also to assess the effectiveness of dietary modifications to reduce such risk. The influence of diet or dietary components on epigenetic modifications and the impact on cancer initiation or progression has been assessed herein.

  13. Histone Methylation and Epigenetic Silencing in Breast Cancer

    National Research Council Canada - National Science Library

    Simon, Jeffrey A; Lange, Carol A

    2008-01-01

    The purpose of this research is to investigate the role of a chromatin-modifying enzyme called EZH2 in breast cancer epigenetics and to develop strategies to identify chemical inhibitors of this, enzyme...

  14. Histone Methylation and Epigenetic Silencing in Breast Cancer

    National Research Council Canada - National Science Library

    Simon, Jeffrey A; Lange, Carol A

    2008-01-01

    .... EZH2 is a histone methyltransferase which modifies lysine-27 of histone H3 an epigenetic mark which is generally linked to gene silencing and is implicated in tumor suppressor silencing during breast cancer progression...

  15. Prostate Cancer Epigenetics: A Review on Gene Regulation

    OpenAIRE

    Diaw, Lena; Woodson, Karen; Gillespie, John W.

    2007-01-01

    Prostate cancer is the most common cancer in men in western countries, and its incidence is increasing steadily worldwide. Molecular changes including both genetic and epigenetic events underlying the development and progression of this disease are still not well understood. Epigenetic events are involved in gene regulation and occur through different mechanisms such as DNA methylation and histone modifi cations. Both DNA methylation and histone modifi cations affect gene regulation and play ...

  16. Alteration of Epigenetic Regulation by Long Noncoding RNAs in Cancer

    Directory of Open Access Journals (Sweden)

    Mariangela Morlando

    2018-02-01

    Full Text Available Long noncoding RNAs (lncRNAs are important regulators of the epigenetic status of the human genome. Besides their participation to normal physiology, lncRNA expression and function have been already associated to many diseases, including cancer. By interacting with epigenetic regulators and by controlling chromatin topology, their misregulation may result in an aberrant regulation of gene expression that may contribute to tumorigenesis. Here, we review the functional role and mechanisms of action of lncRNAs implicated in the aberrant epigenetic regulation that has characterized cancer development and progression.

  17. A tissue biopsy-based epigenetic multiplex PCR assay for prostate cancer detection

    Directory of Open Access Journals (Sweden)

    Van Neste Leander

    2012-06-01

    Full Text Available Abstract Background PSA-directed prostate cancer screening leads to a high rate of false positive identifications and an unnecessary biopsy burden. Epigenetic biomarkers have proven useful, exhibiting frequent and abundant inactivation of tumor suppressor genes through such mechanisms. An epigenetic, multiplex PCR test for prostate cancer diagnosis could provide physicians with better tools to help their patients. Biomarkers like GSTP1, APC and RASSF1 have demonstrated involvement with prostate cancer, with the latter two genes playing prominent roles in the field effect. The epigenetic states of these genes can be used to assess the likelihood of cancer presence or absence. Results An initial test cohort of 30 prostate cancer-positive samples and 12 cancer-negative samples was used as basis for the development and optimization of an epigenetic multiplex assay based on the GSTP1, APC and RASSF1 genes, using methylation specific PCR (MSP. The effect of prostate needle core biopsy sample volume and age of formalin-fixed paraffin-embedded (FFPE samples was evaluated on an independent follow-up cohort of 51 cancer-positive patients. Multiplexing affects copy number calculations in a consistent way per assay. Methylation ratios are therefore altered compared to the respective singleplex assays, but the correlation with patient outcome remains equivalent. In addition, tissue-biopsy samples as small as 20 μm can be used to detect methylation in a reliable manner. The age of FFPE-samples does have a negative impact on DNA quality and quantity. Conclusions The developed multiplex assay appears functionally similar to individual singleplex assays, with the benefit of lower tissue requirements, lower cost and decreased signal variation. This assay can be applied to small biopsy specimens, down to 20 microns, widening clinical applicability. Increasing the sample volume can compensate the loss of DNA quality and quantity in older samples.

  18. DNA Methylation and Chromatin Remodeling: The Blueprint of Cancer Epigenetics

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    Dipanjan Bhattacharjee

    2016-01-01

    Full Text Available Epigenetics deals with the interactions between genes and the immediate cellular environment. These interactions go a long way in shaping up each and every person’s individuality. Further, reversibility of epigenetic interactions may offer a dynamic control over the expression of various critical genes. Thus, tweaking the epigenetic machinery may help cause or cure diseases, especially cancer. Therefore, cancer epigenetics, especially at a molecular level, needs to be scrutinised closely, as it could potentially serve as the future pharmaceutical goldmine against neoplastic diseases. However, in view of its rapidly enlarging scope of application, it has become difficult to keep abreast of scientific information coming out of various epigenetic studies directed against cancer. Using this review, we have attempted to shed light on two of the most important mechanisms implicated in cancer, that is, DNA (deoxyribonucleic acid methylation and histone modifications, and their place in cancer pathogenesis. Further, we have attempted to take stock of the new epigenetic drugs that have emerged onto the market as well as those in the pipeline that offer hope in mankind’s fight against cancer.

  19. Genetic and epigenetic markers in colorectal cancer screening: recent advances.

    Science.gov (United States)

    Singh, Manish Pratap; Rai, Sandhya; Suyal, Shradha; Singh, Sunil Kumar; Singh, Nand Kumar; Agarwal, Akash; Srivastava, Sameer

    2017-07-01

    Colorectal cancer (CRC) is a heterogenous disease which develops from benign intraepithelial lesions known as adenomas to malignant carcinomas. Acquired alterations in Wnt signaling, TGFβ, MAPK pathway genes and clonal propagation of altered cells are responsible for this transformation. Detection of adenomas or early stage cancer in asymptomatic patients and better prognostic and predictive markers is important for improving the clinical management of CRC. Area covered: In this review, the authors have evaluated the potential of genetic and epigenetic alterations as markers for early detection, prognosis and therapeutic predictive potential in the context of CRC. We have discussed molecular heterogeneity present in CRC and its correlation to prognosis and response to therapy. Expert commentary: Molecular marker based CRC screening methods still fail to gain trust of clinicians. Invasive screening methods, molecular heterogeneity, chemoresistance and low quality test samples are some key challenges which need to be addressed in the present context. New sequencing technologies and integrated omics data analysis of individual or population cohort results in GWAS. MPE studies following a GWAS could be future line of research to establish accurate correlations between CRC and its risk factors. This strategy would identify most reliable biomarkers for CRC screening and management.

  20. Dietary factors and epigenetic regulation for prostate cancer prevention.

    Science.gov (United States)

    Ho, Emily; Beaver, Laura M; Williams, David E; Dashwood, Roderick H

    2011-11-01

    The role of epigenetic alterations in various human chronic diseases has gained increasing attention and has resulted in a paradigm shift in our understanding of disease susceptibility. In the field of cancer research, e.g., genetic abnormalities/mutations historically were viewed as primary underlying causes; however, epigenetic mechanisms that alter gene expression without affecting DNA sequence are now recognized as being of equal or greater importance for oncogenesis. Methylation of DNA, modification of histones, and interfering microRNA (miRNA) collectively represent a cadre of epigenetic elements dysregulated in cancer. Targeting the epigenome with compounds that modulate DNA methylation, histone marks, and miRNA profiles represents an evolving strategy for cancer chemoprevention, and these approaches are starting to show promise in human clinical trials. Essential micronutrients such as folate, vitamin B-12, selenium, and zinc as well as the dietary phytochemicals sulforaphane, tea polyphenols, curcumin, and allyl sulfur compounds are among a growing list of agents that affect epigenetic events as novel mechanisms of chemoprevention. To illustrate these concepts, the current review highlights the interactions among nutrients, epigenetics, and prostate cancer susceptibility. In particular, we focus on epigenetic dysregulation and the impact of specific nutrients and food components on DNA methylation and histone modifications that can alter gene expression and influence prostate cancer progression.

  1. Epigenetic reprogramming of breast cancer cells with oocyte extracts

    Directory of Open Access Journals (Sweden)

    Kumari Rajendra

    2011-01-01

    Full Text Available Abstract Background Breast cancer is a disease characterised by both genetic and epigenetic alterations. Epigenetic silencing of tumour suppressor genes is an early event in breast carcinogenesis and reversion of gene silencing by epigenetic reprogramming can provide clues to the mechanisms responsible for tumour initiation and progression. In this study we apply the reprogramming capacity of oocytes to cancer cells in order to study breast oncogenesis. Results We show that breast cancer cells can be directly reprogrammed by amphibian oocyte extracts. The reprogramming effect, after six hours of treatment, in the absence of DNA replication, includes DNA demethylation and removal of repressive histone marks at the promoters of tumour suppressor genes; also, expression of the silenced genes is re-activated in response to treatment. This activity is specific to oocytes as it is not elicited by extracts from ovulated eggs, and is present at very limited levels in extracts from mouse embryonic stem cells. Epigenetic reprogramming in oocyte extracts results in reduction of cancer cell growth under anchorage independent conditions and a reduction in tumour growth in mouse xenografts. Conclusions This study presents a new method to investigate tumour reversion by epigenetic reprogramming. After testing extracts from different sources, we found that axolotl oocyte extracts possess superior reprogramming ability, which reverses epigenetic silencing of tumour suppressor genes and tumorigenicity of breast cancer cells in a mouse xenograft model. Therefore this system can be extremely valuable for dissecting the mechanisms involved in tumour suppressor gene silencing and identifying molecular activities capable of arresting tumour growth. These applications can ultimately shed light on the contribution of epigenetic alterations in breast cancer and advance the development of epigenetic therapies.

  2. Epigenetics in mammary gland biology and cancer

    Science.gov (United States)

    In the post genome era, the focus has shifted to understanding the mechanisms that regulate the interpretation of the genetic code. "Epigenetics" as a research field is taking center stage. Epigenetics is a term which is now being used throughout the scientific community in different contexts from p...

  3. PET Metabolic Biomarkers for Cancer

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    Etienne Croteau

    2016-01-01

    Full Text Available The body's main fuel sources are fats, carbohydrates (glucose, proteins, and ketone bodies. It is well known that an important hallmark of cancer cells is the overconsumption of glucose. Positron emission tomography (PET imaging using the glucose analog 18 F-fluorodeoxyglucose ( 18 F-FDG has been a powerful cancer diagnostic tool for many decades. Apart from surgery, chemotherapy and radiotherapy represent the two main domains for cancer therapy, targeting tumor proliferation, cell division, and DNA replication–-all processes that require a large amount of energy. Currently, in vivo clinical imaging of metabolism is performed almost exclusively using PET radiotracers that assess oxygen consumption and mechanisms of energy substrate consumption. This paper reviews the utility of PET imaging biomarkers for the detection of cancer proliferation, vascularization, metabolism, treatment response, and follow-up after radiation therapy, chemotherapy, and chemotherapy-related side effects.

  4. Genetic Variants in Epigenetic Pathways and Risks of Multiple Cancers in the GAME-ON Consortium.

    Science.gov (United States)

    Toth, Reka; Scherer, Dominique; Kelemen, Linda E; Risch, Angela; Hazra, Aditi; Balavarca, Yesilda; Issa, Jean-Pierre J; Moreno, Victor; Eeles, Rosalind A; Ogino, Shuji; Wu, Xifeng; Ye, Yuanqing; Hung, Rayjean J; Goode, Ellen L; Ulrich, Cornelia M

    2017-06-01

    Background: Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background. Methods: In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate-corrected P values (q values cancer type. For example, variants in BABAM1 were confirmed as a susceptibility locus for squamous cell lung, overall breast, estrogen receptor (ER)-negative breast, and overall prostate, and overall serous ovarian cancer; the most significant variant was rs4808076 [OR = 1.14; 95% confidence interval (CI) = 1.10-1.19; q = 6.87 × 10 -5 ]. DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, and overall and aggressive prostate cancer risk (OR = 0.93; 95% CI = 0.91-0.96; q = 0.005). Variants in L3MBTL3 were associated with colorectal, overall breast, ER-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g., rs9388766: OR = 1.06; 95% CI = 1.03-1.08; q = 0.02). Variants in TET2 were significantly associated with overall breast, overall prostate, overall ovarian, and endometrioid ovarian cancer risk, with rs62331150 showing bidirectional effects. Analyses of subpathways did not reveal gene subsets that contributed disproportionately to susceptibility. Conclusions: Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology. Impact: This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes. Cancer Epidemiol Biomarkers Prev; 26(6); 816-25. ©2017 AACR . ©2017 American Association for Cancer Research.

  5. Prostate Cancer: Epigenetic Alterations, Risk Factors, and Therapy

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    Mankgopo M. Kgatle

    2016-01-01

    Full Text Available Prostate cancer (PCa is the most prevalent urological cancer that affects aging men in South Africa, and mechanisms underlying prostate tumorigenesis remain elusive. Research advancements in the field of PCa and epigenetics have allowed for the identification of specific alterations that occur beyond genetics but are still critically important in the pathogenesis of tumorigenesis. Anomalous epigenetic changes associated with PCa include histone modifications, DNA methylation, and noncoding miRNA. These mechanisms regulate and silence hundreds of target genes including some which are key components of cellular signalling pathways that, when perturbed, promote tumorigenesis. Elucidation of mechanisms underlying epigenetic alterations and the manner in which these mechanisms interact in regulating gene transcription in PCa are an unmet necessity that may lead to novel chemotherapeutic approaches. This will, therefore, aid in developing combination therapies that will target multiple epigenetic pathways, which can be used in conjunction with the current conventional PCa treatment.

  6. Nanotechnology Approaches to Studying Epigenetic Changes in Cancer

    Science.gov (United States)

    Riehn, Robert

    2011-03-01

    Placing polyelectrolytes into confined geometries has a profound effect on their molecular configuration. For instance, placing long DNA molecules into channels with a cross-section of about 100 nm 2 stretches them out to about 70% of their contour length. We are using this effect to map epigenetic changes on single DNA and chromatin strands. This mapping on single molecules becomes central in the study of the heterogeneity of cell population in cancer, since rapid change of epigenetic makeup, propagated through rare cancer stem cells, is a hallmark of its progression. We demonstrate the basic building blocks for the single-molecule epigenetic analysis of genomic sized DNA. In particular, we have achieved the mapping of methylated regions in DNA with heterogeneous 5-methyl cytosine modification using a specific fluorescent marker. We further show that chromatin with an intact histone structure can be stretched similar to DNA, and that the epigenetic state of histone tails can be detected using fluorescent antibodies.

  7. Biomarkers of HIV-associated Cancer

    OpenAIRE

    Flepisi, Brian Thabile; Bouic, Patrick; Sissolak, Gerhard; Rosenkranz, Bernd

    2014-01-01

    Cancer biomarkers have provided great opportunities for improving the management of cancer patients by enhancing the efficiency of early detection, diagnosis, and efficacy of treatment. Every cell type has a unique molecular signature, referred to as biomarkers, which are identifiable characteristics such as levels or activities of a myriad of genes, proteins, or other molecular features. Biomarkers can facilitate the molecular definition of cancer, provide information about the course of can...

  8. Epigenetic diet: impact on the epigenome and cancer

    Science.gov (United States)

    Hardy, Tabitha M; Tollefsbol, Trygve O

    2011-01-01

    A number of bioactive dietary components are of particular interest in the field of epigenetics. Many of these compounds display anticancer properties and may play a role in cancer prevention. Numerous studies suggest that a number of nutritional compounds have epigenetic targets in cancer cells. Importantly, emerging evidence strongly suggests that consumption of dietary agents can alter normal epigenetic states as well as reverse abnormal gene activation or silencing. Epigenetic modifications induced by bioactive dietary compounds are thought to be beneficial. Substantial evidence is mounting proclaiming that commonly consumed bioactive dietary factors act to modify the epigenome and may be incorporated into an ‘epigenetic diet’. Bioactive nutritional components of an epigenetic diet may be incorporated into one’s regular dietary regimen and used therapeutically for medicinal or chemopreventive purposes. This article will primarily focus on dietary factors that have been demonstrated to influence the epigenome and that may be used in conjunction with other cancer prevention and chemotherapeutic therapies. PMID:22022340

  9. Molecular biomarkers to guide precision medicine in localized prostate cancer.

    Science.gov (United States)

    Smits, Minke; Mehra, Niven; Sedelaar, Michiel; Gerritsen, Winald; Schalken, Jack A

    2017-08-01

    Major advances through tumor profiling technologies, that include next-generation sequencing, epigenetic, proteomic and transcriptomic methods, have been made in primary prostate cancer, providing novel biomarkers that may guide precision medicine in the near future. Areas covered: The authors provided an overview of novel molecular biomarkers in tissue, blood and urine that may be used as clinical tools to assess prognosis, improve selection criteria for active surveillance programs, and detect disease relapse early in localized prostate cancer. Expert commentary: Active surveillance (AS) in localized prostate cancer is an accepted strategy in patients with very low-risk prostate cancer. Many more patients may benefit from watchful waiting, and include patients of higher clinical stage and grade, however selection criteria have to be optimized and early recognition of transformation from localized to lethal disease has to be improved by addition of molecular biomarkers. The role of non-invasive biomarkers is challenging the need for repeat biopsies, commonly performed at 1 and 4 years in men under AS programs.

  10. Epigenetic susceptibility factors for prostate cancer with aging.

    Science.gov (United States)

    Damaschke, N A; Yang, B; Bhusari, S; Svaren, J P; Jarrard, D F

    2013-12-01

    Increasing age is a significant risk factor for prostate cancer. The prostate is exposed to environmental and endogenous stress that may underlie this remarkable incidence. DNA methylation, genomic imprinting, and histone modifications are examples of epigenetic factors known to undergo change in the aging and cancerous prostate. In this review we examine the data linking epigenetic alterations in the prostate with aging to cancer development. An online search of current and past peer reviewed literature on epigenetic changes with cancer and aging was performed. Relevant articles were analyzed. Epigenetic changes are responsible for modifying expression of oncogenes and tumor suppressors. Several of these changes may represent a field defect that predisposes to cancer development. Focal hypermethylation occurs at CpG islands in the promoters of certain genes including GSTP1, RARβ2, and RASSF1A with both age and cancer, while global hypomethylation is seen in prostate cancer and known to occur in the colon and other organs. A loss of genomic imprinting is responsible for biallelic expression of the well-known Insulin-like Growth Factor 2 (IGF2) gene. Loss of imprinting (LOI) at IGF2 has been documented in cancer and is also known to occur in benign aging prostate tissue marking the presence of cancer. Histone modifications have the ability to dictate chromatin structure and direct gene expression. Epigenetic changes with aging represent molecular mechanisms to explain the increased susceptibly of the prostate to develop cancer in older men. These changes may provide an opportunity for diagnostic and chemopreventive strategies given the epigenome can be modified. © 2013 Wiley Periodicals, Inc.

  11. Epigenetics, Nervous System Tumors, and Cancer Stem Cells

    International Nuclear Information System (INIS)

    Qureshi, Irfan A.; Mehler, Mark F.

    2011-01-01

    Recent advances have begun to elucidate how epigenetic regulatory mechanisms are responsible for establishing and maintaining cell identity during development and adult life and how the disruption of these processes is, not surprisingly, one of the hallmarks of cancer. In this review, we describe the major epigenetic mechanisms (i.e., DNA methylation, histone and chromatin modification, non-coding RNA deployment, RNA editing, and nuclear reorganization) and discuss the broad spectrum of epigenetic alterations that have been uncovered in pediatric and adult nervous system tumors. We also highlight emerging evidence that suggests epigenetic deregulation is a characteristic feature of so-called cancer stem cells (CSCs), which are thought to be present in a range of nervous system tumors and responsible for tumor maintenance, progression, treatment resistance, and recurrence. We believe that better understanding how epigenetic mechanisms operate in neural cells and identifying the etiologies and consequences of epigenetic deregulation in tumor cells and CSCs, in particular, are likely to promote the development of enhanced molecular diagnostics and more targeted and effective therapeutic agents for treating recalcitrant nervous system tumors

  12. Epigenetics, Nervous System Tumors, and Cancer Stem Cells

    Energy Technology Data Exchange (ETDEWEB)

    Qureshi, Irfan A. [Rosyln and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Mehler, Mark F., E-mail: mark.mehler@einstein.yu.edu [Rosyln and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States); Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, New York, NY 10461 (United States)

    2011-09-13

    Recent advances have begun to elucidate how epigenetic regulatory mechanisms are responsible for establishing and maintaining cell identity during development and adult life and how the disruption of these processes is, not surprisingly, one of the hallmarks of cancer. In this review, we describe the major epigenetic mechanisms (i.e., DNA methylation, histone and chromatin modification, non-coding RNA deployment, RNA editing, and nuclear reorganization) and discuss the broad spectrum of epigenetic alterations that have been uncovered in pediatric and adult nervous system tumors. We also highlight emerging evidence that suggests epigenetic deregulation is a characteristic feature of so-called cancer stem cells (CSCs), which are thought to be present in a range of nervous system tumors and responsible for tumor maintenance, progression, treatment resistance, and recurrence. We believe that better understanding how epigenetic mechanisms operate in neural cells and identifying the etiologies and consequences of epigenetic deregulation in tumor cells and CSCs, in particular, are likely to promote the development of enhanced molecular diagnostics and more targeted and effective therapeutic agents for treating recalcitrant nervous system tumors.

  13. Epigenetic transgenerational inheritance of vinclozolin induced mouse adult onset disease and associated sperm epigenome biomarkers.

    Science.gov (United States)

    Guerrero-Bosagna, Carlos; Covert, Trevor R; Haque, Md M; Settles, Matthew; Nilsson, Eric E; Anway, Matthew D; Skinner, Michael K

    2012-12-01

    The endocrine disruptor vinclozolin has previously been shown to promote epigenetic transgenerational inheritance of adult onset disease in the rat. The current study was designed to investigate the transgenerational actions of vinclozolin on the mouse. Transient exposure of the F0 generation gestating female during gonadal sex determination promoted transgenerational adult onset disease in F3 generation male and female mice, including spermatogenic cell defects, testicular abnormalities, prostate abnormalities, kidney abnormalities and polycystic ovarian disease. Pathology analysis demonstrated 75% of the vinclozolin lineage animals developed disease with 34% having two or more different disease states. Interestingly, the vinclozolin induced transgenerational disease was observed in the outbred CD-1 strain, but not the inbred 129 mouse strain. Analysis of the F3 generation sperm epigenome identified differential DNA methylation regions that can potentially be utilized as epigenetic biomarkers for transgenerational exposure and disease. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. German-Catalan workshop on epigenetics and cancer.

    Science.gov (United States)

    Vizoso, Miguel; Esteller, Manel

    2013-09-01

    In the First German-Catalan Workshop on Epigenetics and Cancer held in Heidelberg, Germany (June 17-19, 2013), cutting-edge laboratories (PEBC, IMPPC, DKFZ, and the Collaborative Research Centre Medical Epigenetics of Freiburg) discussed the latest breakthroughs in the field. The importance of DNA demethylation, non-coding and imprinted genes, metabolic stress, and cell transdifferentiation processes in cancer and non-cancer diseases were addressed in several lectures in a very participative and dynamic atmosphere.   The meeting brought together leading figures in the field of cancer epigenetics to present their research work from the last five years. Experts in different areas of oncology described important advances in colorectal, lung, neuroblastoma, leukemia, and lymphoma cancers. The workshop also provided an interesting forum for pediatrics, and focused on the need to improve the treatment of childhood tumors in order to avoid, as far as possible, brain damage and disruption of activity in areas of high plasticity. From the beginning, the relevance of "omics" and the advances in genome-wide analysis platforms, which allow cancer to be studied in a more comprehensive and inclusive way, was very clear. Modern "omics" offer the possibility of identifying metastases of uncertain origin and establishing epigenetic signatures linked to a specific cluster of patients with a particular prognosis. In this context, invited speakers described novel tumor-associated histone variants and DNA-specific methylation, highlighting their close connection with other processes such as cell-lineage commitment and stemness.

  15. Quantitative imaging as cancer biomarker

    Science.gov (United States)

    Mankoff, David A.

    2015-03-01

    The ability to assay tumor biologic features and the impact of drugs on tumor biology is fundamental to drug development. Advances in our ability to measure genomics, gene expression, protein expression, and cellular biology have led to a host of new targets for anticancer drug therapy. In translating new drugs into clinical trials and clinical practice, these same assays serve to identify patients most likely to benefit from specific anticancer treatments. As cancer therapy becomes more individualized and targeted, there is an increasing need to characterize tumors and identify therapeutic targets to select therapy most likely to be successful in treating the individual patient's cancer. Thus far assays to identify cancer therapeutic targets or anticancer drug pharmacodynamics have been based upon in vitro assay of tissue or blood samples. Advances in molecular imaging, particularly PET, have led to the ability to perform quantitative non-invasive molecular assays. Imaging has traditionally relied on structural and anatomic features to detect cancer and determine its extent. More recently, imaging has expanded to include the ability to image regional biochemistry and molecular biology, often termed molecular imaging. Molecular imaging can be considered an in vivo assay technique, capable of measuring regional tumor biology without perturbing it. This makes molecular imaging a unique tool for cancer drug development, complementary to traditional assay methods, and a potentially powerful method for guiding targeted therapy in clinical trials and clinical practice. The ability to quantify, in absolute measures, regional in vivo biologic parameters strongly supports the use of molecular imaging as a tool to guide therapy. This review summarizes current and future applications of quantitative molecular imaging as a biomarker for cancer therapy, including the use of imaging to (1) identify patients whose tumors express a specific therapeutic target; (2) determine

  16. Imaging biomarker roadmap for cancer studies

    NARCIS (Netherlands)

    O'Connor, James P. B.; Aboagye, Eric O.; Adams, Judith E.; Aerts, Hugo J. W. L.; Barrington, Sally F.; Beer, Ambros J.; Boellaard, Ronald; Bohndiek, Sarah E.; Brady, Michael; Brown, Gina; Buckley, David L.; Chenevert, Thomas L.; Clarke, Laurence P.; Collette, Sandra; Cook, Gary J.; Desouza, Nandita M.; Dickson, John C.; Dive, Caroline; Evelhoch, Jeffrey L.; Faivre-Finn, Corinne; Gallagher, Ferdia A.; Gilbert, Fiona J.; Gillies, Robert J.; Goh, Vicky; Griffiths, J. R.; Groves, Ashley M.; Halligan, Steve; Harris, Adrian L.; Hawkes, David J.; Hoekstra, Otto S.; Huang, Erich P.; Hutton, Brian F.; Jackson, Edward F.; Jayson, Gordon C.; Jones, Andrew; Koh, Dow-Mu; Lacombe, Denis; Lambin, Philippe; Lassau, Nathalie; Leach, Martin O.; Lee, Ting-Yim; Leen, Edward L.; Lewis, Jason S.; Liu, Yan; Lythgoe, Mark F.; Manoharan, Prakash; Maxwell, Ross J.; Miles, Kenneth A.; Morgan, Bruno; Morris, Steve; Ng, Tony; Padhani, Anwar R.; Parker, Geoff J. M.; Partridge, Mike; Pathak, Arvind P.; Peet, Andrew C.; Punwani, Shonit; Reynolds, Andrew R.; Robinson, Simon P.; Shankar, Lalitha K.; Sharma, Ricky A.; Soloviev, Dmitry; Stroobants, Sigrid G.; Sullivan, Daniel C.; Taylor, Stuart A.; Tofts, Paul S.; Tozer, Gillian M.; van Herk, Marcel B.; Walker-Samuel, Simon; Wason, James; Williams, Kaye J.; Workman, Paul; Yankeelov, Thomas E.; Brindle, Kevin M.; McShane, Lisa M.; Jackson, Alan; Waterton, John C.

    Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and

  17. Meeting Report of the Fifth International Cancer Epigenetics Conference in Beijing, China, October 2016.

    Science.gov (United States)

    Gao, Dan; Herman, James G; Cui, Hengmi; Jen, Jin; Fuks, Francois; Brock, Malcolm V; Ushijima, Toshikazu; Croce, Carlo; Akiyama, Yoshimitsu; Guo, Mingzhou

    2017-07-01

    Fifth International Cancer Epigenetics Conference, Beijing, China, 21-23 October 2016 This meeting reported many new findings in the field of cancer epigenetics, including basic science, translational and clinical studies. In this report, we summarize some of the main advancements and prospects in cancer epigenetics presented at this meeting.

  18. Cancer Progenitor Cells: The Result of an Epigenetic Event?

    Science.gov (United States)

    Lapinska, Karolina; Faria, Gabriela; McGonagle, Sandra; Macumber, Kate Morgan; Heerboth, Sarah; Sarkar, Sibaji

    2018-01-01

    The concept of cancer stem cells was proposed in the late 1990s. Although initially the idea seemed controversial, the existence of cancer stem cells is now well established. However, the process leading to the formation of cancer stem cells is still not clear and thus requires further research. This article discusses epigenetic events that possibly produce cancer progenitor cells from predisposed cells by the influence of their environment. Every somatic cell possesses an epigenetic signature in terms of histone modifications and DNA methylation, which are obtained during lineage-specific differentiation of pluripotent stem cells, which is specific to that particular tissue. We call this signature an epigenetic switch. The epigenetic switch is not fixed. Our epigenome alters with aging. However, depending on the predisposition of the cells of a particular tissue and their microenvironment, the balance of the switch (histone modifications and the DNA methylation) may be tilted to immortality in a few cells, which generates cancer progenitor cells. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  19. Other biomarkers for detecting prostate cancer.

    Science.gov (United States)

    Nogueira, Lucas; Corradi, Renato; Eastham, James A

    2010-01-01

    Prostate-specific antigen (PSA) has been used for detecting prostate cancer since 1994. Although it is the best cancer biomarker available, PSA is not perfect. It lacks both the sensitivity and specificity to accurately detect the presence of prostate cancer. None of the PSA thresholds currently in use consistently identify patients with prostate cancer and exclude patients without cancer. Novel approaches to improve our ability to detect prostate cancer and predict the course of the disease are needed. Additional methods for detecting prostate cancer have been evaluated. Despite the discovery of many new biomarkers, only a few have shown some clinical value. These markers include human kallikrein 2, urokinase-type plasminogen activator receptor, prostate-specific membrane antigen, early prostate cancer antigen, PCA3, alpha-methylacyl-CoA racemase and glutathione S-transferase pi hypermethylation. We review the reports on biomarkers for prostate cancer detection, and their possible role in the clinical practice.

  20. Phytochemicals from cruciferous vegetables, epigenetics, and prostate cancer prevention.

    Science.gov (United States)

    W Watson, Gregory; M Beaver, Laura; E Williams, David; H Dashwood, Roderick; Ho, Emily

    2013-10-01

    Epidemiological evidence has demonstrated a reduced risk of prostate cancer associated with cruciferous vegetable intake. Follow-up studies have attributed this protective activity to the metabolic products of glucosinolates, a class of secondary metabolites produced by crucifers. The metabolic products of glucoraphanin and glucobrassicin, sulforaphane, and indole-3-carbinol respectively, have been the subject of intense investigation by cancer researchers. Sulforaphane and indole-3-carbinol inhibit prostate cancer by both blocking initiation and suppressing prostate cancer progression in vitro and in vivo. Research has largely focused on the anti-initiation and cytoprotective effects of sulforaphane and indole-3-carbinol through induction of phases I and II detoxification pathways. With regards to suppressive activity, research has focused on the ability of sulforaphane and indole-3-carbinol to antagonize cell signaling pathways known to be dysregulated in prostate cancer. Recent investigations have characterized the ability of sulforaphane and indole-3-carbinol derivatives to modulate the activity of enzymes controlling the epigenetic status of prostate cancer cells. In this review, we will summarize the well-established, "classic" non-epigenetic targets of sulforaphane and indole-3-carbinol, and highlight more recent evidence supporting these phytochemicals as epigenetic modulators for prostate cancer chemoprevention.

  1. Current and Future Prospects for Epigenetic Biomarkers of Substance Use Disorders

    Directory of Open Access Journals (Sweden)

    Allan M. Andersen

    2015-10-01

    Full Text Available Substance abuse has an enormous impact on economic and quality of life measures throughout the world. In more developed countries, overutilization of the most common forms of substances of abuse, alcohol and tobacco, is addressed primarily through prevention of substance use initiation and secondarily through the treatment of those with substance abuse or dependence. In general, these therapeutic approaches to substance abuse are deemed effective. However, there is a broad consensus that the development of additional tools to aid diagnosis, prioritize treatment selection and monitor treatment response could have substantial impact on the effectiveness of both substance use prevention and treatment. The recent demonstrations by a number of groups that substance use exposure is associated with robust changes in DNA methylation signatures of peripheral blood cells suggests the possibility that methylation assessments of blood or saliva could find broad clinical applications. In this article, we review recent progress in epigenetic approaches to substance use assessment with a particular emphasis on smoking (and alcohol related applications. In addition, we highlight areas, such as the epigenetics of psychostimulant, opioid and cannabis abuse, which are markedly understudied and could benefit from intensified collaborative efforts to define epigenetic biomarkers of abuse and dependence.

  2. Epigenetics modifications and therapeutic prospects in human thyroid cancer

    Directory of Open Access Journals (Sweden)

    Maria Graziella eCatalano

    2012-03-01

    Full Text Available At present no successful treatment is available for advanced thyroid cancer, which comprises poorly differentiated, anaplastic, and metastatic or recurrent differentiated thyroid cancer not responding to radioiodine. In the last few years, biologically targeted therapies for advanced thyroid carcinomas have been proposed on the basis of the recognition of key oncogenic mutations. Although the results of several phase II trials look promising, none of the patients treated had a complete response, and only a minority of them had a partial response, suggesting that the treatment is, at best, effective in stabilizing patients with progressive disease. Epigenetic refers to the study of heritable changes in gene expression that occur without any alteration in the primary DNA sequence. The epigenetic processes establish and maintain the global and local chroma¬tin states that determine gene expression. Epigenetic abnormalities are present in almost all cancers and, together with genetic changes, drive tumour progression. Various genes involved in the control of cell proliferation and invasion (p16INK4A, RASSF1A,PTEN, Rap1GAP, TIMP3, DAPK, RARβ2, E-cadherin, and CITED1 as well as genes specific of thyroid differentiation (Na+/I- symport, TSH receptor, pendrin, SL5A8, and TTF-1 present aberrant methylation in thyroid cancer.This review deals with the most frequent epigenetic alterations in thyroid cancer and focuses on epigenetic therapy, whose goal is to target the chromatin in rapidly dividing tumour cells and potentially restore normal cell functions. Experimental data and clinical trials, especially using deacetylase inhibitors and demethylating agents, are discussed.

  3. How to stomach an epigenetic insult: the gastric cancer epigenome.

    Science.gov (United States)

    Padmanabhan, Nisha; Ushijima, Toshikazu; Tan, Patrick

    2017-08-01

    Gastric cancer is a deadly malignancy afflicting close to a million people worldwide. Patient survival is poor and largely due to late diagnosis and suboptimal therapies. Disease heterogeneity is a substantial obstacle, underscoring the need for precision treatment strategies. Studies have identified different subgroups of gastric cancer displaying not just genetic, but also distinct epigenetic hallmarks. Accumulating evidence suggests that epigenetic abnormalities in gastric cancer are not mere bystander events, but rather promote carcinogenesis through active mechanisms. Epigenetic aberrations, induced by pathogens such as Helicobacter pylori, are an early component of gastric carcinogenesis, probably preceding genetic abnormalities. This Review summarizes our current understanding of the gastric cancer epigenome, highlighting key advances in recent years in both tumours and pre-malignant lesions, made possible through targeted and genome-wide technologies. We focus on studies related to DNA methylation and histone modifications, linking these findings to potential therapeutic opportunities. Lessons learned from the gastric cancer epigenome might also prove relevant for other gastrointestinal cancers.

  4. Acceleration of leukocytes' epigenetic age as an early tumor and sex-specific marker of breast and colorectal cancer.

    Science.gov (United States)

    Durso, Danielle Fernandes; Bacalini, Maria Giulia; Sala, Claudia; Pirazzini, Chiara; Marasco, Elena; Bonafé, Massimiliano; do Valle, Ítalo Faria; Gentilini, Davide; Castellani, Gastone; Faria, Ana Maria Caetano; Franceschi, Claudio; Garagnani, Paolo; Nardini, Christine

    2017-04-04

    Changes in blood epigenetic age have been associated with several pathological conditions and have recently been described to anticipate cancer development. In this work, we analyze a publicly available leukocytes methylation dataset to evaluate the relation between DNA methylation age and the prospective development of specific types of cancer. We calculated DNA methylation age acceleration using five state-of-the-art estimators (three multi-site: Horvath, Hannum, Weidner; and two CpG specific: ELOV2 and FHL2) in a cohort including 845 subjects from the EPIC-Italy project and we compared 424 samples that remained cancer-free over the approximately ten years of follow-up with 235 and 166 subjects who developed breast and colorectal cancer, respectively. We show that the epigenetic age estimated from blood DNA methylation data is statistically significantly associated to future breast and male colorectal cancer development. These results are corroborated by survival analysis that shows significant association between age acceleration and cancer incidence suggesting that the chance of developing age-related diseases may be predicted by circulating epigenetic markers, with a dependence upon tumor type, sex and age estimator. These are encouraging results towards the non-invasive and perspective usage of epigenetic biomarkers.

  5. Replication stress, a source of epigenetic aberrations in cancer?

    DEFF Research Database (Denmark)

    Jasencakova, Zusana; Groth, Anja

    2010-01-01

    . Chromatin organization is transiently disrupted during DNA replication and maintenance of epigenetic information thus relies on faithful restoration of chromatin on the new daughter strands. Acute replication stress challenges proper chromatin restoration by deregulating histone H3 lysine 9 mono......-methylation on new histones and impairing parental histone recycling. This could facilitate stochastic epigenetic silencing by laying down repressive histone marks at sites of fork stalling. Deregulation of replication in response to oncogenes and other tumor-promoting insults is recognized as a significant source...... of genome instability in cancer. We propose that replication stress not only presents a threat to genome stability, but also jeopardizes chromatin integrity and increases epigenetic plasticity during tumorigenesis....

  6. Epigenetic effects of green tea polyphenols in cancer

    Science.gov (United States)

    Henning, Susanne M; Wang, Piwen; Carpenter, Catherine L; Heber, David

    2014-01-01

    Epigenetics describes heritable alterations of gene expression and chromatin organization without changes in DNA sequence. Both hypermethylation and hypomethylation of DNA can affect gene expression and the multistep process of carcinogenesis. Epigenetic changes are reversible and may be targeted by dietary interventions. Bioactive compounds from green tea (GT) such as (–)-epigallocatechin gallate have been shown to alter DNA methyltransferase activity in studies of esophageal, oral, skin, Tregs, lung, breast and prostate cancer cells, which may contribute to the chemopreventive effect of GT. Three out of four mouse model studies have confirmed the inhibitory effect of (–)-epigallocatechin gallate on DNA methylation. A human study demonstrated that decreased methylation of CDX2 and BMP-2 in gastric carcinoma was associated with higher GT consumption. It is the goal of this review to summarize our current knowledge of the potential of GT to alter epigenetic processes, which may be useful in chemoprevention. PMID:24283885

  7. Epigenetic Silencing of the MLH1 Promoter in Relation to the Development of Gastric Cancer and its use as a Biomarker for Patients with Microsatellite Instability: a Systematic Analysis.

    Science.gov (United States)

    Hu, Guimei; Qin, Lijun; Zhang, Xinjun; Ye, Guoliang; Huang, Tao

    2018-01-01

    Human mutL homolog 1 (MLH1) promoter methylation was reported in gastric cancer (GC). This study determined the clinicopathological, prognostic, and diagnostic effects of MLH1 promoter methylation in GC. The combined odds ratio (OR) or hazard ratio (HR) and their corresponding 95% confidence intervals (95% CI) were calculated. The pooled sensitivity, specificity, and area under the curve (AUC) were analyzed. A total of 4654 GC patients and 3669 non-malignant controls were identified in this systematic analysis. MLH1 promoter methylation was significantly higher in GC samples than in gastric adenomas, chronic gastritis, adjacent tissues, normal gastric mucosa, and normal healthy blood samples, but it exhibited a similar frequency in GC vs. intestinal metaplasia and dysplasia samples. MLH1 promoter methylation correlated with age and microsatellite instability (MSI), but it was not associated with gender, H. pylori infection, smoking, drinking behaviors, pathological histology, tumor differentiation, clinical stage, lymph node status, distant metastasis, or overall survival of GC. MLH1 promoter methylation exhibited a poor sensitivity value (MLH1 promoter methylation in GC with MSI vs. GC with microsatellite stability (MSS) samples were 0.64, 0.96, and 0.90, respectively. Our results suggest that the detection of MLH1 promoter methylation may be a potential prognostic biomarker for GC patients with MSI. © 2018 The Author(s). Published by S. Karger AG, Basel.

  8. Epigenetics of prostate cancer and the prospect of identification of novel drug targets by RNAi screening of epigenetic enzymes.

    Science.gov (United States)

    Björkman, Mari; Rantala, Juha; Nees, Matthias; Kallioniemi, Olli

    2010-10-01

    Alterations in epigenetic processes probably underlie most human malignancies. Novel genome-wide techniques, such as chromatin immunoprecipitation and high-throughput sequencing, have become state-of-the-art methods to map the epigenomic landscape of development and disease, such as in cancers. Despite these advances, the functional significance of epigenetic enzymes in cancer progression, such as prostate cancer, remain incompletely understood. A comprehensive mapping and functional understanding of the cancer epigenome will hopefully help to facilitate development of novel cancer therapy targets and improve future diagnostics. The authors have developed a novel cell microarray-based high-content siRNA screening technique suitable to address the putative functional role and impact of all known putative and novel epigenetic enzymes in cancer, including prostate cancer.

  9. Implications of Genetic and Epigenetic Alterations of CDKN2A (p16INK4a in Cancer

    Directory of Open Access Journals (Sweden)

    Ran Zhao

    2016-06-01

    Full Text Available Aberrant gene silencing is highly associated with altered cell cycle regulation during carcinogenesis. In particular, silencing of the CDKN2A tumor suppressor gene, which encodes the p16INK4a protein, has a causal link with several different types of cancers. The p16INK4a protein plays an executional role in cell cycle and senescence through the regulation of the cyclin-dependent kinase (CDK 4/6 and cyclin D complexes. Several genetic and epigenetic aberrations of CDKN2A lead to enhanced tumorigenesis and metastasis with recurrence of cancer and poor prognosis. In these cases, the restoration of genetic and epigenetic reactivation of CDKN2A is a practical approach for the prevention and therapy of cancer. This review highlights the genetic status of CDKN2A as a prognostic and predictive biomarker in various cancers.

  10. Epigenetic Silencing of the MLH1 Promoter in Relation to the Development of Gastric Cancer and its use as a Biomarker for Patients with Microsatellite Instability: a Systematic Analysis

    Directory of Open Access Journals (Sweden)

    Guimei Hu

    2018-01-01

    Full Text Available Background/Aims: Human mutL homolog 1 (MLH1 promoter methylation was reported in gastric cancer (GC. This study determined the clinicopathological, prognostic, and diagnostic effects of MLH1 promoter methylation in GC. Methods: The combined odds ratio (OR or hazard ratio (HR and their corresponding 95% confidence intervals (95% CI were calculated. The pooled sensitivity, specificity, and area under the curve (AUC were analyzed. Results: A total of 4654 GC patients and 3669 non-malignant controls were identified in this systematic analysis. MLH1 promoter methylation was significantly higher in GC samples than in gastric adenomas, chronic gastritis, adjacent tissues, normal gastric mucosa, and normal healthy blood samples, but it exhibited a similar frequency in GC vs. intestinal metaplasia and dysplasia samples. MLH1 promoter methylation correlated with age and microsatellite instability (MSI, but it was not associated with gender, H. pylori infection, smoking, drinking behaviors, pathological histology, tumor differentiation, clinical stage, lymph node status, distant metastasis, or overall survival of GC. MLH1 promoter methylation exhibited a poor sensitivity value (< 0.5 in patients with GC compared with adjacent tissues, gastric adenomas, chronic gastritis, normal gastric mucosa, and normal healthy blood samples. The pooled sensitivity, specificity, and AUC of MLH1 promoter methylation in GC with MSI vs. GC with microsatellite stability (MSS samples were 0.64, 0.96, and 0.90, respectively. Conclusions: Our results suggest that the detection of MLH1 promoter methylation may be a potential prognostic biomarker for GC patients with MSI.

  11. Epigenetic changes of DNA repair genes in cancer.

    Science.gov (United States)

    Lahtz, Christoph; Pfeifer, Gerd P

    2011-02-01

    'Every Hour Hurts, The Last One Kills'. That is an old saying about getting old. Every day, thousands of DNA damaging events take place in each cell of our body, but efficient DNA repair systems have evolved to prevent that. However, our DNA repair system and that of most other organisms are not as perfect as that of Deinococcus radiodurans, for example, which is able to repair massive amounts of DNA damage at one time. In many instances, accumulation of DNA damage has been linked to cancer, and genetic deficiencies in specific DNA repair genes are associated with tumor-prone phenotypes. In addition to mutations, which can be either inherited or somatically acquired, epigenetic silencing of DNA repair genes may promote tumorigenesis. This review will summarize current knowledge of the epigenetic inactivation of different DNA repair components in human cancer.

  12. Novel epigenetic target therapy for prostate cancer: a preclinical study.

    Directory of Open Access Journals (Sweden)

    Ilaria Naldi

    Full Text Available Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine, hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap and hormone refractory (DU145 prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs drug delivery system (DDS carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.

  13. Novel epigenetic target therapy for prostate cancer: a preclinical study.

    Science.gov (United States)

    Naldi, Ilaria; Taranta, Monia; Gherardini, Lisa; Pelosi, Gualtiero; Viglione, Federica; Grimaldi, Settimio; Pani, Luca; Cinti, Caterina

    2014-01-01

    Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.

  14. EpiGeNet: A Graph Database of Interdependencies Between Genetic and Epigenetic Events in Colorectal Cancer.

    Science.gov (United States)

    Balaur, Irina; Saqi, Mansoor; Barat, Ana; Lysenko, Artem; Mazein, Alexander; Rawlings, Christopher J; Ruskin, Heather J; Auffray, Charles

    2017-10-01

    The development of colorectal cancer (CRC)-the third most common cancer type-has been associated with deregulations of cellular mechanisms stimulated by both genetic and epigenetic events. StatEpigen is a manually curated and annotated database, containing information on interdependencies between genetic and epigenetic signals, and specialized currently for CRC research. Although StatEpigen provides a well-developed graphical user interface for information retrieval, advanced queries involving associations between multiple concepts can benefit from more detailed graph representation of the integrated data. This can be achieved by using a graph database (NoSQL) approach. Data were extracted from StatEpigen and imported to our newly developed EpiGeNet, a graph database for storage and querying of conditional relationships between molecular (genetic and epigenetic) events observed at different stages of colorectal oncogenesis. We illustrate the enhanced capability of EpiGeNet for exploration of different queries related to colorectal tumor progression; specifically, we demonstrate the query process for (i) stage-specific molecular events, (ii) most frequently observed genetic and epigenetic interdependencies in colon adenoma, and (iii) paths connecting key genes reported in CRC and associated events. The EpiGeNet framework offers improved capability for management and visualization of data on molecular events specific to CRC initiation and progression.

  15. The role of epigenetics and long noncoding RNA MIAT in neuroendocrine prostate cancer.

    Science.gov (United States)

    Crea, Francesco; Venalainen, Erik; Ci, Xinpei; Cheng, Hongwei; Pikor, Larissa; Parolia, Abhijit; Xue, Hui; Nur Saidy, Nur Ridzwan; Lin, Dong; Lam, Wan; Collins, Colin; Wang, Yuzhuo

    2016-05-01

    Neuroendocrine prostate cancer (NEPC) is the most lethal prostatic neoplasm. NEPC is thought to originate from the transdifferentiation of AR-positive adenocarcinoma cells. We have previously shown that an epigenetic/noncoding interactome (ENI) orchestrates cancer cells' plasticity, thereby allowing the emergence of metastatic, drug-resistant neoplasms. The primary objective of this manuscript is to discuss evidence indicating that some components of the ENI (Polycomb genes, miRNAs) play a key role in NEPC initiation and progression. Long noncoding RNAs represent vast and largely unexplored component of the ENI. Their role in NEPC has not been investigated. We show preliminary evidence indicating that a lncRNA (MIAT) is selectively upregulated in NEPCs and might interact with Polycomb genes. Our results indicate that long noncoding RNAs can be exploited as new biomarkers and therapeutic targets for NEPC.

  16. Biomarkers and Targeted Therapy in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Fataneh Karandish

    2016-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC constitutes 90% of pancreatic cancers. PDAC is a complex and devastating disease with only 1%–3% survival rate in five years after the second stage. Treatment of PDAC is complicated due to the tumor microenvironment, changing cell behaviors to the mesenchymal type, altered drug delivery, and drug resistance. Considering that pancreatic cancer shows early invasion and metastasis, critical research is needed to explore different aspects of the disease, such as elaboration of biomarkers, specific signaling pathways, and gene aberration. In this review, we highlight the biomarkers, the fundamental signaling pathways, and their importance in targeted drug delivery for pancreatic cancers.

  17. Biomarkers and Targeted Therapy in Pancreatic Cancer.

    Science.gov (United States)

    Karandish, Fataneh; Mallik, Sanku

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) constitutes 90% of pancreatic cancers. PDAC is a complex and devastating disease with only 1%-3% survival rate in five years after the second stage. Treatment of PDAC is complicated due to the tumor microenvironment, changing cell behaviors to the mesenchymal type, altered drug delivery, and drug resistance. Considering that pancreatic cancer shows early invasion and metastasis, critical research is needed to explore different aspects of the disease, such as elaboration of biomarkers, specific signaling pathways, and gene aberration. In this review, we highlight the biomarkers, the fundamental signaling pathways, and their importance in targeted drug delivery for pancreatic cancers.

  18. Epigenetics and cancer: implications for drug discovery and safety assessment

    International Nuclear Information System (INIS)

    Moggs, Jonathan G.; Goodman, Jay I.; Trosko, James E.; Roberts, Ruth A.

    2004-01-01

    It is necessary to determine whether chemicals or drugs have the potential to pose a threat to human health. Research conducted over the last two decades has led to the paradigm that chemicals can cause cancer either by damaging DNA or by altering cellular growth, probably via receptor-mediated changes in gene expression. However, recent evidence suggests that gene expression can be altered markedly via several diverse epigenetic mechanisms that can lead to permanent or reversible changes in cellular behavior. Key molecular events underlying these mechanisms include the alteration of DNA methylation and chromatin, and changes in the function of cell surface molecules. Thus, for example, DNA methyltransferase enzymes together with chromatin-associated proteins such as histone modifying enzymes and remodelling factors can modify the genetic code and contribute to the establishment and maintenance of altered epigenetic states. This is relevant to many types of toxicity including but not limited to cancer. In this paper, we describe the potential for interplay between genetic alteration and epigenetic changes in cell growth regulation and discuss the implications for drug discovery and safety assessment

  19. Epigenetic: a molecular link between testicular cancer and environmental exposures?

    Directory of Open Access Journals (Sweden)

    Aurelie eVega

    2012-11-01

    Full Text Available In the last decades, studies in rodents have highlighted links between in utero and/or neonatal exposures to molecules that alter endocrine functions and the development of genital tract abnormalities, such as cryptorchidism, hypospadias, and impaired spermatogenesis. Most of these molecules, called endocrine disrupters (EDs exert estrogenic and/or antiandrogenic activities. These data led to the hypothesis of the Testicular Dysgenesis Syndrome which postulates that these disorders are one clinical entity and are linked by epidemiological and pathophysiological relations. Futhermore, infertility has been stated as a risk factor for testicular cancer. The incidence of testicular cancer has been increasing over the past decades. Most of testicular germ cell cancers develop through a pre-invasive carcinoma in situ (CIS from fetal germ cells (primordial germ cell or gonocyte. During their development, fetal germ cells undergo epigenetic modifications. Interestingly, several lines of evidence have shown that gene regulation through epigenetic mechanisms (DNA and histone modifications plays an important role in normal development as well as in various diseases, including testicular cancer.Here we will review chromatin modifications which can affect testicular physiology leading to the development of testicular cancer; and highlight potential molecular pathways involved in these alterations in the context of environmental exposures.

  20. Genetics, Cytogenetics, and Epigenetics of Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Lucia Migliore

    2011-01-01

    Full Text Available Most of the colorectal cancer (CRC cases are sporadic, only 25% of the patients have a family history of the disease, and major genes causing syndromes predisposing to CRC only account for 5-6% of the total cases. The following subtypes can be recognized: MIN (microsatellite instability, CIN (chromosomal instability, and CIMP (CpG island methylator phenotype. CIN occurs in 80–85% of CRC. Chromosomal instability proceeds through two major mechanisms, missegregation that results in aneuploidy through the gain or loss of whole chromosomes, and unbalanced structural rearrangements that lead to the loss and/or gain of chromosomal regions. The loss of heterozygosity that occur in the first phases of the CRC cancerogenesis (in particular for the genes on 18q as well as the alteration of methylation pattern of multiple key genes can drive the development of colorectal cancer by facilitating the acquisition of multiple tumor-associated mutations and the instability phenotype.

  1. Methylated genes as new cancer biomarkers.

    LENUS (Irish Health Repository)

    Duffy, M J

    2012-02-01

    Aberrant hypermethylation of promoter regions in specific genes is a key event in the formation and progression of cancer. In at least some situations, these aberrant alterations occur early in the formation of malignancy and appear to be tumour specific. Multiple reports have suggested that measurement of the methylation status of the promoter regions of specific genes can aid early detection of cancer, determine prognosis and predict therapy responses. Promising DNA methylation biomarkers include the use of methylated GSTP1 for aiding the early diagnosis of prostate cancer, methylated PITX2 for predicting outcome in lymph node-negative breast cancer patients and methylated MGMT in predicting benefit from alkylating agents in patients with glioblastomas. However, prior to clinical utilisation, these findings require validation in prospective clinical studies. Furthermore, assays for measuring gene methylation need to be standardised, simplified and evaluated in external quality assurance programmes. It is concluded that methylated genes have the potential to provide a new generation of cancer biomarkers.

  2. Exosomal microRNA Biomarkers: Emerging Frontiers in Colorectal and Other Human Cancers

    Science.gov (United States)

    Goel, Ajay; Tovar-Camargo, Oscar A; Toden, Shusuke

    2016-01-01

    Diagnostic strategies, particularly non-invasive blood-based screening approaches, are gaining increased attention for the early detection and attenuation of mortality associated with colorectal cancer (CRC). However, the majority of current screening approaches are inadequate at replacing the conventional CRC diagnostic procedures. Yet, due to technological advances and a better understanding of molecular events underlying human cancer, a new category of biomarkers are on the horizon. Recent evidence indicates that cells release a distinct class of small vesicles called ‘exosomes’, which contain nucleic acids and proteins that reflect and typify host-cell molecular architecture. Intriguingly, exosomes released from cancer cells have a distinct genetic and epigenetic makeup, which allows them to undertake their tumorigenic function. From a clinical standpoint, these unique cancer-specific fingerprints present in exosomes appear to be detectable in a small amount of blood, making them very attractive substrates for developing cancer biomarkers, particularly noninvasive diagnostic approaches. PMID:26892862

  3. CBD: a biomarker database for colorectal cancer.

    Science.gov (United States)

    Zhang, Xueli; Sun, Xiao-Feng; Cao, Yang; Ye, Benchen; Peng, Qiliang; Liu, Xingyun; Shen, Bairong; Zhang, Hong

    2018-01-01

    Colorectal cancer (CRC) biomarker database (CBD) was established based on 870 identified CRC biomarkers and their relevant information from 1115 original articles in PubMed published from 1986 to 2017. In this version of the CBD, CRC biomarker data were collected, sorted, displayed and analysed. The CBD with the credible contents as a powerful and time-saving tool provide more comprehensive and accurate information for further CRC biomarker research. The CBD was constructed under MySQL server. HTML, PHP and JavaScript languages have been used to implement the web interface. The Apache was selected as HTTP server. All of these web operations were implemented under the Windows system. The CBD could provide to users the multiple individual biomarker information and categorized into the biological category, source and application of biomarkers; the experiment methods, results, authors and publication resources; the research region, the average age of cohort, gender, race, the number of tumours, tumour location and stage. We only collect data from the articles with clear and credible results to prove the biomarkers are useful in the diagnosis, treatment or prognosis of CRC. The CBD can also provide a professional platform to researchers who are interested in CRC research to communicate, exchange their research ideas and further design high-quality research in CRC. They can submit their new findings to our database via the submission page and communicate with us in the CBD.Database URL: http://sysbio.suda.edu.cn/CBD/.

  4. Using Aptamers for Cancer Biomarker Discovery

    Directory of Open Access Journals (Sweden)

    Yun Min Chang

    2013-01-01

    Full Text Available Aptamers are single-stranded synthetic DNA- or RNA-based oligonucleotides that fold into various shapes to bind to a specific target, which includes proteins, metals, and molecules. Aptamers have high affinity and high specificity that are comparable to that of antibodies. They are obtained using iterative method, called (Systematic Evolution of Ligands by Exponential Enrichment SELEX and cell-based SELEX (cell-SELEX. Aptamers can be paired with recent advances in nanotechnology, microarray, microfluidics, and other technologies for applications in clinical medicine. One particular area that aptamers can shed a light on is biomarker discovery. Biomarkers are important in diagnosis and treatment of cancer. In this paper, we will describe ways in which aptamers can be used to discover biomarkers for cancer diagnosis and therapeutics.

  5. Potential epigenetic biomarkers of obesity-related insulin resistance in human whole-blood.

    Science.gov (United States)

    Day, Samantha E; Coletta, Richard L; Kim, Joon Young; Garcia, Luis A; Campbell, Latoya E; Benjamin, Tonya R; Roust, Lori R; De Filippis, Elena A; Mandarino, Lawrence J; Coletta, Dawn K

    2017-04-03

    Obesity can increase the risk of complex metabolic diseases, including insulin resistance. Moreover, obesity can be caused by environmental and genetic factors. However, the epigenetic mechanisms of obesity are not well defined. Therefore, the identification of novel epigenetic biomarkers of obesity allows for a more complete understanding of the disease and its underlying insulin resistance. The aim of our study was to identify DNA methylation changes in whole-blood that were strongly associated with obesity and insulin resistance. Whole-blood was obtained from lean (n = 10; BMI = 23.6 ± 0.7 kg/m 2 ) and obese (n = 10; BMI = 34.4 ± 1.3 kg/m 2 ) participants in combination with euglycemic hyperinsulinemic clamps to assess insulin sensitivity. We performed reduced representation bisulfite sequencing on genomic DNA isolated from the blood. We identified 49 differentially methylated cytosines (DMCs; q obese compared with lean participants. We identified 2 sites (Chr.21:46,957,981 and Chr.21:46,957,915) in the 5' untranslated region of solute carrier family 19 member 1 (SLC19A1) with decreased methylation in obese participants (lean 0.73 ± 0.11 vs. obese 0.09 ± 0.05; lean 0.68 ± 0.10 vs. obese 0.09 ± 0.05, respectively). These 2 DMCs identified by obesity were also significantly predicted by insulin sensitivity (r = 0.68, P = 0.003; r = 0.66; P = 0.004). In addition, we performed a differentially methylated region (DMR) analysis and demonstrated a decrease in methylation of Chr.21:46,957,915-46,958,001 in SLC19A1 of -34.9% (70.4% lean vs. 35.5% obese). The decrease in whole-blood SLC19A1 methylation in our obese participants was similar to the change observed in skeletal muscle (Chr.21:46,957,981, lean 0.70 ± 0.09 vs. obese 0.31 ± 0.11 and Chr.21:46,957,915, lean 0.72 ± 0.11 vs. obese 0.31 ± 0.13). Pyrosequencing analysis further demonstrated a decrease in methylation at Chr.21:46,957,915 in both whole-blood (lean 0.71 ± 0.10 vs. obese 0.18 ± 0

  6. Regulation of epigenetic traits of the glutathione S-transferase P1 gene:From detoxification towards cancer prevention and diagnosis

    Directory of Open Access Journals (Sweden)

    Marc eDiederich

    2014-07-01

    Full Text Available Glutathione S-transferases (GSTs are phase II drug detoxifying enzymes that play an essential role in maintenance of cell integrity and protection against DNA damage by catalyzing the conjugation of glutathione to a wide variety of exo- and endogenous electrophilic substrates. GSTP1, the gene encoding the pi­class GST is frequently inactivated by acquired somatic CpG island promoter hypermethylation in multiple cancer subtypes including prostate, breast, liver and blood cancers. Epigenetically mediated GSTP1 silencing is associated with enhanced cancer susceptibility by decreasing its caretaker gene function, which tends to promote neoplastic transformation allowing the cell to acquire additional alterations. Thus, this epigenetic alteration is now considered as a cancer biomarker but could as well play a driving role in multistep cancer development especially well documented in prostate cancer development.The present review discusses application of epigenetic alterations affecting GSTP1 in cancer medicine used alone or in combination with other biomarkers for cancer detection and diagnosis as well as for future targeted preventive and therapeutic interventions including by dietary agents.

  7. Molecular epigenetics in the management of ovarian cancer: Are we investigating a rational clinical promise?

    Directory of Open Access Journals (Sweden)

    Ha eNguyen

    2014-04-01

    Full Text Available Epigenetics is essentially a phenotypical change in gene expression without any alteration of the DNA sequence; the emergence of epigenetics in cancer research and mainstream oncology is fueling new hope. However, it is not yet known whether this knowledge will translate to improved clinical management of ovarian cancer. In this malignancy, women are still undergoing chemotherapy similar to what was approved in 1978, which to this day represents one of the biggest breakthroughs for treating ovarian cancer. While liquid tumors are benefitting from epigenetically-related therapies, solid tumors like ovarian cancer are not (yet?. Herein we will review the science of molecular epigenetics, especially DNA methylation, histone modifications and microRNA, but also include transcription factors since they, too, are important in ovarian cancer. Preclinical and clinical research on the role of epigenetic modifications is summarized as well. Sadly, ovarian cancer remains an idiopathic disease, for the most part, and there are many areas of patient management which could benefit from improved technology. This review will also highlight the evidence suggesting that epigenetics may have preclinical utility in pharmacology and clinical applications for prognosis and diagnosis. Lastly, drugs currently in clinical trials (i.e. histone deacetylase inhibitors are discussed along with the promise for epigenetics in the exploitation of chemoresistance. Whether epigenetics will ultimately be the answer to better management in ovarian cancer is currently unknown; what we have now is hope.

  8. Potential biomarker panels in overall breast cancer management: advancements by multilevel diagnostics.

    Science.gov (United States)

    Girotra, Shantanu; Yeghiazaryan, Kristina; Golubnitschaja, Olga

    2016-09-01

    Breast cancer (BC) prevalence has reached an epidemic scale with half a million deaths annually. Current deficits in BC management include predictive and preventive approaches, optimized screening programs, individualized patient profiling, highly sensitive detection technologies for more precise diagnostics and therapy monitoring, individualized prediction and effective treatment of BC metastatic disease. To advance BC management, paradigm shift from delayed to predictive, preventive and personalized medical services is essential. Corresponding step forwards requires innovative multilevel diagnostics procuring specific panels of validated biomarkers. Here, we discuss current instrumental advancements including genomics, proteomics, epigenetics, miRNA, metabolomics, circulating tumor cells and cancer stem cells with a focus on biomarker discovery and multilevel diagnostic panels. A list of the recommended biomarker candidates is provided.

  9. Epigenetic: a molecular link between testicular cancer and environmental exposures.

    Science.gov (United States)

    Vega, Aurelie; Baptissart, Marine; Caira, Françoise; Brugnon, Florence; Lobaccaro, Jean-Marc A; Volle, David H

    2012-01-01

    In the last decades, studies in rodents have highlighted links between in utero and/or neonatal exposures to molecules that alter endocrine functions and the development of genital tract abnormalities, such as cryptorchidism, hypospadias, and impaired spermatogenesis. Most of these molecules, called endocrine disrupters exert estrogenic and/or antiandrogenic activities. These data led to the hypothesis of the testicular dysgenesis syndrome which postulates that these disorders are one clinical entity and are linked by epidemiological and pathophysiological relations. Furthermore, infertility has been stated as a risk factor for testicular cancer (TC). The incidence of TC has been increasing over the past decade. Most of testicular germ cell cancers develop through a pre-invasive carcinoma in situ from fetal germ cells (primordial germ cell or gonocyte). During their development, fetal germ cells undergo epigenetic modifications. Interestingly, several lines of evidence have shown that gene regulation through epigenetic mechanisms (DNA and histone modifications) plays an important role in normal development as well as in various diseases, including TC. Here we will review chromatin modifications which can affect testicular physiology leading to the development of TC; and highlight potential molecular pathways involved in these alterations in the context of environmental exposures.

  10. New clinical developments in histone deacetylase inhibitors for epigenetic therapy of cancer

    Directory of Open Access Journals (Sweden)

    Ma Yuehua

    2009-06-01

    Full Text Available Abstract DNA methylation and histone acetylation are two well known epigenetic chromatin modifications. Epigenetic agents leading to DNA hypomethylation and histone hyperacetylation have been approved for treatment of hematological disorders. The first histone deacetylase inhibitor, vorinostat, has been licensed for cutaneous T cell lymphoma treatment. More than 11 new epigenetic agents are in various stages of clinical development for therapy of multiple cancer types. In this review we summarize novel histone deacetylase inhibitors and new regimens from clinical trials for epigenetic therapy of cancer.

  11. Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

    Science.gov (United States)

    Suzuki, H; Toyota, M; Caraway, H; Gabrielson, E; Ohmura, T; Fujikane, T; Nishikawa, N; Sogabe, Y; Nojima, M; Sonoda, T; Mori, M; Hirata, K; Imai, K; Shinomura, Y; Baylin, S B; Tokino, T

    2008-01-01

    Although mutation of APC or CTNNB1 (β-catenin) is rare in breast cancer, activation of Wnt signalling is nonetheless thought to play an important role in breast tumorigenesis, and epigenetic silencing of Wnt antagonist genes, including the secreted frizzled-related protein (SFRP) and Dickkopf (DKK) families, has been observed in various tumours. In breast cancer, frequent methylation and silencing of SFRP1 was recently documented; however, altered expression of other Wnt antagonist genes is largely unknown. In the present study, we found frequent methylation of SFRP family genes in breast cancer cell lines (SFRP1, 7 out of 11, 64%; SFRP2, 11 out of 11, 100%; SFRP5, 10 out of 11, 91%) and primary breast tumours (SFRP1, 31 out of 78, 40%; SFRP2, 60 out of 78, 77%; SFRP5, 55 out of 78, 71%). We also observed methylation of DKK1, although less frequently, in cell lines (3 out of 11, 27%) and primary tumours (15 out of 78, 19%). Breast cancer cell lines express various Wnt ligands, and overexpression of SFRPs inhibited cancer cell growth. In addition, overexpression of a β-catenin mutant and depletion of SFRP1 using small interfering RNA synergistically upregulated transcriptional activity of T-cell factor/lymphocyte enhancer factor. Our results confirm the frequent methylation and silencing of Wnt antagonist genes in breast cancer, and suggest that their loss of function contributes to activation of Wnt signalling in breast carcinogenesis. PMID:18283316

  12. Epigenetic regulation of CpG promoter methylation in invasive prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Farrar William L

    2010-10-01

    method we can begin to understand which genes are epigenetically regulated in the invasive population compared to the bulk tumor cells. These aggressive sub-populations of cells may be linked to the cancer stem cell hypothesis, making their patterns of epigenetic regulation very attractive for biomarker analysis.

  13. Molecular alterations and biomarkers in colorectal cancer

    Science.gov (United States)

    Grady, William M.; Pritchard, Colin C.

    2013-01-01

    The promise of precision medicine is now a clinical reality. Advances in our understanding of the molecular genetics of colorectal cancer genetics is leading to the development of a variety of biomarkers that are being used as early detection markers, prognostic markers, and markers for predicting treatment responses. This is no more evident than in the recent advances in testing colorectal cancers for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor (EGFR). In this review, we update a prior review published in 2010 and describe our current understanding of the molecular pathogenesis of colorectal cancer and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers), and the prediction of treatment responses (predictive markers). PMID:24178577

  14. Role of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer development.

    Directory of Open Access Journals (Sweden)

    Allison Jones

    2013-11-01

    Full Text Available Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development.Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64 and control samples (n = 23 revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A. Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop

  15. Exosome: emerging biomarker in breast cancer

    Science.gov (United States)

    Jia, Yunlu; Chen, Yongxia; Wang, Qinchuan; Jayasinghe, Ushani; Luo, Xiao; Wei, Qun; Wang, Ji; Xiong, Hanchu; Chen, Cong; Xu, Bin; Hu, Wenxian; Wang, Linbo; Zhao, Wenhe; Zhou, Jichun

    2017-01-01

    Exosomes are nano-sized membrane vesicles released by a variety of cell types, and are thought to play important roles in intercellular communications. In breast cancer, through horizontal transfer of various bioactive molecules, such as proteins and mRNAs, exosomes are emerging as local and systemic cell-to-cell mediators of oncogenic information and play an important role on cancer progression. This review outlines the current knowledge and concepts concerning the exosomes involvement in breast cancer pathogenesis (including tumor initiation, invasion and metastasis, angiogenesis, immune system modulation and tumor microenvironment) and cancer therapy resistance. Moreover, the potential use of exosomes as promising diagnostic and therapeutic biomarkers in breast cancer are also discussed. PMID:28402944

  16. dbEM: A database of epigenetic modifiers curated from cancerous and normal genomes

    Science.gov (United States)

    Singh Nanda, Jagpreet; Kumar, Rahul; Raghava, Gajendra P. S.

    2016-01-01

    We have developed a database called dbEM (database of Epigenetic Modifiers) to maintain the genomic information of about 167 epigenetic modifiers/proteins, which are considered as potential cancer targets. In dbEM, modifiers are classified on functional basis and comprise of 48 histone methyl transferases, 33 chromatin remodelers and 31 histone demethylases. dbEM maintains the genomic information like mutations, copy number variation and gene expression in thousands of tumor samples, cancer cell lines and healthy samples. This information is obtained from public resources viz. COSMIC, CCLE and 1000-genome project. Gene essentiality data retrieved from COLT database further highlights the importance of various epigenetic proteins for cancer survival. We have also reported the sequence profiles, tertiary structures and post-translational modifications of these epigenetic proteins in cancer. It also contains information of 54 drug molecules against different epigenetic proteins. A wide range of tools have been integrated in dbEM e.g. Search, BLAST, Alignment and Profile based prediction. In our analysis, we found that epigenetic proteins DNMT3A, HDAC2, KDM6A, and TET2 are highly mutated in variety of cancers. We are confident that dbEM will be very useful in cancer research particularly in the field of epigenetic proteins based cancer therapeutics. This database is available for public at URL: http://crdd.osdd.net/raghava/dbem.

  17. Gene expression and epigenetic discovery screen reveal methylation of SFRP2 in prostate cancer.

    LENUS (Irish Health Repository)

    Perry, Antoinette S

    2013-04-15

    Aberrant activation of Wnts is common in human cancers, including prostate. Hypermethylation associated transcriptional silencing of Wnt antagonist genes SFRPs (Secreted Frizzled-Related Proteins) is a frequent oncogenic event. The significance of this is not known in prostate cancer. The objectives of our study were to (i) profile Wnt signaling related gene expression and (ii) investigate methylation of Wnt antagonist genes in prostate cancer. Using TaqMan Low Density Arrays, we identified 15 Wnt signaling related genes with significantly altered expression in prostate cancer; the majority of which were upregulated in tumors. Notably, histologically benign tissue from men with prostate cancer appeared more similar to tumor (r = 0.76) than to benign prostatic hyperplasia (BPH; r = 0.57, p < 0.001). Overall, the expression profile was highly similar between tumors of high (≥ 7) and low (≤ 6) Gleason scores. Pharmacological demethylation of PC-3 cells with 5-Aza-CdR reactivated 39 genes (≥ 2-fold); 40% of which inhibit Wnt signaling. Methylation frequencies in prostate cancer were 10% (2\\/20) (SFRP1), 64.86% (48\\/74) (SFRP2), 0% (0\\/20) (SFRP4) and 60% (12\\/20) (SFRP5). SFRP2 methylation was detected at significantly lower frequencies in high-grade prostatic intraepithelial neoplasia (HGPIN; 30%, (6\\/20), p = 0.0096), tumor adjacent benign areas (8.82%, (7\\/69), p < 0.0001) and BPH (11.43% (4\\/35), p < 0.0001). The quantitative level of SFRP2 methylation (normalized index of methylation) was also significantly higher in tumors (116) than in the other samples (HGPIN = 7.45, HB = 0.47, and BPH = 0.12). We show that SFRP2 hypermethylation is a common event in prostate cancer. SFRP2 methylation in combination with other epigenetic markers may be a useful biomarker of prostate cancer.

  18. HPV epigenetic mechanisms related to Oropharyngeal and Cervix cancers.

    Science.gov (United States)

    Di Domenico, Marina; Giovane, Giancarlo; Kouidhi, Soumaya; Iorio, Rosamaria; Romano, Maurizio; De Francesco, Francesco; Feola, Antonia; Siciliano, Camilla; Califano, Luigi; Giordano, Antonio

    2017-03-31

    Human Papilloma Virus infection is very frequent in humans and is mainly transmitted sexually. The majority of infections are transient and asymptomatic, however, if the infection persists, it can occur with a variety of injuries to skin and mucous membranes, depending on the type of HPV involved. Some types of HPV are classified as high oncogenic risk as associated with the onset of cancer. The tumors most commonly associated with HPV are cervical and oropharyngeal cancer, epigenetic mechanisms related to HPV infection include methylation changes to host and viral DNA and chromatin modification in host species. This review is focused about epigenethic mechanism, such as MiRNAs expression, related to cervix and oral cancer. Specifically it discuss about molecular markers associated to a more aggressive phenotype. In this way we will analyze genes involved in meiotic sinaptonemal complex, transcriptional factors, of orthokeratins, sinaptogirin, they are all expressed in cancer in a way not more dependent on cell differentiation but HPV-dependent.

  19. Cancer biomarker discovery: the entropic hallmark.

    Science.gov (United States)

    Berretta, Regina; Moscato, Pablo

    2010-08-18

    It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles

  20. Epigenetic regulation leading to induced pluripotency drives cancer development in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Ohnishi, Kotaro [Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507 (Japan); Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194 (Japan); Semi, Katsunori [Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507 (Japan); Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507 (Japan); Yamada, Yasuhiro, E-mail: y-yamada@cira.kyoto-u.ac.jp [Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507 (Japan); Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507 (Japan)

    2014-12-05

    Highlights: • Epigenetic regulation of failed reprogramming-associated cancer cells is discussed. • Similarity between pediatric cancer and reprogramming-associated cancer is discussed. • Concept for epigenetic cancer is discussed. - Abstract: Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by the transient expression of reprogramming factors. During the reprogramming process, somatic cells acquire the ability to undergo unlimited proliferation, which is also an important characteristic of cancer cells, while their underlying DNA sequence remains unchanged. Based on the characteristics shared between pluripotent stem cells and cancer cells, the potential involvement of the factors leading to reprogramming toward pluripotency in cancer development has been discussed. Recent in vivo reprogramming studies provided some clues to understanding the role of reprogramming-related epigenetic regulation in cancer development. It was shown that premature termination of the in vivo reprogramming result in the development of tumors that resemble pediatric cancers. Given that epigenetic modifications play a central role during reprogramming, failed reprogramming-associated cancer development may have provided a proof of concept for epigenetics-driven cancer development in vivo.

  1. Epigenetic regulation leading to induced pluripotency drives cancer development in vivo

    International Nuclear Information System (INIS)

    Ohnishi, Kotaro; Semi, Katsunori; Yamada, Yasuhiro

    2014-01-01

    Highlights: • Epigenetic regulation of failed reprogramming-associated cancer cells is discussed. • Similarity between pediatric cancer and reprogramming-associated cancer is discussed. • Concept for epigenetic cancer is discussed. - Abstract: Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by the transient expression of reprogramming factors. During the reprogramming process, somatic cells acquire the ability to undergo unlimited proliferation, which is also an important characteristic of cancer cells, while their underlying DNA sequence remains unchanged. Based on the characteristics shared between pluripotent stem cells and cancer cells, the potential involvement of the factors leading to reprogramming toward pluripotency in cancer development has been discussed. Recent in vivo reprogramming studies provided some clues to understanding the role of reprogramming-related epigenetic regulation in cancer development. It was shown that premature termination of the in vivo reprogramming result in the development of tumors that resemble pediatric cancers. Given that epigenetic modifications play a central role during reprogramming, failed reprogramming-associated cancer development may have provided a proof of concept for epigenetics-driven cancer development in vivo

  2. Epigenetics of Estrogen Receptor Signaling: Role in Hormonal Cancer Progression and Therapy

    International Nuclear Information System (INIS)

    Mann, Monica; Cortez, Valerie; Vadlamudi, Ratna K.

    2011-01-01

    Estrogen receptor (ERα) signaling plays a key role in hormonal cancer progression. ERα is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERα signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERα target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERα -mediated epigenetic pathway could play a vital role in ERα driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERα driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERα signaling potentiates epigenetic changes in cancer cells via histone modifications

  3. Epigenetics of Estrogen Receptor Signaling: Role in Hormonal Cancer Progression and Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Mann, Monica; Cortez, Valerie [Department of Cellular and Structural Biology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229 (United States); Vadlamudi, Ratna K., E-mail: vadlamudi@uthscsa.edu [Department of Obstetrics and Gynecology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229 (United States)

    2011-03-29

    Estrogen receptor (ERα) signaling plays a key role in hormonal cancer progression. ERα is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERα signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERα target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERα -mediated epigenetic pathway could play a vital role in ERα driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERα driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERα signaling potentiates epigenetic changes in cancer cells via histone modifications.

  4. The physics of cancer: The role of epigenetics and chromosome conformation in cancer progression

    Energy Technology Data Exchange (ETDEWEB)

    Naimark, Oleg B.; Nikitiuk, Aleksandr S. [Institute of Continuous Media Mechanics UrB RAS, Perm, 614013 (Russian Federation); Baudement, Marie-Odile; Forné, Thierry [Institut de Génétique Moléculaire de Montpellier UMR 5535, CNRS, Université de Montpellier, 1919 route de Mende, Montpellier cedex 5, 34293 France (France); Lesne, Annick, E-mail: annick.lesne@igmm.cnrs.fr [Institut de Génétique Moléculaire de Montpellier UMR 5535, CNRS, Université de Montpellier, 1919 route de Mende, Montpellier cedex 5, 34293 France (France); Laboratoire de Physique Théorique de la Matière Condensée UMR 7600, CNRS, UPMC, Sorbonne Universités, 4 place Jussieu, Paris cedex 5, 75252 France (France)

    2016-08-02

    Cancer progression is generally described in terms of accumulated genetic alterations and ensuing changes in cell properties. However, intermediary modifications are involved in the establishment of cancer cell phenotypes, at different levels of nuclear organization: DNA damages and their structural consequences, epigenetic modifications and their impact on chromatin architecture, changes in chromosome 3D organization. We review some of these alterations with a focus on their physical aspects. The challenge is to understand the multiscale interplay between generic physical mechanisms and specific biological factors in cancer cells. We argue that such an interdisciplinary perspective offers a novel viewpoint on cancer progression, early diagnosis and possibly therapeutic targets.

  5. New serum biomarkers for prostate cancer diagnosis

    Science.gov (United States)

    Chadha, Kailash C.; Miller, Austin; Nair, Bindukumar B.; Schwartz, Stanley A.; Trump, Donald L.; Underwood, Willie

    2014-01-01

    Background Prostate-specific antigen (PSA) is currently used as a biomarker for diagnosis and management of prostate cancer (CaP). However, PSA typically lacks the sensitivity and specificity desired of a diagnostic marker. Objective The goal of this study was to identify an additional biomarker or a panel of biomarkers that is more sensitive and specific than PSA in differentiating benign versus malignant prostate disease and/or localized CaP versus metastatic CaP. Methods Concurrent measurements of circulating interleukin-8 (IL-8), Tumor necrosis factor-α (TNF-α) and soluble tumor necrosis factor-α receptors 1 (sTNFR1) were obtained from four groups of men: (1) Controls (2) with elevated prostate-specific antigen with a negative prostate biopsy (elPSA_negBx) (3) with clinically localized CaP and (4) with castration resistant prostate cancer. Results TNF-α Area under the receiver operating characteristic curve (AUC = 0.93) and sTNFR1 (AUC = 0.97) were strong predictors of elPSA_negBx (vs. CaP). The best predictor of elPSA_negBx vs CaP was sTNFR1 and IL-8 combined (AUC = 0.997). The strongest single predictors of localized versus metastatic CaP were TNF-α (AUC = 0.992) and PSA (AUC = 0.963) levels. Conclusions The specificity and sensitivity of a PSA-based CaP diagnosis can be significantly enhanced by concurrent serum measurements of IL-8, TNF-α and sTNFR1. In view of the concerns about the ability of PSA to distinguish clinically relevant CaP from indolent disease, assessment of these biomarkers in the larger cohort is warranted. PMID:25593898

  6. Phase II cancer clinical trials for biomarker-guided treatments.

    Science.gov (United States)

    Jung, Sin-Ho

    2018-01-01

    The design and analysis of cancer clinical trials with biomarker depend on various factors, such as the phase of trials, the type of biomarker, whether the used biomarker is validated or not, and the study objectives. In this article, we demonstrate the design and analysis of two Phase II cancer clinical trials, one with a predictive biomarker and the other with an imaging prognostic biomarker. Statistical testing methods and their sample size calculation methods are presented for each trial. We assume that the primary endpoint of these trials is a time to event variable, but this concept can be used for any type of endpoint.

  7. Glycosylation-Based Serum Biomarkers for Cancer Diagnostics and Prognostics.

    Science.gov (United States)

    Kirwan, Alan; Utratna, Marta; O'Dwyer, Michael E; Joshi, Lokesh; Kilcoyne, Michelle

    2015-01-01

    Cancer is the second most common cause of death in developed countries with approximately 14 million newly diagnosed individuals and over 6 million cancer-related deaths in 2012. Many cancers are discovered at a more advanced stage but better survival rates are correlated with earlier detection. Current clinically approved cancer biomarkers are most effective when applied to patients with widespread cancer. Single biomarkers with satisfactory sensitivity and specificity have not been identified for the most common cancers and some biomarkers are ineffective for the detection of early stage cancers. Thus, novel biomarkers with better diagnostic and prognostic performance are required. Aberrant protein glycosylation is well known hallmark of cancer and represents a promising source of potential biomarkers. Glycoproteins enter circulation from tissues or blood cells through active secretion or leakage and patient serum is an attractive option as a source for biomarkers from a clinical and diagnostic perspective. A plethora of technical approaches have been developed to address the challenges of glycosylation structure detection and determination. This review summarises currently utilised glycoprotein biomarkers and novel glycosylation-based biomarkers from the serum glycoproteome under investigation as cancer diagnostics and for monitoring and prognostics and includes details of recent high throughput and other emerging glycoanalytical techniques.

  8. Renal Cancer Biomarkers | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    The National Cancer Institute's Laboratory of Proteomics and Analytical Technologies is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize diagnostic, therapeutic and prognostic cancer biomarkers from clinical specimens.

  9. Epigenetics in radiotherapy: Where are we heading?

    International Nuclear Information System (INIS)

    Smits, Kim M.; Melotte, Veerle; Niessen, Hanneke E.C.; Dubois, Ludwig; Oberije, Cary; Troost, Esther G.C.; Starmans, Maud H.W.; Boutros, Paul C.; Vooijs, Marc; Engeland, Manon van; Lambin, Philippe

    2014-01-01

    Radiotherapy is an important component of anti-cancer treatment. However, not all cancer patients respond to radiotherapy, and with current knowledge clinicians are unable to predict which patients are at high risk of recurrence after radiotherapy. There is therefore an urgent need for biomarkers to guide clinical decision-making. Although the importance of epigenetic alterations is widely accepted, their application as biomarkers in radiotherapy has not been studied extensively. In addition, it has been suggested that radiotherapy itself introduces epigenetic alterations. As epigenetic alterations can potentially be reversed by drug treatment, they are interesting candidate targets for anticancer therapy or radiotherapy sensitizers. The application of demethylating drugs or histone deacetylase inhibitors to sensitize patients for radiotherapy has been studied in vitro, in vivo as well as in clinical trials with promising results. This review describes the current knowledge on epigenetics in radiotherapy

  10. Methylated genes as new cancer biomarkers

    DEFF Research Database (Denmark)

    Brunner, Nils; Duffy, M.J; Napieralski, R.

    2009-01-01

    Aberrant hypermethylation of promoter regions in specific genes is a key event in the formation and progression of cancer. In at least some situations, these aberrant alterations occur early in the formation of malignancy and appear to be tumour specific. Multiple reports have suggested that meas......Aberrant hypermethylation of promoter regions in specific genes is a key event in the formation and progression of cancer. In at least some situations, these aberrant alterations occur early in the formation of malignancy and appear to be tumour specific. Multiple reports have suggested...... that measurement of the methylation status of the promoter regions of specific genes can aid early detection of cancer, determine prognosis and predict therapy responses. Promising DNA methylation biomarkers include the use of methylated GSTP1 for aiding the early diagnosis of prostate cancer, methylated PITX2...... for predicting outcome in lymph node-negative breast cancer patients and methylated MGMT in predicting benefit from alkylating agents in patients with glioblastomas. However, prior to clinical utilisation, these findings require validation in prospective clinical studies. Furthermore, assays for measuring gene...

  11. Distinct epigenetic signatures elucidate enhancer-gene relationships that delineate CIMP and non-CIMP colorectal cancers.

    Science.gov (United States)

    Chong, Allen; Teo, Jing Xian; Ban, Kenneth H K

    2016-05-10

    Epigenetic changes, like DNA methylation, affect gene expression and in colorectal cancer (CRC), a distinct phenotype called the CpG island methylator phenotype ("CIMP") has significantly higher levels of DNA methylation at so-called "Type C loci" within the genome. We postulate that enhancer-gene pairs are coordinately controlled through DNA methylation in order to regulate the expression of key genes/biomarkers for a particular phenotype.Firstly, we found 24 experimentally-validated enhancers (VISTA enhancer browser) that contained statistically significant (FDR-adjusted q-value of CIMP versus non-CIMP CRCs. Of these, the methylation of 2 enhancers, 1702 and 1944, were found to be very well correlated with the methylation of the genes Wnt3A and IGDCC3, respectively, in two separate and independent datasets.We show for the first time that there are indeed distinct and dynamic changes in the methylation pattern of specific enhancer-gene pairs in CRCs. Such a coordinated epigenetic event could be indicative of an interaction between (1) enhancer 1702 and Wnt3A and (2) enhancer 1944 and IGDCC3. Moreover, our study shows that the methylation patterns of these 2 enhancer-gene pairs can potentially be used as biomarkers to delineate CIMP from non-CIMP CRCs.

  12. Cancer Biomarker Discovery: Lectin-Based Strategies Targeting Glycoproteins

    Directory of Open Access Journals (Sweden)

    David Clark

    2012-01-01

    Full Text Available Biomarker discovery can identify molecular markers in various cancers that can be used for detection, screening, diagnosis, and monitoring of disease progression. Lectin-affinity is a technique that can be used for the enrichment of glycoproteins from a complex sample, facilitating the discovery of novel cancer biomarkers associated with a disease state.

  13. Dying to Be Noticed: Epigenetic Regulation of Immunogenic Cell Death for Cancer Immunotherapy

    Directory of Open Access Journals (Sweden)

    Brianne Cruickshank

    2018-04-01

    Full Text Available Immunogenic cell death (ICD activates both innate and adaptive arms of the immune system during apoptotic cancer cell death. With respect to cancer immunotherapy, the process of ICD elicits enhanced adjuvanticity and antigenicity from dying cancer cells and consequently, promotes the development of clinically desired antitumor immunity. Cancer ICD requires the presentation of various “hallmarks” of immunomodulation, which include the cell-surface translocation of calreticulin, production of type I interferons, and release of high-mobility group box-1 and ATP, which through their compatible actions induce an immune response against cancer cells. Interestingly, recent reports investigating the use of epigenetic modifying drugs as anticancer therapeutics have identified several connections to ICD hallmarks. Epigenetic modifiers have a direct effect on cell viability and appear to fundamentally change the immunogenic properties of cancer cells, by actively subverting tumor microenvironment-associated immunoevasion and aiding in the development of an antitumor immune response. In this review, we critically discuss the current evidence that identifies direct links between epigenetic modifications and ICD hallmarks, and put forward an otherwise poorly understood role for epigenetic drugs as ICD inducers. We further discuss potential therapeutic innovations that aim to induce ICD during epigenetic drug therapy, generating highly efficacious cancer immunotherapies.

  14. Emerging Concepts and Methodologies in Cancer Biomarker Discovery.

    Science.gov (United States)

    Lu, Meixia; Zhang, Jinxiang; Zhang, Lanjing

    2017-01-01

    Cancer biomarker discovery is a critical part of cancer prevention and treatment. Despite the decades of effort, only a small number of cancer biomarkers have been identified for and validated in clinical settings. Conceptual and methodological breakthroughs may help accelerate the discovery of additional cancer biomarkers, particularly their use for diagnostics. In this review, we have attempted to review the emerging concepts in cancer biomarker discovery, including real-world evidence, open access data, and data paucity in rare or uncommon cancers. We have also summarized the recent methodological progress in cancer biomarker discovery, such as high-throughput sequencing, liquid biopsy, big data, artificial intelligence (AI), and deep learning and neural networks. Much attention has been given to the methodological details and comparison of the methodologies. Notably, these concepts and methodologies interact with each other and will likely lead to synergistic effects when carefully combined. Newer, more innovative concepts and methodologies are emerging as the current emerging ones became mainstream and widely applied to the field. Some future challenges are also discussed. This review contributes to the development of future theoretical frameworks and technologies in cancer biomarker discovery and will contribute to the discovery of more useful cancer biomarkers.

  15. Identification of cancer protein biomarkers using proteomic techniques

    Energy Technology Data Exchange (ETDEWEB)

    Mor, Gil G.; Ward, David C.; Bray-Ward, Patricia

    2016-10-18

    The claimed invention describes methods to diagnose or aid in the diagnosis of cancer. The claimed methods are based on the identification of biomarkers which are particularly well suited to discriminate between cancer subjects and healthy subjects. These biomarkers were identified using a unique and novel screening method described herein. The biomarkers identified herein can also be used in the prognosis and monitoring of cancer. The invention comprises the use of leptin, prolactin, OPN and IGF-II for diagnosing, prognosis and monitoring of ovarian cancer.

  16. Exploring epigenetic regulation of fear memory and biomarkers associated with Post-traumatic stress disorder

    Directory of Open Access Journals (Sweden)

    Stephanie A. Maddox

    2013-07-01

    Full Text Available This review examines recent work on epigenetic mechanisms underlying animal models of fear learning as well as its translational implications in disorders of fear regulation, such as Posttraumatic Stress Disorder (PTSD. Specifically, we will examine work outlining roles of differential histone acetylation and DNA methylation associated with consolidation, reconsolidation and extinction in Pavlovian fear paradigms. We then focus on the numerous studies examining the epigenetic modifications of the Brain-derived neurotrophin factor (BDNF pathway and the extension of these findings from animal models to recent work in human clinical populations. We will also review recently published data on FKBP5 regulation of glucocorticoid receptor function, and how this is modulated in animal models of PTSD and in human clinical populations via epigenetic mechanisms. As glucocorticoid regulation of memory consolidation is well established in fear models, we examine how these recent data contribute to our broader understanding of fear memory formation. The combined recent progress in epigenetic modulation of memory with the advances in fear neurobiology suggest that this area may be critical to progress in our understanding of fear-related disorders with implications for new approaches to treatment and prevention.

  17. The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer

    OpenAIRE

    Chaligné, Ronan; Popova, Tatiana; Mendoza-Parra, Marco-Antonio; Saleem, Mohamed-Ashick M.; Gentien, David; Ban, Kristen; Piolot, Tristan; Leroy, Olivier; Mariani, Odette; Gronemeyer, Hinrich; Vincent-Salomon, Anne; Stern, Marc-Henri; Heard, Edith

    2015-01-01

    Disappearance of the Barr body is considered a hallmark of cancer, although whether this corresponds to genetic loss or to epigenetic instability and transcriptional reactivation is unclear. Here we show that breast tumors and cell lines frequently display major epigenetic instability of the inactive X chromosome, with highly abnormal 3D nuclear organization and global perturbations of heterochromatin, including gain of euchromatic marks and aberrant distributions of repressive marks such as ...

  18. New insights in oncology: Epi-genetics and cancer stem cells

    International Nuclear Information System (INIS)

    Krutovskikh, V.; Partensky, C.

    2011-01-01

    Cancer is a multi-etiologic, multistage disease with a prevalent genetic component, which happens when a large number of genes, critical for cell growth, death, differentiation, migration, and metabolic plasticity are altered irreversibly, so as to either 'gain' (oncogenes) or 'lose' (tumour suppressors) their function. Recent discoveries have revealed the previously underestimated etiologic importance of multiple epigenetic, that is to say, reversible factors (histone modifications, DNA methylation, non-coding RNA) involved in the transcriptional and post-transcriptional regulation of proteins, indispensable for the control of cancerous phenotype. Stable alterations of epigenetic machinery ('epi-mutations') turn out to play a critical role at different steps of carcinogenesis. In addition, due to substantial recent progress in stem cell biology, the new concept of cancer stem cells has emerged. This, along with newly discovered epigenetic cancer mechanisms, gives rise to a hope to overcome radio- and chemo-resistance and to eradicate otherwise incurable neoplasms. (authors)

  19. Epigenetic Regulation by Sulforaphane: Opportunities for Breast and Prostate Cancer Chemoprevention.

    Science.gov (United States)

    Atwell, Lauren L; Beaver, Laura M; Shannon, Jackilen; Williams, David E; Dashwood, Roderick H; Ho, Emily

    2015-04-01

    Sulforaphane (SFN) is a phytochemical derived from cruciferous vegetables that has multiple molecular targets and anti-cancer properties. Researchers have demonstrated several chemopreventive benefits of SFN consumption, such as reductions in tumor growth, increases in cancer cell apoptosis, and disruption of signaling within tumor microenvironments both in vitro and in vivo . Emerging evidence indicates that SFN exerts several of its chemopreventive effects by altering epigenetic mechanisms. This review summarizes evidence of the impact of SFN on epigenetic events and how they relate to the chemopreventive effects of SFN observed in preclinical and clinical studies of breast and prostate cancers. Specific areas of focus include the role of SFN in the regulation of cell cycle, apoptosis, inflammation, antioxidant defense, and cancer cell signaling and their relationships to epigenetic mechanisms. Finally, remaining challenges and research needs for translating mechanistic work with SFN into human studies and clinical intervention trials are discussed.

  20. Targeting epigenetics for the treatment of prostate cancer: recent progress and future directions.

    Science.gov (United States)

    Lin, Jianqing; Wang, Chenguang; Kelly, Wm Kevin

    2013-06-01

    Epigenetic aberrations contribute to prostate cancer carcinogenesis and disease progression. Efforts have been made to target DNA methyltransferase and histone deacetylases (HDACs) in prostate cancer and other solid tumors but have not had the success that was seen in the hematologic malignancies. Oral, less toxic, and more specific agents are being developed in solid tumors including prostate cancer. Combinations of epigenetic agents alone or with a targeted agent such as androgen receptor signaling inhibitors are promising approaches and will be discussed further. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Biomarker assessment and molecular testing for prognostication in breast cancer.

    Science.gov (United States)

    Kos, Zuzana; Dabbs, David J

    2016-01-01

    Current treatment of breast cancer incorporates clinical, pathological and molecular data. Oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) define prognosis and identify tumours for targeted therapy, and remain the sole established single-molecule biomarkers defining the minimum breast cancer pathology data set. Ki67 remains one of the most promising yet controversial biomarkers in breast cancer, implemented routinely in some, but not all, pathology departments. Beyond the single-molecule biomarkers, a host of multigene expression tests have been developed to interrogate the driver pathways and biology of individual breast cancers to predict clinical outcome more accurately. A minority of these assays have entered into clinical practice. This review focuses on the established biomarkers of ER, PR and HER2, the controversial but clinically implemented biomarker Ki67 and the currently marketed gene expression signatures. © 2015 John Wiley & Sons Ltd.

  2. Association of Smoking, Alcohol Use, and Betel Quid Chewing with Epigenetic Aberrations in Cancers.

    Science.gov (United States)

    Wang, Tong-Hong; Hsia, Shih-Min; Shih, Yin-Hwa; Shieh, Tzong-Ming

    2017-06-06

    Numerous environmental factors such as diet, alcohol use, stress, and environmental chemicals are known to elicit epigenetic changes, leading to increased rates of cancers and other diseases. The incidence of head and neck cancer, one of the most common cancers in Taiwanese males, is increasing: oral cancer and nasopharyngeal carcinoma are ranked fourth and tenth respectively, among the top ten cancers in this group, and a major cause of cancer-related deaths in Taiwanese males. Previous studies have identified smoking, alcohol use, and betel quid chewing as the three major causes of head and neck cancers; these three social habits are commonly observed in Taiwanese males, resulting in an increasing morbidity rate of head and neck cancers in this population. In this literature review, we discuss the association between specific components of betel quid, alcohol, and tobacco, and the occurrence of head and neck cancers, lung cancer, gastrointestinal cancers, and urethral cancer. We focus on regulatory mechanisms at the epigenetic level and their oncogenic effects. The review further discusses the application of FDA-approved epigenetic drugs as therapeutic strategies against cancer.

  3. Association of Smoking, Alcohol Use, and Betel Quid Chewing with Epigenetic Aberrations in Cancers

    Directory of Open Access Journals (Sweden)

    Tong-Hong Wang

    2017-06-01

    Full Text Available Numerous environmental factors such as diet, alcohol use, stress, and environmental chemicals are known to elicit epigenetic changes, leading to increased rates of cancers and other diseases. The incidence of head and neck cancer, one of the most common cancers in Taiwanese males, is increasing: oral cancer and nasopharyngeal carcinoma are ranked fourth and tenth respectively, among the top ten cancers in this group, and a major cause of cancer-related deaths in Taiwanese males. Previous studies have identified smoking, alcohol use, and betel quid chewing as the three major causes of head and neck cancers; these three social habits are commonly observed in Taiwanese males, resulting in an increasing morbidity rate of head and neck cancers in this population. In this literature review, we discuss the association between specific components of betel quid, alcohol, and tobacco, and the occurrence of head and neck cancers, lung cancer, gastrointestinal cancers, and urethral cancer. We focus on regulatory mechanisms at the epigenetic level and their oncogenic effects. The review further discusses the application of FDA-approved epigenetic drugs as therapeutic strategies against cancer.

  4. Clinical investigation of TROP-2 as an independent biomarker and potential therapeutic target in colon cancer.

    Science.gov (United States)

    Zhao, Peng; Yu, Hai-Zheng; Cai, Jian-Hui

    2015-09-01

    Colon cancer is associated with a severe demographic and economic burden worldwide. The pathogenesis of colon cancer is highly complex and involves sequential genetic and epigenetic mechanisms. Despite extensive investigation, the pathogenesis of colon cancer remains to be elucidated. As the third most common type of cancer worldwide, the treatment options for colon cancer are currently limited. Human trophoblast cell‑surface marker (TROP‑2), is a cell‑surface transmembrane glycoprotein overexpressed by several types of epithelial carcinoma. In addition, TROP‑2 has been demonstrated to be associated with tumorigenesis and invasiveness in solid types of tumor. The aim of the present study was to investigate the protein expression of TROP‑2 in colon cancer tissues, and further explore the association between the expression of TROP‑2 and clinicopathological features of patients with colon cancer. The expression and localization of the TROP‑2 protein was examined using western blot analysis and immunofluorescence staining. Finally, the expression of TROP‑2 expression was correlated to conventional clinicopathological features of colon cancer using a χ2 test. The results revealed that TROP‑2 protein was expressed at high levels in the colon cancer tissues, which was associated with the development and pathological process of colon cancer. Therefore, TROP‑2 may be used as a biomarker to determine the clinical prognosis, and as a potential therapeutic target in colon cancer.

  5. Detection of Methylated Circulating DNA as Noninvasive Biomarkers for Breast Cancer Diagnosis

    Science.gov (United States)

    Cheuk, Isabella Wai Yin; Shin, Vivian Yvonne

    2017-01-01

    Internationally, breast cancer is the most common female cancer, and is induced by a combination of environmental, genetic, and epigenetic risk factors. Despite the advancement of imaging techniques, invasive sampling of breast epithelial cells is the only definitive diagnostic procedure for patients with breast cancer. To date, molecular biomarkers with high sensitivity and specificity for the screening and early detection of breast cancer are lacking. Recent evidence suggests that the detection of methylated circulating cell-free DNA in the peripheral blood of patients with cancer may be a promising quantitative and noninvasive method for cancer diagnosis. Methylation detection based on a multi-gene panel, rather than on the methylation status of a single gene, may be used to increase the sensitivity and specificity of breast cancer screening. In this review, the results of 14 relevant studies, investigating the efficacy of cell-free DNA methylation screening for breast cancer diagnosis, have been summarized. The genetic risk factors for breast cancer, the methods used for breast cancer detection, and the techniques and limitations related to the detection of cell-free DNA methylation status, have also been reviewed and discussed. From this review, we conclude that the analysis of peripheral blood or other samples to detect differentially methylated cell-free DNA is a promising technique for use in clinical settings, and may improve the sensitivity of screening for both, early detection and disease relapse, and thus improve the future prognosis of patients with breast cancer. PMID:28382090

  6. Epigenetics in Medullary Thyroid Cancer: From Pathogenesis to Targeted Therapy.

    Science.gov (United States)

    Vitale, Giovanni; Dicitore, Alessandra; Messina, Erika; Sciammarella, Concetta; Faggiano, Antongiulio; Colao, Annamaria

    2016-01-01

    Medullary thyroid carcinoma (MTC) originates from the parafollicular C cells of the thyroid gland. Mutations of the RET proto-oncogene are implicated in the pathogenesis of MTC. Germline activating mutations of this gene have been reported in about 88-98% of familial MTCs, while somatic mutations of RET gene have been detected in about 23-70% of sporadic forms. Although these genetic events are well characterized, much less is known about the role of epigenetic abnormalities in MTC. The present review reports a detailed description of epigenetic abnormalities (DNA methylation, histone modifications and miRNA profile), probably involved in the pathogenesis and progression of MTC. A systematic review was performed using Pubmed and Google patents databases. We report the current understanding of epigenetic patterns in MTC and discuss the potential use of current knowledge in designing novel therapeutic strategies through epigenetic drugs, focusing on recent patents in this field. Taking into account the reversibility of epigenetic alterations and the recent development in this field, epigenetic therapy may emerge for clinical use in the near future for patients with advanced MTC.

  7. Plasma YKL-40: a potential new cancer biomarker?

    DEFF Research Database (Denmark)

    Johansen, Julia S; Schultz, Nicolai A; Jensen, Benny V

    2009-01-01

    tissue remodeling. Plasma levels of YKL-40 are elevated in a subgroup of patients with primary or advanced cancer compared with age-matched healthy subjects, but also in patients with many different diseases characterized by inflammation. Elevated plasma YKL-40 levels are an independent prognostic...... by inflammation. Large prospective, longitudinal clinical cancer studies are needed to determine if plasma YKL-40 is a new cancer biomarker, or is mainly a biomarker of inflammation....

  8. The relevance of gastric cancer biomarkers in prognosis and pre- and post- chemotherapy in clinical practice.

    Science.gov (United States)

    Abbas, Muhammad; Habib, Murad; Naveed, Muhammad; Karthik, Kumaragurubaran; Dhama, Kuldeep; Shi, Meiqi; Dingding, Chen

    2017-11-01

    Gastric cancer (GC) is one among the major cancer types, causing human deaths and present noticeable heterogeneity. The incidences and mortality rates are higher in males in comparison to females with a male to female ratio of 2.3:1. A lot of studies have revealed out the molecular basis, pathogenesis, invasion and metastasis related findings of gastric stomach cancer. Present review encompasses the salient information on various biomarkers for the early diagnosis, treatment and prognosis of gastric cancer elaborate the clinical importance of serum tumor markers in patients with this cancer as well as checking the growths, together with epigenetic changes and genetic polymorphisms. A deep and rigorous search was carried out in Pub Med/MEDLINE using specific key words; "gastric cancer", with "tumor marker". Our search yielded 4947 important reports about related topic from books and articles that were published before the end of August 2017. Conclusively, Scientists are utilizing high time and resource to salvage this nemesis which is of global importance and cause health burden. Classical and novel biomarkers are important for treatment as well as pre- and post- diagnosis of GC. Major causes for GC are cigarette smoking, infection by Helicobacter pylori, atrophic gastritis, sex/gender, and high salt intake. Early diagnoses of GC is important for the management, treatment, pathological diagnoses by stage prognosis and metastatic setting; although the treatment outcome proved to be not much fruitful following chemotherapy, and oral medication with oxaliplatin, capecitabine, cisplatin and 5- fluorouracil (5-FU). More research studies and exploring the practical usage of gastric cancer biomarkers in diagnosis, prognosis and pre- and post- chemotherapy in clinical practice for countering gastric cancers would alleviate to some extent the ill health sufferings of humans being caused by this important and common cancerous condition. Copyright © 2017 Elsevier Masson SAS

  9. Epigenetics and genetics in endometrial cancer: new carcinogenic mechanisms and relationship with clinical practice.

    Science.gov (United States)

    Banno, Kouji; Kisu, Iori; Yanokura, Megumi; Masuda, Kenta; Ueki, Arisa; Kobayashi, Yusuke; Susumu, Nobuyuki; Aoki, Daisuke

    2012-04-01

    Endometrial cancer is the seventh most common cancer worldwide among females. An increased incidence and a younger age of patients are also predicted to occur, and therefore elucidation of the pathological mechanisms is important. However, several aspects of the mechanism of carcinogenesis in the endometrium remain unclear. Associations with genetic mutations of cancer-related genes have been shown, but these do not provide a complete explanation. Therefore, epigenetic mechanisms have been examined. Silencing of genes by DNA hypermethylation, hereditary epimutation of DNA mismatch repair genes and regulation of gene expression by miRNAs may underlie carcinogenesis in endometrial cancer. New therapies include targeting epigenetic changes using histone deacetylase inhibitors. Some cases of endometrial cancer may also be hereditary. Thus, patients with Lynch syndrome which is a hereditary disease, have a higher risk for developing endometrial cancer than the general population. Identification of such disease-related genes may contribute to early detection and prevention of endometrial cancer.

  10. Convergence of biomarkers, bioinformatics and nanotechnology for individualized cancer treatment

    Science.gov (United States)

    Phan, John H.; Moffitt, Richard A.; Stokes, Todd H.; Liu, Jian; Young, Andrew N.; Nie, Shuming; Wang, May D.

    2013-01-01

    Recent advances in biomarker discovery, biocomputing, and nanotechnology have raised new opportunities for the emerging field of personalized medicine in which disease detection, diagnosis, and therapy are tailored to each individual’s molecular profile, and also for predictive medicine that uses genetic/molecular information to predict disease development, progression, and clinical outcome. Here we discuss advanced biocomputing tools for cancer biomarker discovery and multiplexed nanoparticle probes for cancer biomarker profiling, together with prospects and challenges in correlating biomolecular signatures with clinical outcome. This bio-nano-info convergence holds great promise for molecular diagnosis and individualized therapy of cancer and other human diseases. PMID:19409634

  11. MicroRNAs as new Characters in the Plot between Epigenetics and Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Alessio ePaone

    2011-09-01

    Full Text Available Prostate cancer (PCA still represents a leading cause of death. An increasing number of studies have documented that microRNAs (miRNAs, a subgroup of non-coding RNAs with gene regulatory functions, are differentially expressed in PCA respect to the normal tissue counterpart, suggesting their involvement in prostate carcinogenesis and dissemination. Interestingly, it has been shown that miRNAs undergo the same regulatory mechanisms than any other protein coding gene, including epigenetic regulation. In turn, miRNAs can also affect the expression of oncogenes and tumor suppressor genes by targeting effectors of the epigenetic machinery, therefore indirectly affecting the epigenetic controls on these genes. Among the genes that undergo this complex regulation, there is the androgen receptor (AR, a key therapeutic target for PCA. This review will focus on the role of epigenetically regulated and epigenetically regulating miRNAs in prostate cancer and on the fine regulation of AR expression, as mediated by this miRNA-epigenetics interaction.

  12. Epigenetic Modifications and Head and Neck Cancer: Implications for Tumor Progression and Resistance to Therapy

    Directory of Open Access Journals (Sweden)

    Rogerio M. Castilho

    2017-07-01

    Full Text Available Head and neck squamous carcinoma (HNSCC is the sixth most prevalent cancer and one of the most aggressive malignancies worldwide. Despite continuous efforts to identify molecular markers for early detection, and to develop efficient treatments, the overall survival and prognosis of HNSCC patients remain poor. Accumulated scientific evidences suggest that epigenetic alterations, including DNA methylation, histone covalent modifications, chromatin remodeling and non-coding RNAs, are frequently involved in oral carcinogenesis, tumor progression, and resistance to therapy. Epigenetic alterations occur in an unsystematic manner or as part of the aberrant transcriptional machinery, which promotes selective advantage to the tumor cells. Epigenetic modifications also contribute to cellular plasticity during tumor progression and to the formation of cancer stem cells (CSCs, a small subset of tumor cells with self-renewal ability. CSCs are involved in the development of intrinsic or acquired therapy resistance, and tumor recurrences or relapse. Therefore, the understanding and characterization of epigenetic modifications associated with head and neck carcinogenesis, and the prospective identification of epigenetic markers associated with CSCs, hold the promise for novel therapeutic strategies to fight tumors. In this review, we focus on the current knowledge on epigenetic modifications observed in HNSCC and emerging Epi-drugs capable of sensitizing HNSCC to therapy.

  13. A New Serum Biomarker for Lung Cancer - Transthyretin

    Directory of Open Access Journals (Sweden)

    Liyun LIU

    2009-04-01

    Full Text Available Background and objective Lung cancer is the leading cause of cancer death worldwide and very few specific biomarkers could be used in clinical diagnosis at present. The aim of this study is to find novel potential serum biomarkers for lung cancer using Surface Enhanced Laser Desorption/Ionization (SELDI technique. Methods Serumsample of 227 cases including 146 lung cancer, 13 pneumonia, 28 tuberculous pleurisy and 40 normal individuals were analyzed by CM10 chips. The candidate biomarkers were identified by ESI/MS-MS and database searching, and further confirmed by immunoprecipitation. The same sets of serum sample from all groups were re-measured by ELISA assay. Results Three protein peaks with the molecular weight 13.78 kDa, 13.90 kDa and 14.07 kDa were found significantlydecreased in lung cancer serum compared to the other groups and were all automatically selected as specific biomarkers by Biomarker Wizard software. The candidate biomarkers obtained from 1-D SDS gel bands by matching the molecular weight with peaks on CM10 chips were identified by Mass spectrometry as the native transthyretin (nativeTTR, cysTTR and glutTTR, and the identity was further validated by immunoprecipitation using commercial TTR antibodies. Downregulated of TTR was found in both ELISA and SELDI analysis. Conclusion TTRs acted as the potentially useful biomarkers for lung cancer by SELDI technique.

  14. A review of molecular biomarkers for bladder cancer | Miakhil ...

    African Journals Online (AJOL)

    Background: Numerous molecular markers for bladder cancer have been identified and investigated with various laboratory techniques. Molecular markers are isolated from tissue, serum and urine. They fall into proteomic, genetic and epigenetic categories. Some of molecular markers show promising results in terms of ...

  15. Biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy

    DEFF Research Database (Denmark)

    Stenvang, Jan; Kümler, Iben; Nygård, Sune Boris

    2013-01-01

    -standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I (Top1...

  16. Impact of nutrition on noncoding RNA epigenetics in breast and gynecological cancer

    Directory of Open Access Journals (Sweden)

    Rosanna H. E. Krakowsky

    2015-05-01

    Full Text Available Cancer is the second leading cause of death in females. According to the American Cancer Society, there are 327,660 new cases in breast and gynecological cancers estimated in 2014, placing emphasis on the need for cancer prevention and new cancer treatment strategies. One important approach to cancer prevention involves phytochemicals, biologically active compounds derived from plants. A variety of studies on the impact of dietary compounds found in cruciferous vegetables, green tea and spices like curry and black pepper have revealed epigenetic changes in female cancers. Thus, an important emerging topic comprises epigenetic changes due to the modulation of noncoding RNA levels. Since it has been shown that noncoding RNAs such as microRNAs and long noncoding RNAs are aberrantly expressed in cancer and furthermore are linked to distinct cancer phenotypes, understanding the effects of dietary compounds and supplements on the epigenetic modulator noncoding RNA is of great interest. This article reviews the current findings on nutrition-induced changes in breast and gynecological cancers at the noncoding RNA level.

  17. Withaferin A and sulforaphane regulate breast cancer cell cycle progression through epigenetic mechanisms.

    Science.gov (United States)

    Royston, Kendra J; Paul, Bidisha; Nozell, Susan; Rajbhandari, Rajani; Tollefsbol, Trygve O

    2018-07-01

    Little is known about the effects of combinatorial dietary compounds on the regulation of epigenetic mechanisms involved in breast cancer prevention. The human diet consists of a multitude of components, and there is a need to elucidate how certain compounds interact in collaboration. Withaferin A (WA), found in the Indian winter cherry and documented as a DNA methyltransferase (DNMT) inhibitor, and sulforaphane (SFN), a well-known histone deacetylase (HDAC) inhibitor found in cruciferous vegetables, are two epigenetic modifying compounds that have only recently been studied in conjunction. The use of DNMT and HDAC inhibitors to reverse the malignant expression of certain genes in breast cancer has shown considerable promise. Previously, we found that SFN + WA synergistically promote breast cancer cell death. Herein, we determined that these compounds inhibit cell cycle progression from S to G2 phase in MDA-MB-231 and MCF-7 breast cancer. Furthermore, we demonstrate that this unique combination of epigenetic modifying compounds down-regulates the levels of Cyclin D1 and CDK4, and pRB; conversely, the levels of E2F mRNA and tumor suppressor p21 are increased independently of p53. We find these events coincide with an increase in unrestricted histone methylation. We propose SFN + WA-induced breast cancer cell death is attributed, in part, to epigenetic modifications that result in the modulated expression of key genes responsible for the regulation of cancer cell senescence. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. The Role of Epigenetics in Resistance to Cisplatin Chemotherapy in Lung Cancer

    International Nuclear Information System (INIS)

    O'Byrne, Kenneth J.; Barr, Martin P.; Gray, Steven G.

    2011-01-01

    Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in the world. Cisplatin and carboplatin are the most commonly used cytotoxic chemotherapeutic agents to treat the disease. These agents, usually combined with drugs such as gemcitabine or pemetrexed, induce objective tumor responses in only 20–30% of patients. Aberrant epigenetic regulation of gene expression is a frequent event in NSCLC. In this article we review the emerging evidence that epigenetics and the cellular machinery involved with this type of regulation may be key elements in the development of cisplatin resistance in NSCLC

  19. The Role of Epigenetics in Resistance to Cisplatin Chemotherapy in Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    O' Byrne, Kenneth J.; Barr, Martin P.; Gray, Steven G., E-mail: sgray@stjames.ie [Trinity College Dublin, Department of Clinical Medicine, Trinity Centre for Health Sciences, St James Hospital, James Street, Dublin 8 (Ireland)

    2011-03-17

    Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in the world. Cisplatin and carboplatin are the most commonly used cytotoxic chemotherapeutic agents to treat the disease. These agents, usually combined with drugs such as gemcitabine or pemetrexed, induce objective tumor responses in only 20–30% of patients. Aberrant epigenetic regulation of gene expression is a frequent event in NSCLC. In this article we review the emerging evidence that epigenetics and the cellular machinery involved with this type of regulation may be key elements in the development of cisplatin resistance in NSCLC.

  20. More Accurate Oral Cancer Screening with Fewer Salivary Biomarkers

    Directory of Open Access Journals (Sweden)

    James Michael Menke

    2017-10-01

    Full Text Available Signal detection and Bayesian inferential tools were applied to salivary biomarkers to improve screening accuracy and efficiency in detecting oral squamous cell carcinoma (OSCC. Potential cancer biomarkers are identified by significant differences in assay concentrations, receiver operating characteristic areas under the curve (AUCs, sensitivity, and specificity. However, the end goal is to report to individual patients their risk of having disease given positive or negative test results. Likelihood ratios (LRs and Bayes factors (BFs estimate evidential support and compile biomarker information to optimize screening accuracy. In total, 26 of 77 biomarkers were mentioned as having been tested at least twice in 137 studies and published in 16 summary papers through 2014. Studies represented 10 212 OSCC and 25 645 healthy patients. The measure of biomarker and panel information value was number of biomarkers needed to approximate 100% positive predictive value (PPV. As few as 5 biomarkers could achieve nearly 100% PPV for a disease prevalence of 0.2% when biomarkers were ordered from highest to lowest LR. When sequentially interpreting biomarker tests, high specificity was more important than test sensitivity in achieving rapid convergence toward a high PPV. Biomarkers ranked from highest to lowest LR were more informative and easier to interpret than AUC or Youden index. The proposed method should be applied to more recently published biomarker data to test its screening value.

  1. Breast Cancer Biomarkers Based on Nipple and Fine Needle Aspirates

    National Research Council Canada - National Science Library

    Russo, Irma H

    2005-01-01

    ... of the cytological normal breast epithelium of women at high risk for breast cancer. This signature will serve as an intermediate biomarker for evaluating the response of the breast to novel chemopreventive agents...

  2. DNA fingerprinting techniques for the analysis of genetic and epigenetic alterations in colorectal cancer.

    Science.gov (United States)

    Samuelsson, Johanna K; Alonso, Sergio; Yamamoto, Fumiichiro; Perucho, Manuel

    2010-11-10

    Genetic somatic alterations are fundamental hallmarks of cancer. In addition to point and other small mutations targeting cancer genes, solid tumors often exhibit aneuploidy as well as multiple chromosomal rearrangements of large fragments of the genome. Whether somatic chromosomal alterations and aneuploidy are a driving force or a mere consequence of tumorigenesis remains controversial. Recently it became apparent that not only genetic but also epigenetic alterations play a major role in carcinogenesis. Epigenetic regulation mechanisms underlie the maintenance of cell identity crucial for development and differentiation. These epigenetic regulatory mechanisms have been found substantially altered during cancer development and progression. In this review, we discuss approaches designed to analyze genetic and epigenetic alterations in colorectal cancer, especially DNA fingerprinting approaches to detect changes in DNA copy number and methylation. DNA fingerprinting techniques, despite their modest throughput, played a pivotal role in significant discoveries in the molecular basis of colorectal cancer. The aim of this review is to revisit the fingerprinting technologies employed and the oncogenic processes that they unveiled. 2010 Elsevier B.V. All rights reserved.

  3. MicroRNAs as New Characters in the Plot between Epigenetics and Prostate Cancer.

    Science.gov (United States)

    Paone, Alessio; Galli, Roberta; Fabbri, Muller

    2011-01-01

    Prostate cancer (PCA) still represents a leading cause of death. An increasing number of studies have documented that microRNAs (miRNAs), a subgroup of non-coding RNAs with gene regulatory functions, are differentially expressed in PCA respect to the normal tissue counterpart, suggesting their involvement in prostate carcinogenesis and dissemination. Interestingly, it has been shown that miRNAs undergo the same regulatory mechanisms than any other protein coding gene, including epigenetic regulation. In turn, miRNAs can also affect the expression of oncogenes and tumor suppressor genes by targeting effectors of the epigenetic machinery, therefore indirectly affecting the epigenetic controls on these genes. Among the genes that undergo this complex regulation, there is the androgen receptor (AR), a key therapeutic target for PCA. This review will focus on the role of epigenetically regulated and epigenetically regulating miRNAs in PCA and on the fine regulation of AR expression, as mediated by this miRNA-epigenetics interaction.

  4. New Insights into the Androgen-Targeted Therapies and Epigenetic Therapies in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Abhijit M. Godbole

    2011-01-01

    Full Text Available Prostate cancer is the most common cancer in men in the United States, and it is the second leading cause of cancer-related death in American men. The androgen receptor (AR, a receptor of nuclear family and a transcription factor, is the most important target in this disease. While most efforts in the clinic are currently directed at lowering levels of androgens that activate AR, resistance to androgen deprivation eventually develops. Most prostate cancer deaths are attributable to this castration-resistant form of prostate cancer (CRPC. Recent work has shed light on the importance of epigenetic events including facilitation of AR signaling by histone-modifying enzymes, posttranslational modifications of AR such as sumoylation. Herein, we provide an overview of the structure of human AR and its key structural domains that can be used as targets to develop novel antiandrogens. We also summarize recent findings about the antiandrogens and the epigenetic factors that modulate the action of AR.

  5. Biomarkers for predicting complete debulking in ovarian cancer

    DEFF Research Database (Denmark)

    Fagö-Olsen, Carsten Lindberg; Ottesen, Bent; Christensen, Ib Jarle

    2014-01-01

    AIM: We aimed to construct and validate a model based on biomarkers to predict complete primary debulking surgery for ovarian cancer patients. PATIENTS AND METHODS: The study consisted of three parts: Part I: Biomarker data obtained from mass spectrometry, baseline data and, surgical outcome were...... used to construct predictive indices for complete tumour resection; Part II: sera from randomly selected patients from part I were analyzed using enzyme-linked immunosorbent assay (ELISA) to investigate the correlation to mass spectrometry; Part III: the indices from part I were validated in a new.......64. CONCLUSION: Our validated model based on biomarkers was unable to predict surgical outcome for patients with ovarian cancer....

  6. Biomarkers for bladder cancer management: present and future

    Science.gov (United States)

    Ye, Fei; Wang, Li; Castillo-Martin, Mireia; McBride, Russell; Galsky, Matthew D; Zhu, Jun; Boffetta, Paolo; Zhang, David Y; Cordon-Cardo, Carlos

    2014-01-01

    Accurate and sensitive detection of bladder cancer is critical to diagnose this deadly disease at an early stage, estimate prognosis, predict response to treatment, and monitor recurrence. In past years, laboratory diagnosis and surveillance of urinary bladder cancer have improved significantly. Although urine cytology remains the gold standard test, many new urinary biomarkers have been identified. Furthermore, recent advances in genomic studies of bladder cancer have helped to refine our understanding of the pathogenesis of the disease, the biological basis for outcome disparities, and to inform more efficient treatment and surveillance strategies. In this article, the established diagnostic tests, newly identified biomarkers and genomic landscape of bladder cancer will be reviewed. PMID:25374904

  7. Colorectal cancer tumour markers and biomarkers: Recent therapeutic advances

    Science.gov (United States)

    Lech, Gustaw; Słotwiński, Robert; Słodkowski, Maciej; Krasnodębski, Ireneusz Wojciech

    2016-01-01

    Colorectal cancer (CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnostic and therapeutic methods. Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer. Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease. Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients. There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers. In this review, we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening, diagnosis, treatment and follow-up. Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis, as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments. PMID:26855534

  8. Colorectal cancer tumour markers and biomarkers: Recent therapeutic advances.

    Science.gov (United States)

    Lech, Gustaw; Słotwiński, Robert; Słodkowski, Maciej; Krasnodębski, Ireneusz Wojciech

    2016-02-07

    Colorectal cancer (CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnostic and therapeutic methods. Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer. Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease. Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients. There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers. In this review, we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening, diagnosis, treatment and follow-up. Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis, as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments.

  9. Aberrantly methylated DNA as a biomarker in breast cancer

    DEFF Research Database (Denmark)

    Kristiansen, Søren; Jørgensen, Lars Mønster; Guldberg, Per

    2013-01-01

    hypermethylation events, their use as tumor biomarkers is usually not hampered by analytical signals from normal cells, which is a general problem for existing protein tumor markers used for clinical assessment of breast cancer. There is accumulating evidence that DNA-methylation changes in breast cancer patients...... occur early during tumorigenesis. This may open up for effective screening, and analysis of blood or nipple aspirate may later help in diagnosing breast cancer. As a more detailed molecular characterization of different types of breast cancer becomes available, the ability to divide patients...... as a versatile biomarker tool for screening, diagnosis, prognosis and monitoring of breast cancer. Standardization of methods and biomarker panels will be required to fully exploit this clinical potential....

  10. Early life exposure to famine and colorectal cancer risk: A role for epigenetic mechanisms

    NARCIS (Netherlands)

    Hughes, L.A.E.; Brandt, P.A. van den; Bruïne, A.P. de; Wouters, K.A.D.; Hulsmans, S.; Spiertz, A.; Goldbohm, R.A.; Goeij, A.F.P.M. de; Herman, J.G.; Weijenberg, M.P.; Engeland, M. van

    2009-01-01

    Background: Exposure to energy restriction during childhood and adolescence is associated with a lower risk of developing colorectal cancer (CRC). Epigenetic dysregulation during this critical period of growth and development may be a mechanism to explain such observations. Within the Netherlands

  11. Biomarkers in cancer screening: a public health perspective.

    Science.gov (United States)

    Srivastava, Sudhir; Gopal-Srivastava, Rashmi

    2002-08-01

    The last three decades have witnessed a rapid advancement and diffusion of technology in health services. Technological innovations have given health service providers the means to diagnose and treat an increasing number of illnesses, including cancer. In this effort, research on biomarkers for cancer detection and risk assessment has taken a center stage in our effort to reduce cancer deaths. For the first time, scientists have the technologies to decipher and understand these biomarkers and to apply them to earlier cancer detection. By identifying people at high risk of developing cancer, it would be possible to develop intervention efforts on prevention rather than treatment. Once fully developed and validated, then the regular clinical use of biomarkers in early detection and risk assessment will meet nationally recognized health care needs: detection of cancer at its earliest stage. The dramatic rise in health care costs in the past three decades is partly related to the proliferation of new technologies. More recent analysis indicates that technological change, such as new procedures, products and capabilities, is the primary explanation of the historical increase in expenditure. Biomarkers are the new entrants in this competing environment. Biomarkers are considered as a competing, halfway or add-on technology. Technology such as laboratory tests of biomarkers will cost less compared with computed tomography (CT) scans and other radiographs. However, biomarkers for earlier detection and risk assessment have not achieved the level of confidence required for clinical applications. This paper discusses some issues related to biomarker development, validation and quality assurance. Some data on the trends of diagnostic technologies, proteomics and genomics are presented and discussed in terms of the market share. Eventually, the use of biomarkers in health care could reduce cost by providing noninvasive, sensitive and reliable assays at a fraction of the cost of

  12. Global DNA methylation in earthworms: A candidate biomarker of epigenetic risks related to the presence of metals/metalloids in terrestrial environments

    Energy Technology Data Exchange (ETDEWEB)

    Maldonado Santoyo, Maria; Rodriguez Flores, Crescencio; Lopez Torres, Adolfo; Wrobel, Kazimierz [Department of Chemistry, University of Guanajuato, L de Retana No 5, 36000 Guanajuato (Mexico); Wrobel, Katarzyna, E-mail: katarzyn@quijote.ugto.mx [Department of Chemistry, University of Guanajuato, L de Retana No 5, 36000 Guanajuato (Mexico)

    2011-10-15

    In this work, possible relationships between global DNA methylation and metal/metalloid concentrations in earthworms have been explored. Direct correlation was observed between soil and tissue As, Se, Sb, Zn, Cu, Mn, Ag, Co, Hg, Pb (p < 0.05). Speciation results obtained for As and Hg hint at the capability of earthworms for conversion of inorganic element forms present in soil to methylated species. Inverse correlation was observed between the percentage of methylated DNA cytosines and total tissue As, As + Hg, As + Hg + Se + Sb ({beta} = -0.8456, p = 0.071; {beta} = -0.9406, p = 0.017; {beta} = -0.9526, p = 0.012 respectively), as well as inorganic As + Hg ({beta} = -0.8807, p = 0.049). It was concluded that earthworms would be particularly helpful as bioindicators of elements undergoing in vivo methylation and might also be used to assess the related risk of epigenetic changes in DNA methylation. - Graphical abstract: Display Omitted Highlights: > Several metals and metalloids contribute to epigenetic gene regulation. > As, Hg, Se, Sb inversely correlated with global DNA methylation in earthworms. > Biomethylation of the above elements in worms suggested. > Elements biomethylation apparently competes with DNA methylation. > DNA methylation a biomarker of epigenetic risks related to soil metals/metalloids. - Biomethylation of As, Hg in earthworms versus DNA methylation - a candidate biomarker of epigenetic risks related to the presence of metals/metalloids in soil.

  13. Epigenetic Transgenerational Actions of Vinclozolin on the Development of Disease and Cancer

    Science.gov (United States)

    Skinner, Michael K.; Anway, Matthew D.

    2018-01-01

    Exposure to an environmental endocrine disruptor (e.g., vinclozolin) during embryonic gonadal sex determination appears to alter the male germ line epigenome and subsequently promotes transgenerational adult onset disease. The epigenetic mechanism involves the induction of new imprinted-like genes/DNA sequences in the germ line that appear to transmit disease phenotypes. The disease phenotypes include testis abnormalities, prostate disease, kidney disease, immune abnormalities, and tumor development. This epigenetic transgenerational disease mechanism provides a unique perspective from which to view inheritable adult onset disease states, such as cancer, and ultimately offers new insights into novel diagnostic and therapeutic strategies. PMID:17956218

  14. Epigenetic Machinery Regulates Alternative Splicing of Androgen Receptor (AR) Gene in Castration-Resistant Prostate Cancer (CRPC)

    Science.gov (United States)

    2017-09-01

    Splicing of Androgen Receptor (AR) Gene in Castration-Resistant Prostate Cancer (CRPC) 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Jer...Epigenetic regulation of androgen receptor signaling in prostate cancer . Epigenetics. 5, 100-104. 2. Duan LL, Rai G , Roggero C, Zhang Q-J, Wei Q... Prostate Cancer (CRPC) PRINCIPAL INVESTIGATOR: Hsieh, Jer-Tsong CONTRACTING ORGANIZATION: University of Texas Southwestern Medical Center

  15. DNA Fingerprinting Techniques for the Analysis of Genetic and Epigenetic Alterations in Colorectal Cancer

    OpenAIRE

    Samuelsson, Johanna K.; Alonso, Sergio; Yamamoto, Fumiichiro; Perucho, Manuel

    2010-01-01

    Genetic somatic alterations are fundamental hallmarks of cancer. In addition to point and other small mutations targeting cancer genes, solid tumors often exhibit aneuploidy as well as multiple chromosomal rearrangements of large fragments of the genome. Whether somatic chromosomal alterations and aneuploidy are a driving force or a mere consequence of tumorigenesis remains controversial. Recently it became apparent that not only genetic but also epigenetic alterations play a major role in ca...

  16. DWI as an Imaging Biomarker for Bladder Cancer

    NARCIS (Netherlands)

    Yoshida, Soichiro; Takahara, Taro; Kwee, Thomas C.; Waseda, Yuma; Kobayashi, Shuichiro; Fujii, Yasuhisa

    OBJECTIVE. DWI has been increasingly applied in the management of bladder cancer. In this article, we discuss the role of DWI as an imaging biomarker for bladder cancer. CONCLUSION. The DWI signal is derived from the motion of water molecules, which represents the physiologic characteristics of the

  17. Aberrantly methylated DNA as a biomarker in breast cancer.

    Science.gov (United States)

    Kristiansen, Søren; Jørgensen, Lars M; Guldberg, Per; Sölétormos, György

    2013-01-01

    Aberrant DNA hypermethylation at gene promoters is a frequent event in human breast cancer. Recent genome-wide studies have identified hundreds of genes that exhibit differential methylation between breast cancer cells and normal breast tissue. Due to the tumor-specific nature of DNA hypermethylation events, their use as tumor biomarkers is usually not hampered by analytical signals from normal cells, which is a general problem for existing protein tumor markers used for clinical assessment of breast cancer. There is accumulating evidence that DNA-methylation changes in breast cancer patients occur early during tumorigenesis. This may open up for effective screening, and analysis of blood or nipple aspirate may later help in diagnosing breast cancer. As a more detailed molecular characterization of different types of breast cancer becomes available, the ability to divide patients into subgroups based on DNA biomarkers may improve prognosis. Serial monitoring of DNA-methylation markers in blood during treatment may be useful, particularly when the cancer burden is below the detection level for standard imaging techniques. Overall, aberrant DNA methylation has a great potential as a versatile biomarker tool for screening, diagnosis, prognosis and monitoring of breast cancer. Standardization of methods and biomarker panels will be required to fully exploit this clinical potential.

  18. Urinary metalloproteinases: noninvasive biomarkers for breast cancer risk assessment

    DEFF Research Database (Denmark)

    Pories, Susan E; Zurakowski, David; Roy, Roopali

    2008-01-01

    Matrix metalloproteinases (MMP) and a disintegrin and metalloprotease 12 (ADAM 12) can be detected in the urine of breast cancer patients and provide independent prediction of disease status. To evaluate the potential of urinary metalloproteinases as biomarkers to predict breast cancer risk statu...

  19. Metabolomics in cancer biomarker discovery: current trends and future perspectives.

    Science.gov (United States)

    Armitage, Emily G; Barbas, Coral

    2014-01-01

    Cancer is one of the most devastating human diseases that causes a vast number of mortalities worldwide each year. Cancer research is one of the largest fields in the life sciences and despite many astounding breakthroughs and contributions over the past few decades, there is still a considerable amount to unveil on the function of cancer. It is well known that cancer metabolism differs from that of normal tissue and an important hypothesis published in the 1950s by Otto Warburg proposed that cancer cells rely on anaerobic metabolism as the source for energy, even under physiological oxygen levels. Following this, cancer central carbon metabolism has been researched extensively and beyond respiration, cancer has been found to involve a wide range of metabolic processes, and many more are still to be unveiled. Studying cancer through metabolomics could reveal new biomarkers for cancer that could be useful for its future prognosis, diagnosis and therapy. Metabolomics is becoming an increasingly popular tool in the life sciences since it is a relatively fast and accurate technique that can be applied with either a particular focus or in a global manner to reveal new knowledge about biological systems. There have been many examples of its application to reveal potential biomarkers in different cancers that have employed a range of different analytical platforms. In this review, approaches in metabolomics that have been employed in cancer biomarker discovery are discussed and some of the most noteworthy research in the field is highlighted. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Epigenetic markers in circulating cell-free DNA as prognostic markers for survival of castration-resistant prostate cancer patients.

    Science.gov (United States)

    Hendriks, Rianne J; Dijkstra, Siebren; Smit, Frank P; Vandersmissen, Johan; Van de Voorde, Hendrik; Mulders, Peter F A; van Oort, Inge M; Van Criekinge, Wim; Schalken, Jack A

    2018-04-01

    Noninvasive biomarkers to guide personalized treatment for castration-resistant prostate cancer (CRPC) are needed. In this study, we analyzed hypermethylation patterns of two genes (GSTP1 and APC) in plasma cell-free DNA (cfDNA) of CRPC patients. The aim of this study was to analyze the cfDNA concentrations and levels of the epigenetic markers and to assess the value of these biomarkers for prognosis. In this prospective study, patients were included before starting new treatment after developing CRPC. The blood samples were collected prior to start of the treatment and at three time points thereafter. cfDNA was extracted from 1.5 mL of plasma and before performing a methylation-specific PCR, bisulfate modification was carried out. The median levels of cfDNA, GSTP1, and APC copies in the baseline samples of CRPC patients (n = 47) were higher than in controls (n = 30). In the survival analysis, the group with baseline marker levels below median had significant less PCa-related deaths (P-values Prostate Published by Wiley Periodicals, Inc.

  1. MicroRNA dysregulation as a prognostic biomarker in colorectal cancer

    International Nuclear Information System (INIS)

    Dong, Yujuan; Yu, Jun; Ng, Simon SM

    2014-01-01

    Colorectal cancer (CRC) is one of the most potentially curable cancers, yet it remains the fourth most common overall cause of cancer death worldwide. The identification of robust molecular prognostic biomarkers can refine the conventional tumor–node–metastasis staging system, avoid understaging of tumor, and help pinpoint patients with early-stage CRC who may benefit from aggressive treatments. Recently, epigenetic studies have provided new molecular evidence to better categorize the CRC subtypes and predict clinical outcomes. In this review, we summarize recent findings concerning the prognostic potential of microRNAs (miRNAs) in CRC. We first discuss the prognostic value of three tissue miRNAs (miR-21-5p, miR-29-3p, miR-148-3p) that have been examined in multiple studies. We also summarize the dysregulation of miRNA processing machinery DICER in CRC and its association with risk for mortality. We also reviewe the potential application of miRNA-associated single-nucleotide polymorphisms as prognostic biomarkers for CRC, especially the miRNA-associated polymorphism in the KRAS gene. Last but not least, we discuss the microsatellite instability-related miRNA candidates. Among all these candidates, miR-21-5p is the most promising prognostic marker, yet further prospective validation studies are required before it can go into clinical usage

  2. New Epigenetic Therapeutic Intervention for Metastatic Breast Cancer

    Science.gov (United States)

    2017-04-01

    Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China...Foundation 2016 NIH - New Innovator Award 2017 NIH - “ Cancer Drug Development & Therapeutics” (CDDT) 2017 NIH/NIAID - Special Emphasis Panel...Chemistry 2011 - Editor, Cancer Reports, Pancreatic Disorders & Therapy 2015 - Associate Editor, Molecular and Cellular Oncology (sections of

  3. Dissecting epigenetic silencing complexity in the mouse lung cancer suppressor gene Cadm1.

    Directory of Open Access Journals (Sweden)

    Stella Marie Reamon-Buettner

    Full Text Available Disease-oriented functional analysis of epigenetic factors and their regulatory mechanisms in aberrant silencing is a prerequisite for better diagnostics and therapy. Yet, the precise mechanisms are still unclear and complex, involving the interplay of several effectors including nucleosome positioning, DNA methylation, histone variants and histone modifications. We investigated the epigenetic silencing complexity in the tumor suppressor gene Cadm1 in mouse lung cancer progenitor cell lines, exhibiting promoter hypermethylation associated with transcriptional repression, but mostly unresponsive to demethylating drug treatments. After predicting nucleosome positions and transcription factor binding sites along the Cadm1 promoter, we carried out single-molecule mapping with DNA methyltransferase M.SssI, which revealed in silent promoters high nucleosome occupancy and occlusion of transcription factor binding sites. Furthermore, M.SssI maps of promoters varied within and among the different lung cancer cell lines. Chromatin analysis with micrococcal nuclease also indicated variations in nucleosome positioning to have implications in the binding of transcription factors near nucleosome borders. Chromatin immunoprecipitation showed that histone variants (H2A.Z and H3.3, and opposing histone modification marks (H3K4me3 and H3K27me3 all colocalized in the same nucleosome positions that is reminiscent of epigenetic plasticity in embryonic stem cells. Altogether, epigenetic silencing complexity in the promoter region of Cadm1 is not only defined by DNA hypermethylation, but high nucleosome occupancy, altered nucleosome positioning, and 'bivalent' histone modifications, also likely contributed in the transcriptional repression of this gene in the lung cancer cells. Our results will help define therapeutic intervention strategies using epigenetic drugs in lung cancer.

  4. Targeting Epigenetics Therapy for Estrogen Receptor-Negative Breast Cancers

    Science.gov (United States)

    2015-10-01

    and by Duke University. This manuscript is dedicated to Professor William F. DeGrado on the occasion of his 60th birthday. Burg and Link contributed...Muller-Tidow, C.; Petrie, K.; Zelent, A. Nat Med 2012, 18, 605–611. 69. Mould, D. P.; McGonagle, A. E.; Wiseman, D. H.; Williams , E. L.; Jordan, A. M...206. 178. Nicholson, T. B.; Chen, T. Epigenetics 2009, 4, 129–132. 179. Hauber, J.; Malim, M. H.; Cullen , B. R. J Virol 1989, 63, 1181– 1187. 180

  5. Epigenetics-related genes in prostate cancer: expression profile in prostate cancer tissues, androgen-sensitive and -insensitive cell lines.

    Science.gov (United States)

    Shaikhibrahim, Zaki; Lindstrot, Andreas; Ochsenfahrt, Jacqueline; Fuchs, Kerstin; Wernert, Nicolas

    2013-01-01

    Epigenetic changes have been suggested to drive prostate cancer (PCa) development and progression. Therefore, in this study, we aimed to identify novel epigenetics-related genes in PCa tissues, and to examine their expression in metastatic PCa cell lines. We analyzed the expression of epigenetics-related genes via a clustering analysis based on gene function in moderately and poorly differentiated PCa glands compared to normal glands of the peripheral zone (prostate proper) from PCa patients using Whole Human Genome Oligo Microarrays. Our analysis identified 12 epigenetics-related genes with a more than 2-fold increase or decrease in expression and a p-value epigenetics-related genes that we identified in primary PCa tissues may provide further insight into the role that epigenetic changes play in PCa. Moreover, some of the genes that we identified may play important roles in primary PCa and metastasis, in primary PCa only, or in metastasis only. Follow-up studies are required to investigate the functional role and the role that the expression of these genes play in the outcome and progression of PCa using tissue microarrays.

  6. Serum and Plasma Metabolomic Biomarkers for Lung Cancer.

    Science.gov (United States)

    Kumar, Nishith; Shahjaman, Md; Mollah, Md Nurul Haque; Islam, S M Shahinul; Hoque, Md Aminul

    2017-01-01

    In drug invention and early disease prediction of lung cancer, metabolomic biomarker detection is very important. Mortality rate can be decreased, if cancer is predicted at the earlier stage. Recent diagnostic techniques for lung cancer are not prognosis diagnostic techniques. However, if we know the name of the metabolites, whose intensity levels are considerably changing between cancer subject and control subject, then it will be easy to early diagnosis the disease as well as to discover the drug. Therefore, in this paper we have identified the influential plasma and serum blood sample metabolites for lung cancer and also identified the biomarkers that will be helpful for early disease prediction as well as for drug invention. To identify the influential metabolites, we considered a parametric and a nonparametric test namely student׳s t-test as parametric and Kruskal-Wallis test as non-parametric test. We also categorized the up-regulated and down-regulated metabolites by the heatmap plot and identified the biomarkers by support vector machine (SVM) classifier and pathway analysis. From our analysis, we got 27 influential (p-value<0.05) metabolites from plasma sample and 13 influential (p-value<0.05) metabolites from serum sample. According to the importance plot through SVM classifier, pathway analysis and correlation network analysis, we declared 4 metabolites (taurine, aspertic acid, glutamine and pyruvic acid) as plasma biomarker and 3 metabolites (aspartic acid, taurine and inosine) as serum biomarker.

  7. Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Abderrahim Oussalah

    2018-04-01

    associated with HCC diagnosis (initial: OR = 6.30, for each mSEPT9 positive triplicate [2.92–13.61, p < 0.0001]; replication: OR = 6.07 [3.25–11.35, p < 0.0001]; meta-analysis: OR = 6.15 [2.93–9.38, p < 0.0001], no heterogeneity: I2 = 0%, p = 0.95; no publication bias. AUROC associated with the discrimination of the logistic regression models in initial and validation studies were 0.969 (0.930–0.989 and 0.942 (0.878–0.978, respectively, with a pooled AUROC of 0.962 ([0.937–0.987, p < 0.0001], no heterogeneity: I2 = 0%, p = 0.36; and no publication bias. Interpretation: Among patients with cirrhosis, the mSEPT9 test constitutes a promising circulating epigenetic biomarker for HCC diagnosis at the individual patient level. Future prospective studies should assess the mSEPT9 test in the screening algorithm for cirrhotic patients to improve risk prediction and personalized therapeutic management of HCC. Keywords: Cirrhosis, Hepatocellular carcinoma, Circulating cell-free DNA-based epigenetic biomarker, DNA methylation, mSEPT9

  8. Coumestrol Epigenetically Suppresses Cancer Cell Proliferation: Coumestrol Is a Natural Haspin Kinase Inhibitor

    Directory of Open Access Journals (Sweden)

    Jong-Eun Kim

    2017-10-01

    Full Text Available Targeting epigenetic changes in gene expression in cancer cells may offer new strategies for the development of selective cancer therapies. In the present study, we investigated coumestrol, a natural compound exhibiting broad anti-cancer effects against skin melanoma, lung cancer and colon cancer cell growth. Haspin kinase was identified as a direct target protein of coumestrol using kinase profiling analysis. Histone H3 is a direct substrate of haspin kinase. We observed haspin kinase overexpression as well as greater phosphorylation of histone H3 at threonine 3 (Thr-3 in the cancer cells compared to normal cells. Computer modeling using the Schrödinger Suite program identified the binding interface within the ATP binding site. These findings suggest that the anti-cancer effect of coumestrol is due to the direct targeting of haspin kinase. Coumestrol has considerable potential for further development as a novel anti-cancer agent.

  9. Evaluation of Multimodal Imaging Biomarkers of Prostate Cancer

    Science.gov (United States)

    2016-11-01

    relationship prostate cancer growth, androgen receptor (AR) levels, hypoxia, and translocator protein (TSPO) levels. As described in the statement of work... bladder uptake) that enable robust detection of small prostate cancers . In contrast, high background and variable uptake of FDHT and FMISO confounded the...Award Number: W81XWH-12-1-0245 TITLE: Evaluation of Multimodal Imaging Biomarkers of Prostate Cancer PRINCIPAL INVESTIGATOR: Christopher Chad

  10. Proteomic Approaches in Biomarker Discovery: New Perspectives in Cancer Diagnostics

    Science.gov (United States)

    Kocevar, Nina; Komel, Radovan

    2014-01-01

    Despite remarkable progress in proteomic methods, including improved detection limits and sensitivity, these methods have not yet been established in routine clinical practice. The main limitations, which prevent their integration into clinics, are high cost of equipment, the need for highly trained personnel, and last, but not least, the establishment of reliable and accurate protein biomarkers or panels of protein biomarkers for detection of neoplasms. Furthermore, the complexity and heterogeneity of most solid tumours present obstacles in the discovery of specific protein signatures, which could be used for early detection of cancers, for prediction of disease outcome, and for determining the response to specific therapies. However, cancer proteome, as the end-point of pathological processes that underlie cancer development and progression, could represent an important source for the discovery of new biomarkers and molecular targets for tailored therapies. PMID:24550697

  11. Xenopatients 2.0: reprogramming the epigenetic landscapes of patient-derived cancer genomes.

    Science.gov (United States)

    Menendez, Javier A; Alarcón, Tomás; Corominas-Faja, Bruna; Cuyàs, Elisabet; López-Bonet, Eugeni; Martin, Angel G; Vellon, Luciano

    2014-01-01

    In the science-fiction thriller film Minority Report, a specialized police department called "PreCrime" apprehends criminals identified in advance based on foreknowledge provided by 3 genetically altered humans called "PreCogs". We propose that Yamanaka stem cell technology can be similarly used to (epi)genetically reprogram tumor cells obtained directly from cancer patients and create self-evolving personalized translational platforms to foresee the evolutionary trajectory of individual tumors. This strategy yields a large stem cell population and captures the cancer genome of an affected individual, i.e., the PreCog-induced pluripotent stem (iPS) cancer cells, which are immediately available for experimental manipulation, including pharmacological screening for personalized "stemotoxic" cancer drugs. The PreCog-iPS cancer cells will re-differentiate upon orthotopic injection into the corresponding target tissues of immunodeficient mice (i.e., the PreCrime-iPS mouse avatars), and this in vivo model will run through specific cancer stages to directly explore their biological properties for drug screening, diagnosis, and personalized treatment in individual patients. The PreCog/PreCrime-iPS approach can perform sets of comparisons to directly observe changes in the cancer-iPS cell line vs. a normal iPS cell line derived from the same human genetic background. Genome editing of PreCog-iPS cells could create translational platforms to directly investigate the link between genomic expression changes and cellular malignization that is largely free from genetic and epigenetic noise and provide proof-of-principle evidence for cutting-edge "chromosome therapies" aimed against cancer aneuploidy. We might infer the epigenetic marks that correct the tumorigenic nature of the reprogrammed cancer cell population and normalize the malignant phenotype in vivo. Genetically engineered models of conditionally reprogrammable mice to transiently express the Yamanaka stemness factors

  12. Cancer-germline antigen vaccines and epigenetic enhancers

    DEFF Research Database (Denmark)

    Gjerstorff, Morten Frier; Burns, Jorge; Ditzel, Henrik Jorn

    2010-01-01

    IMPORTANCE OF THE FIELD: Immunotherapy holds great potential for disseminated cancer, and cancer-germline (CG) antigens are among the most promising tumor targets. They are widely expressed in different cancer types and are essentially tumor-specific, since their expression in normal tissues is l...

  13. Prostate cancer: The main risk and protective factors-Epigenetic modifications.

    Science.gov (United States)

    Adjakly, Mawussi; Ngollo, Marjolaine; Dagdemir, Aslihan; Judes, Gaëlle; Pajon, Amaury; Karsli-Ceppioglu, Seher; Penault-Llorca, Frédérique; Boiteux, Jean-Paul; Bignon, Yves-Jean; Guy, Laurent; Bernard-Gallon, Dominique

    2015-02-01

    With 13 million new cases worldwide every year, prostate cancer is as a very real public health concern. Prostate cancer is common in over-50s men and the sixth-leading cause of cancer-related death in men worldwide. Like all cancers, prostate cancer is multifactorial - there are non-modifiable risk factors like heredity, ethnicity and geographic location, but also modifiable risk factors such as diet. Diet-cancer linkages have risen to prominence in the last few years, with accruing epidemiological data pointing to between-population incidence differentials in numerous cancers. Indeed, there are correlations between fat-rich diet and risk of hormone-dependent cancers like prostate cancer and breast cancer. Diet is a risk factor for prostate cancer, but certain micronutrients in specific diets are considered protective factors against prostate cancer. Examples include tomato lycopene, green tea epigallocatechin gallate, and soy phytoestrogens. These micronutrients are thought to exert cancer-protective effects via anti-oxidant pathways and inhibition of cell proliferation. Here, we focus in on the effects of phytoestrogens, and chiefly genistein and daidzein, which are the best-researched to date. Soy phytoestrogens are nonsteroid molecules whose structural similarity lends them the ability to mimic the effects of 17ß-estradiol. On top of anti-oxidant effects, there is evidence that soy phytoestrogens can modulate the epigenetic modifications found in prostate cancer. We also studied the impact of phytoestrogens on epigenetic modifications in prostate cancer, with special focus on DNA methylation, miRNA-mediated regulation and histone modifications. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  14. Genetic variants of methyl metabolizing enzymes and epigenetic regulators: Associations with promoter CpG island hypermethylation in colorectal cancer

    NARCIS (Netherlands)

    Vogel, S. de; Wouters, K.A.D.; Gottschalk, R.W.H.; Schooten, F.J. van; Goeij, A.F.P.M. de; Bruïne, A.P. de; Goldbohm, R.A.; Brandt, P.A. van den; Weijenberg, M.P.; Engeland, M. van

    2009-01-01

    Aberrant DNA methylation affects carcinogenesis of colorectal cancer. Folate metabolizing enzymes may influence the bioavailability of methyl groups, whereas DNA and histone methyltransferases are involved in epigenetic regulation of gene expression. We studied associations of genetic variants of

  15. Evaluation of a Serum Lung Cancer Biomarker Panel.

    Science.gov (United States)

    Mazzone, Peter J; Wang, Xiao-Feng; Han, Xiaozhen; Choi, Humberto; Seeley, Meredith; Scherer, Richard; Doseeva, Victoria

    2018-01-01

    A panel of 3 serum proteins and 1 autoantibody has been developed to assist with the detection of lung cancer. We aimed to validate the accuracy of the biomarker panel in an independent test set and explore the impact of adding a fourth serum protein to the panel, as well as the impact of combining molecular and clinical variables. The training set of serum samples was purchased from commercially available biorepositories. The testing set was from a biorepository at the Cleveland Clinic. All lung cancer and control subjects were >50 years old and had smoked a minimum of 20 pack-years. A panel of biomarkers including CEA (carcinoembryonic antigen), CYFRA21-1 (cytokeratin-19 fragment 21-1), CA125 (carbohydrate antigen 125), HGF (hepatocyte growth factor), and NY-ESO-1 (New York esophageal cancer-1 antibody) was measured using immunoassay techniques. The multiple of the median method, multivariate logistic regression, and random forest modeling was used to analyze the results. The training set consisted of 604 patient samples (268 with lung cancer and 336 controls) and the testing set of 400 patient samples (155 with lung cancer and 245 controls). With a threshold established from the training set, the sensitivity and specificity of both the 4- and 5-biomarker panels on the testing set was 49% and 96%, respectively. Models built on the testing set using only clinical variables had an area under the receiver operating characteristic curve of 0.68, using the biomarker panel 0.81 and by combining clinical and biomarker variables 0.86. This study validates the accuracy of a panel of proteins and an autoantibody in a population relevant to lung cancer detection and suggests a benefit to combining clinical features with the biomarker results.

  16. Epigenetic regulation of miRNA-cancer stem cells nexus by nutraceuticals.

    Science.gov (United States)

    Ahmad, Aamir; Li, Yiwei; Bao, Bin; Kong, Dejuan; Sarkar, Fazlul H

    2014-01-01

    Nutraceuticals, the bioactive food components represented by many naturally occurring dietary compounds, have been investigated for a few decades for their numerous beneficial effects, including their anticancer properties. The initial interest in the cancer-preventing/therapeutic ability of these agents was based on their ability to affect multiple signaling pathways that are deregulated in cancer cells. With a shift in the focus of cancer research to the emerging areas such as epigenetic regulation, microRNAs (miRNAs) and the cancer stem cells (CSCs), nutraceuticals initially appeared out of place. However, research investigations over the last several years have slowly but firmly presented evidence that supports a relevance of these agents in modern day research. While nutraceuticals are increasingly being realized to alter miRNA/CSCs expression and function, the molecular mechanism(s) are not very clearly understood. Epigenetic regulation is one mechanism by which these agents exert their anticancer effects. In this focused mini review, we summarize our current understanding of epigenetic regulation of miRNAs and CSCs by nutraceuticals. We discuss both direct and indirect evidences that support such an activity of these compounds. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Molecular Biomarkers in the Clinical Management of Prostate Cancer.

    Science.gov (United States)

    Udager, Aaron M; Tomlins, Scott A

    2018-01-08

    Prostate cancer, one of the most common noncutaneous malignancies in men, is a heterogeneous disease with variable clinical outcome. Although the majority of patients harbor indolent tumors that are essentially cured by local therapy, subsets of patients present with aggressive disease or recur/progress after primary treatment. With this in mind, modern clinical approaches to prostate cancer emphasize the need to reduce overdiagnosis and overtreatment via personalized medicine. Advances in our understanding of prostate cancer pathogenesis, coupled with recent technologic innovations, have facilitated the development and validation of numerous molecular biomarkers, representing a range of macromolecules assayed from a variety of patient sample types, to help guide the clinical management of prostate cancer, including early detection, diagnosis, prognostication, and targeted therapeutic selection. Herein, we review the current state of the art regarding prostate cancer molecular biomarkers, emphasizing those with demonstrated utility in clinical practice. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

  18. Emerging biomarkers for cancer immunotherapy in melanoma.

    Science.gov (United States)

    Axelrod, Margaret L; Johnson, Douglas B; Balko, Justin M

    2017-09-14

    The treatment and prognosis of metastatic melanoma has changed substantially since the advent of novel immune checkpoint inhibitors (ICI), agents that enhance the anti-tumor immune response. Despite the success of these agents, clinically actionable biomarkers to aid patient and regimen selection are lacking. Herein, we summarize and review the evidence for candidate biomarkers of response to ICIs in melanoma. Many of these candidates can be examined as parts of a known molecular pathway of immune response, while others are clinical in nature. Due to the ability of ICIs to illicit dramatic and durable responses, well-validated biomarkers that can be effectively implemented in the clinic will require strong negative predictive values that do not limit patients with who may benefit from ICI therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Advances in molecular biomarkers for gastric cancer: miRNAs as emerging novel cancer markers.

    Science.gov (United States)

    Wu, Hua-Hsi; Lin, Wen-chang; Tsai, Kuo-Wang

    2014-01-23

    Carcinoma of the stomach is one of the most prevalent cancer types in the world. Although the incidence of gastric cancer is declining, the outcomes of gastric cancer patients remain dismal because of the lack of effective biomarkers to detect early gastric cancer. Modern biomedical research has explored many potential gastric cancer biomarker genes by utilising serum protein antigens, oncogenic genes or gene families through improving molecular biological technologies, such as microarray, RNA-Seq and the like. Recently, the small noncoding microRNAs (miRNAs) have been suggested to be critical regulators in the oncogenesis pathways and to serve as useful clinical biomarkers. This new class of biomarkers is emerging as a novel molecule for cancer diagnosis and prognosis, including gastric cancer. By translational suppression of target genes, miRNAs play a significant role in the gastric cancer cell physiology and tumour progression. There are potential implications of previously discovered gastric cancer molecular biomarkers and their expression modulations by respective miRNAs. Therefore, many miRNAs are found to play oncogenic roles or tumour-suppressing functions in human cancers. With the surprising stability of miRNAs in tissues, serum or other body fluids, miRNAs have emerged as a new type of cancer biomarker with immeasurable clinical potential.

  20. Exosomal miRNAs as biomarkers for prostate cancer

    Directory of Open Access Journals (Sweden)

    Nina Pettersen Hessvik

    2013-03-01

    Full Text Available miRNAs are small non-coding RNAs that finely regulate gene expression in cells. Alterations in miRNA expression have been associated with development of cancer, and miRNAs are now being investigated as biomarkers for cancer as well as other diseases. Recently, miRNAs have been found outside cells in body fluids. Extracellular miRNAs exist in different forms - associated with Ago2 proteins, loaded into extracellular vesicles (exosomes, microvesicles or apoptotic bodies or into high density lipoprotein particles. These extracellular miRNAs are probably products of distinct cellular processes, and might therefore play different roles. However, their functions in vivo are currently unknown. In spite of this, they are considered as promising, noninvasive diagnostic and prognostic tools. Prostate cancer is the most common cancer in men in the Western world, but the currently used biomarker (prostate specific antigen has low specificity. Therefore, novel biomarkers are highly needed. In this review we will discuss possible biological functions of extracellular miRNAs, as well as the potential use of miRNAs from extracellular vesicles as biomarkers for prostate cancer.

  1. Involvement of epigenetic modifiers in the pathogenesis of testicular dysgenesis and germ cell cancer

    DEFF Research Database (Denmark)

    Lawaetz, Andreas C.; Almstrup, Kristian

    2015-01-01

    Testicular germ cell cancer manifests mainly in young adults as a seminoma or non-seminoma. The solid tumors are preceded by the presence of a non-invasive precursor cell, the carcinoma in situ cell (CIS), which shows great similarity to fetal germ cells. It is therefore hypothesized that the CIS...... of epigenetic modifiers with a focus on jumonji C enzymes in the development of testicular dysgenesis and germ cell cancer in men....... cell is a fetal germ cell that has been arrested during development due to testicular dysgenesis. CIS cells retain a fetal and open chromatin structure, and recently several epigenetic modifiers have been suggested to be involved in testicular dysgenesis in mice. We here review the possible involvement...

  2. Biomarkers in prostate cancer - Current clinical utility and future perspectives.

    Science.gov (United States)

    Kretschmer, Alexander; Tilki, Derya

    2017-12-01

    Current tendencies in the treatment course of prostate cancer patients increase the need for reliable biomarkers that help in decision-making in a challenging clinical setting. Within the last decade, several novel biomarkers have been introduced. In the following comprehensive review article, we focus on diagnostic (PHI ® , 4K score, SelectMDx ® , ConfirmMDx ® , PCA3, MiPS, ExoDX ® , mpMRI) and prognostic (OncotypeDX GPS ® , Prolaris ® , ProMark ® , DNA-ploidy, Decipher ® ) biomarkers that are in widespread clinical use and are supported by evidence. Hereby, we focus on multiple clinical situations in which innovative biomarkers may guide decision-making in prostate cancer therapy. In addition, we describe novel liquid biopsy approaches (circulating tumor cells, cell-free DNA) that have been described as predictive biomarkers in metastatic castration-resistant prostate cancer and might support an individual patient-centred oncological approach in the nearer future. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. MicroRNAs as New Characters in the Plot between Epigenetics and Prostate Cancer

    OpenAIRE

    Paone, Alessio; Galli, Roberta; Fabbri, Muller

    2011-01-01

    Prostate cancer (PCA) still represents a leading cause of death. An increasing number of studies have documented that microRNAs (miRNAs), a subgroup of non-coding RNAs with gene regulatory functions, are differentially expressed in PCA respect to the normal tissue counterpart, suggesting their involvement in prostate carcinogenesis and dissemination. Interestingly, it has been shown that miRNAs undergo the same regulatory mechanisms than any other protein coding gene, including epigenetic reg...

  4. Cancer associated epigenetic transitions identified by genome-wide histone methylation binding profiles in human colorectal cancer samples and paired normal mucosa

    International Nuclear Information System (INIS)

    Enroth, Stefan; Rada-Iglesisas, Alvaro; Andersson, Robin; Wallerman, Ola; Wanders, Alkwin; Påhlman, Lars; Komorowski, Jan; Wadelius, Claes

    2011-01-01

    Despite their well-established functional roles, histone modifications have received less attention than DNA methylation in the cancer field. In order to evaluate their importance in colorectal cancer (CRC), we generated the first genome-wide histone modification profiles in paired normal colon mucosa and tumor samples. Chromatin immunoprecipitation and microarray hybridization (ChIP-chip) was used to identify promoters enriched for histone H3 trimethylated on lysine 4 (H3K4me3) and lysine 27 (H3K27me3) in paired normal colon mucosa and tumor samples from two CRC patients and for the CRC cell line HT29. By comparing histone modification patterns in normal mucosa and tumors, we found that alterations predicted to have major functional consequences were quite rare. Furthermore, when normal or tumor tissue samples were compared to HT29, high similarities were observed for H3K4me3. However, the differences found for H3K27me3, which is important in determining cellular identity, indicates that cell lines do not represent optimal tissue models. Finally, using public expression data, we uncovered previously unknown changes in CRC expression patterns. Genes positive for H3K4me3 in normal and/or tumor samples, which are typically already active in normal mucosa, became hyperactivated in tumors, while genes with H3K27me3 in normal and/or tumor samples and which are expressed at low levels in normal mucosa, became hypersilenced in tumors. Genome wide histone modification profiles can be used to find epigenetic aberrations in genes associated with cancer. This strategy gives further insights into the epigenetic contribution to the oncogenic process and may identify new biomarkers

  5. Epigenetic regulation of APC in the molecular pathogenesis of gallbladder cancer.

    Science.gov (United States)

    Tekcham, Dinesh Singh; Poojary, Satish S; Bhunia, Shushruta; Barbhuiya, Mustafa Ahmed; Gupta, Sanjeev; Shrivastav, Braj Raj; Tiwari, Pramod Kumar

    2016-05-01

    Loss of function of adenomatous polyposis coli (APC) has been reported in cancer. The two promoters of APC, 1A and 1B also have roles in cancer. But, the epigenetic role of APC promoters is not yet clear in gallbladder cancer (GBC) and gallstone diseases (GSD). We undertook this study to determine the epigenetic role of APC in GBC and GSD. Methylation-specific (MS)-PCR was used to analyze the methylation of APC gene. The expression of APC gene was studied by semi-quantitative PCR, real-time PCR and immunohistochemistry (IHC) in GBC, GSD and adjacent normal tissues. Of the two promoters, APC 1A promoter was found methylated in 96 per cent GBC ( P=0.0155) and 80 per cent GSD (P=0.015). Exon 1 was downregulated in grade II (P=0.002) and grade III (P=0.0001) of GBC, while exon 2 was normally expressed. Scoring analysis of IHC revealed 0 or negativity in 34.48 per cent (P=0.057) and 1+ in 24.14 per cent (P=0.005) GBC cases suggesting loss of APC expression. The present findings indicate epigenetic silencing of APC in advanced GBC. The methylation pattern, followed by expression analysis of APC may be suggested for diagnostic, prognostic and therapeutic purposes in GBC in future.

  6. Podoplanin - an emerging cancer biomarker and therapeutic target.

    Science.gov (United States)

    Krishnan, Harini; Rayes, Julie; Miyashita, Tomoyuki; Ishii, Genichiro; Retzbach, Edward P; Sheehan, Stephanie A; Takemoto, Ai; Chang, Yao-Wen; Yoneda, Kazue; Asai, Jun; Jensen, Lasse; Chalise, Lushun; Natsume, Atsushi; Goldberg, Gary S

    2018-03-25

    Podoplanin (PDPN) is a transmembrane receptor glycoprotein that is upregulated on transformed cells, cancer associated fibroblasts (CAFs), and inflammatory macrophages that contribute to cancer progression. In particular, PDPN increases tumor cell clonal capacity, epithelial mesenchymal transition (EMT), migration, invasion, metastasis, and inflammation. Antibodies, CAR-T cells, biologics, and synthetic compounds that target PDPN can inhibit cancer progression and septic inflammation in preclinical models. This review describes recent advances in how PDPN may be used as a biomarker and therapeutic target for many types of cancer including glioma, squamous cell carcinoma, mesothelioma, and melanoma. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  7. Biomarker in Cisplatin-Based Chemotherapy for Urinary Bladder Cancer.

    Science.gov (United States)

    Ecke, Thorsten H

    2015-01-01

    The treatment of metastasized bladder cancer has been evolving during recent years. Cisplatin based chemotherapy combinations are still gold standard in the treatment of advanced and metastasized bladder cancer. But new therapies are approaching. Based to this fact biological markers will become more important for decisions in bladder cancer treatment. A systematic MEDLINE search of the key words "cisplatin", "bladder cancer", "DNA marker", "protein marker", "methylation biomarker", "predictive marker", "prognostic marker" has been made. This review aims to highlight the most relevant clinical and experimental studies investigating markers for metastasized transitional carcinoma of the urothelium treated by cisplatin based regimens.

  8. Resolving breast cancer heterogeneity by searching reliable protein cancer biomarkers in the breast fluid secretome

    International Nuclear Information System (INIS)

    Mannello, Ferdinando; Ligi, Daniela

    2013-01-01

    One of the major goals in cancer research is to find and evaluate the early presence of biomarkers in human fluids and tissues. To resolve the complex cell heterogeneity of a tumor mass, it will be useful to characterize the intricate biomolecular composition of tumor microenvironment (the so called cancer secretome), validating secreted proteins as early biomarkers of cancer initiation and progression. This approach is not broadly applicable because of the paucity of well validated and FDA-approved biomarkers and because most of the candidate biomarkers are mainly organ-specific rather than tumor-specific. For these reasons, there is an urgent need to identify and validate a panel of biomarker combinations for early detection of human tumors. This is especially important for breast cancer, the cancer spread most worldwide among women. It is well known that patients with early diagnosed breast cancer live longer, require less extensive treatment and fare better than patients with more aggressive and/or advanced disease. In the frame of searching breast cancer biomarkers (especially using nipple aspirate fluid mirroring breast microenvironment), studies have highlighted an optimal combination of well-known biomarkers: uPA + PAI-1 + TF. When individually investigated they did not show perfect accuracy in predicting the presence of breast cancer, whereas the triple combination has been demonstrated to be highly predictive of pre-cancer and/or cancerous conditions, approaching 97-100% accuracy. Despite the heterogeneous composition of breast cancer and the difficulties to find specific breast cancer biomolecules, the noninvasive analysis of the nipple aspirate fluid secretome may significantly improve the discovery of promising biomarkers, helping also the differentiation among benign and invasive breast diseases, opening new frontiers in early oncoproteomics

  9. Prognostic and predictive biomarkers in colorectal cancer. Towards precision medicine

    NARCIS (Netherlands)

    Reimers, Marlies Suzanne

    2015-01-01

    The aim of this thesis was to define prognostic and predictive biomarkers in colorectal cancer for improved risk stratification and treatment benefit in the individual patient, with the introduction of precision medicine in the near future as the ultimate goal. By definition, precision medicine is

  10. Prostate cancer biomarker profiles in urinary sediments and exosomes

    NARCIS (Netherlands)

    Dijkstra, Siebren; Birker, Ingrid L.; Smit, Frank P.; Leyten, Gisele H. J. M.; de Reijke, Theo M.; van Oort, Inge M.; Mulders, Peter F. A.; Jannink, Sander A.; Schalken, Jack A.

    2014-01-01

    Urinary biomarker tests for diagnosing prostate cancer have gained considerable interest. Urine is a complex mixture that can be subfractionated. We evaluated 2 urinary fractions that contain nucleic acids, ie cell pellets and exosomes. The influence of digital rectal examination before urine

  11. Prostate cancer biomarker profiles in urinary sediments and exosomes

    NARCIS (Netherlands)

    Dijkstra, S.; Birker, I.L.; Smit, F.P.; Leyten, G.H.J.M.; Reijke, T.M. de; Oort, I.M. van; Mulders, P.F.A.; Jannink, S.A.; Schalken, J.A.

    2014-01-01

    PURPOSE: Urinary biomarker tests for diagnosing prostate cancer have gained considerable interest. Urine is a complex mixture that can be subfractionated. We evaluated 2 urinary fractions that contain nucleic acids, ie cell pellets and exosomes. The influence of digital rectal examination before

  12. A review of molecular biomarkers for bladder cancer

    African Journals Online (AJOL)

    McRoy

    Volume 2 Issue 3 September – December 2013 ... methodology were identified but only half of them have shown consistence ... Conclusion: It is envisaged that a combination ... biomarkers for bladder cancer are adopted in the UK standard practice. ... words used for the literature review were ..... Multi centre validation.

  13. Exosomal Proteins as a Diagnostic Biomarkers in Lung Cancer

    DEFF Research Database (Denmark)

    Sandfeld-Paulsen, B; Jakobsen, K R; Bæk, R

    2016-01-01

    INTRODUCTION: Exosomes have been suggested as promising biomarkers in NSCLC because they contain proteins from their originating cells and are readily available in plasma. In this study, we explored the potential of exosome protein profiling in diagnosing lung cancers of all stages and various...

  14. Comprehensive Evaluation of TFF3 Promoter Hypomethylation and Molecular Biomarker Potential for Prostate Cancer Diagnosis and Prognosis

    DEFF Research Database (Denmark)

    Nørgaard, Maibritt; Haldrup, Christa; Storebjerg, Tine Maj

    2017-01-01

    Overdiagnosis and overtreatment of clinically insignificant tumors remains a major problem in prostate cancer (PC) due to suboptimal diagnostic and prognostic tools. Thus, novel biomarkers are urgently needed. In this study, we investigated the biomarker potential of Trefoil factor 3 (TFF3......) promoter methylation and RNA expression levels for PC. Initially, by quantitative methylation specific PCR (qMSP) analysis of a large radical prostatectomy (RP) cohort (n = 292), we found that the TFF3 promoter was significantly hypomethylated in PC compared to non-malignant (NM) prostate tissue samples (p....... 67 NM) analyzed by Illumina 450K DNA methylation arrays and/or RNA sequencing. TFF3 promoter methylation and transcriptional expression levels were inversely correlated, suggesting that epigenetic mechanisms contribute to the regulation of gene activity. Furthermore, low TFF3 expression...

  15. Epigenetic Mechanisms of Folate Nutrition in Breast Cancer

    Science.gov (United States)

    2012-04-01

    MDAMB231 clones that express non-leaky TetR systems. Test effects of folate deficiency on global and gene specific DNA methylation and gene...cellular differentiation and function. Aberrant DNA methylation is a characteristic of cancer cells, including mammary tumors. The B vitamin folate ...relationships between folate , one-carbon metabolism, DNA methylation , and gene expression within the context of breast cancer. We hypothesize that

  16. New insights into the epigenetics of inflammatory rheumatic diseases.

    Science.gov (United States)

    Ballestar, Esteban; Li, Tianlu

    2017-10-01

    Over the past decade, awareness of the importance of epigenetic alterations in the pathogenesis of rheumatic diseases has grown in parallel with a general recognition of the fundamental role of epigenetics in the regulation of gene expression. Large-scale efforts to generate genome-wide maps of epigenetic modifications in different cell types, as well as in physiological and pathological contexts, illustrate the increasing recognition of the relevance of epigenetics. To date, although several reports have demonstrated the occurrence of epigenetic alterations in a wide range of inflammatory rheumatic conditions, epigenomic information is rarely used in a clinical setting. By contrast, several epigenetic biomarkers and treatments are currently in use for personalized therapies in patients with cancer. This Review highlights advances from the past 5 years in the field of epigenetics and their application to inflammatory rheumatic diseases, delineating the future lines of development for a rational use of epigenetic information in clinical settings and in personalized medicine. These advances include the identification of epipolymorphisms associated with clinical outcomes, DNA methylation as a contributor to disease susceptibility in rheumatic conditions, the discovery of novel epigenetic mechanisms that modulate disease susceptibility and the development of new epigenetic therapies.

  17. Epigenetic mechanisms in the initiation of hematological malignancies

    Directory of Open Access Journals (Sweden)

    Ali Maleki

    2011-10-01

    Full Text Available Background: Cancer development is not restricted to the genetic changes, but also to epigenetic changes. Epigenetic processes are very important in the development of hematological malignancies. The main epigenetic alterations are aberrations in DNA methylation, post-translational modifications of histones, chromatin remodeling and microRNAs patterns, and these are associated with tumor genesis. All the various cellular pathways contributing to the neoplastic phenotype are affected by epigenetic genes in cancer. These pathways can be explored as biomarkers in clinical use for early detection of disease, malignancy classification and response to treatment with classical chemotherapy agents and epigenetic drugs. Materials and Method: A literature review was performed using PUBMED from 1985 to 2008. Cross referencing of discovered articles was also reviewed.Results: In chronic lymphocytic leukemia, regional hypermethylation of gene promoters leads to gene silencing. Many of these genes have tumor suppressor phenotypes. In myelodysplastic syndrome (MDS, CDKN2B (alias, P15, a cyclin-dependent kinase inhibitor that negatively regulates the cell cycle, has been shown to be hypermethylated in marrow stem (CD34+ cells in patients with MDS. At present both Vidaza and Decitabine (DNA methyltransferase inhibitors are approved for the treatment of MDS.Conclusion: Unlike mutations or deletions, DNA hypermethylation and histone deacetylation are potentially reversible by pharmacological inhibition, therefore those epigenetic changes have been recognized as promising novel therapeutic targets in hematopoietic malignances. In this review, we discussed molecular mechanisms of epigenetics, epigenetic changes in hematological malignancies and epigenetic based treatments

  18. Increased expression of long noncoding RNA TUG1 predicts a poor prognosis of gastric cancer and regulates cell proliferation by epigenetically silencing of p57.

    Science.gov (United States)

    Zhang, E; He, X; Yin, D; Han, L; Qiu, M; Xu, T; Xia, R; Xu, L; Yin, R; De, W

    2016-02-25

    Recent evidence highlights long noncoding RNAs (lncRNAs) as crucial regulators of cancer biology that contribute to tumorigenesis. LncRNA TUG1 was initially detected in a genomic screen for genes upregulated in response to taurine treatment in developing mouse retinal cells. Our previous study showed that TUG1 could affect cell proliferation through epigenetically regulating HOXB7 in human non-small cell lung cancer. However, the clinical significance and potential role of TUG1 in GC remains unclear. In this study, we found that TUG1 is significantly increased and is correlated with outcomes in gastric cancer (GC). Further experiments revealed that knockdown of TUG1 repressed GC proliferation both in vitro and in vivo. Mechanistic investigations showed that TUG1 has a key role in G0/G1 arrest. We further demonstrated that TUG1 was associated with PRC2 and that this association was required for epigenetic repression of cyclin-dependent protein kinase inhibitors, including p15, p16, p21, p27 and p57, thus contributing to the regulation of GC cell cycle and proliferation. Together, our results suggest that TUG1, as a regulator of proliferation, may serve as a candidate prognostic biomarker and target for new therapies in human GC.

  19. Potential of epigenetic therapies in the management of solid tumors

    International Nuclear Information System (INIS)

    Valdespino, Victor; Valdespino, Patricia M

    2015-01-01

    Cancer is a complex disease with both genetic and epigenetic origins. The growing field of epigenetics has contributed to our understanding of oncogenesis and tumor progression, and has allowed the development of novel therapeutic drugs. First-generation epigenetic inhibitor drugs have obtained modest clinical results in two types of hematological malignancy. Second-generation epigenetic inhibitors are in development, and have intrinsically greater selectivity for their molecular targets. Solid tumors are more genetic and epigenetically complex than hematological malignancies, but the transcriptome and epigenome biomarkers have been identified for many of these malignancies. This solid tumor molecular aberration profile may be modified using specific or quasi-specific epidrugs together with conventional and innovative anticancer treatments. In this critical review, we briefly analyze the strategies to select the targeted epigenetic changes, enumerate the second-generation epigenetic inhibitors, and describe the main signs indicating the potential of epigenetic therapies in the management of solid tumors. We also highlight the work of consortia or academic organizations that support the undertaking of human epigenetic therapeutic projects as well as some examples of transcriptome/epigenome profile determination in clinical assessment of cancer patients treated with epidrugs. There is a good chance that epigenetic therapies will be able to be used in patients with solid tumors in the future. This may happen soon through collaboration of diverse scientific groups, making the selection of targeted epigenetic aberration(s) more rapid, the design and probe of drug candidates, accelerating in vitro and in vivo assays, and undertaking new cancer epigenetic-therapy clinical trails

  20. Procaine Induces Epigenetic Changes in HCT116 Colon Cancer Cells

    Directory of Open Access Journals (Sweden)

    Hussein Sabit

    2016-01-01

    Full Text Available Colon cancer is the third most commonly diagnosed cancer in the world, and it is the major cause of morbidity and mortality throughout the world. The present study aimed at treating colon cancer cell line (HCT116 with different chemotherapeutic drug/drug combinations (procaine, vorinostat “SAHA,” sodium phenylbutyrate, erlotinib, and carboplatin. Two different final concentrations were applied: 3 μM and 5 μM. Trypan blue test was performed to assess the viability of the cell before and after being treated with the drugs. The data obtained showed that there was a significant decrease in the viability of cells after applying the chemotherapeutic drugs/drug combinations. Also, DNA fragmentation assay was carried out to study the effect of these drugs on the activation of apoptosis-mediated DNA degradation process. The results indicated that all the drugs/drug combinations had a severe effect on inducing DNA fragmentation. Global DNA methylation quantification was performed to identify the role of these drugs individually or in combination in hypo- or hypermethylating the CpG dinucleotide all over the genome of the HCT116 colon cancer cell line. Data obtained indicated that different combinations had different effects in reducing or increasing the level of methylation, which might indicate the effectiveness of combining drugs in treating colon cancer cells.

  1. The contribution of cholesterol and epigenetic changes to the pathophysiology of breast cancer.

    Science.gov (United States)

    Munir, Maliha T; Ponce, Christopher; Powell, Catherine A; Tarafdar, Kaiser; Yanagita, Teru; Choudhury, Mahua; Gollahon, Lauren S; Rahman, Shaikh M

    2018-05-04

    Breast cancer is one of the most commonly diagnosed cancers in women. Accumulating evidence suggests that cholesterol plays an important role in the development of breast cancer. Even though the mechanistic link between these two factors is not well understood, one possibility is that dysregulated cholesterol metabolism may affect lipid raft and membrane fluidity and can promote tumor development. Current studies have shown oxysterol 27-hydroxycholesterol (27-HC) as a critical regulator of cholesterol and breast cancer pathogenesis. This is supported by the significantly higher expression of CYP27A1 (cytochrome P450, family 27, subfamily A, polypeptide 1) in breast cancers. This enzyme is responsible for 27-HC synthesis from cholesterol. It has been shown that 27-HC can not only increase the proliferation of estrogen receptor (ER)-positive breast cancer cells but also stimulate tumor growth and metastasis in several breast cancer models. This phenomenon is surprising since 27-HC and other oxysterols generally reduce intracellular cholesterol levels by activating the liver X receptors (LXRs). Resolving this paradox will elucidate molecular pathways by which cholesterol, ER, and LXR are connected to breast cancer. These findings will also provide the rationale for evaluating pharmaceutical approaches that manipulate cholesterol or 27-HC synthesis in order to mitigate the impact of cholesterol on breast cancer pathophysiology. In addition to cholesterol, epigenetic changes including non-coding RNAs, and microRNAs, DNA methylation, and histone modifications, have all been shown to control tumorigenesis. The purpose of this review is to discuss the link between altered cholesterol metabolism and epigenetic modification during breast cancer progression. Copyright © 2018. Published by Elsevier Ltd.

  2. Targeting Epigenetics Therapy for Estrogen Receptor-Negative Breast Cancers

    Science.gov (United States)

    2014-10-01

    inhibitor of both ERα+ and ERα_ breast cancers in vivo in a clinically -relevant xenograft animal model of breast cancer. In this aim, we...34 FTA EF"! >)8?! O18-38)%9! O-O8)4-! )3?)5)81,7! 9)78-4! )3! S%59-! =BD! N17896! 8?17-! O-O8)4-7! 7?1>-4!>-%V!5)34)3*7! 81!;ɘ=!>)8?!O11,! )3?)5)8)13!%𔄂

  3. Genetic Mutations and Epigenetic Modifications: Driving Cancer and Informing Precision Medicine

    Science.gov (United States)

    Coyle, Krysta Mila; Boudreau, Jeanette E.

    2017-01-01

    Cancer treatment is undergoing a significant revolution from “one-size-fits-all” cytotoxic therapies to tailored approaches that precisely target molecular alterations. Precision strategies for drug development and patient stratification, based on the molecular features of tumors, are the next logical step in a long history of approaches to cancer therapy. In this review, we discuss the history of cancer treatment from generic natural extracts and radical surgical procedures to site-specific and combinatorial treatment regimens, which have incrementally improved patient outcomes. We discuss the related contributions of genetics and epigenetics to cancer progression and the response to targeted therapies and identify challenges and opportunities for the success of precision medicine. The identification of patients who will benefit from targeted therapies is more complex than simply identifying patients whose tumors harbour the targeted aberration, and intratumoral heterogeneity makes it difficult to determine if a precision therapy is successful during treatment. This heterogeneity enables tumors to develop resistance to targeted approaches; therefore, the rational combination of therapeutic agents will limit the threat of acquired resistance to therapeutic success. By incorporating the view of malignant transformation modulated by networks of genetic and epigenetic interactions, molecular strategies will enable precision medicine for effective treatment across cancer subtypes. PMID:28685150

  4. Combinatorial strategy of epigenetic and hormonal therapies: A novel promising approach for treating advanced prostate cancer.

    Science.gov (United States)

    Motawi, Tarek K; Darwish, Hebatallah A; Diab, Iman; Helmy, Maged W; Noureldin, Mohamed H

    2018-04-01

    Estrogens act as key factors in prostate biology, cellular proliferation and differentiation as well as cancer development and progression. The expression of estrogen receptor (ER)-β appears to be lost during prostate cancer progression through hypermethylation mechanism. Epigenetic drugs such as 5-aza-2'-deoxycytidine (5-AZAC) and Trichostatin A (TSA) showed efficacy in restoring ERβ expression in prostate cancer cells. This study was designed to explore the potential anti-carcinogenic effects resulting from re-expressing ERβ1 using 5-AZAC and/or TSA, followed by its stimulation with Diarylpropionitrile (DPN), a selective ERβ1 agonist, in prostate cancer cell line PC-3. Cells were treated with 5-AZAC, TSA, DPN and their combination. Subsequently, they were subjected to proliferation assays, determinations of ERβ1 expression, protein levels of active caspase-3, cyclin D1, β-catenin and VEGF. Treatment with these drugs exhibited an increase in ERβ1 expression to different extents as well as active caspase-3 levels. Meanwhile, a significant reduction in cyclin D1, VEGF and β-catenin levels was achieved as compared to the vehicle control group (p epigenetic and hormonal therapies may be beneficial in treating advanced prostate cancer. Copyright © 2018. Published by Elsevier Inc.

  5. The expanding role of epigenetics in the development, diagnosis and treatment of prostate cancer and benign prostatic hyperplasia.

    Science.gov (United States)

    Dobosy, Joseph R; Roberts, J Lea W; Fu, Vivian X; Jarrard, David F

    2007-03-01

    Prostate cancer research has focused significant attention on the mutation, deletion or amplification of the DNA base sequence that encodes critical growth or suppressor genes. However, these changes have left significant gaps in our understanding of the development and progression of disease. It has become clear that epigenetic changes or modifications that influence phenotype without altering the genotype present a new and entirely different mechanism for gene regulation. Several interrelated epigenetic modifications that are altered in abnormal growth states are DNA methylation changes, histone modifications and genomic imprinting. We discuss the status of epigenetic alterations in prostate cancer and benign prostatic hyperplasia progression. In addition, the rationale and status of ongoing clinical trials altering epigenetic processes in urological diseases are reviewed. An online search of current and past peer reviewed literature on DNA methylation, histone acetylation and methylation, imprinting and epigenetics in prostate cancer and benign prostatic hyperplasia was performed. Relevant articles and reviews were examined and a synopsis of reproducible data was generated with the goal of informing the practicing urologist of these advances and their implications. Only 20 years ago the first study was published demonstrating global changes in DNA methylation patterns in tumors. Accumulating data have now identified specific genes that are commonly hypermethylated and inactivated during prostate cancer progression, including GSTpi, APC, MDR1, GPX3 and 14-3-3sigma. Altered histone modifications, including acetylation and methylation, were also recently described that may modify gene function, including androgen receptor function. These epigenetic changes are now being used to assist in prostate cancer diagnosis and cancer outcome prediction. Epigenetic changes appear to have a role in benign prostatic hyperplasia development as well as in the susceptibility of

  6. MicroRNAs Induce Epigenetic Reprogramming and Suppress Malignant Phenotypes of Human Colon Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Hisataka Ogawa

    Full Text Available Although cancer is a genetic disease, epigenetic alterations are involved in its initiation and progression. Previous studies have shown that reprogramming of colon cancer cells using Oct3/4, Sox2, Klf4, and cMyc reduces cancer malignancy. Therefore, cancer reprogramming may be a useful treatment for chemo- or radiotherapy-resistant cancer cells. It was also reported that the introduction of endogenous small-sized, non-coding ribonucleotides such as microRNA (miR 302s and miR-369-3p or -5p resulted in the induction of cellular reprogramming. miRs are smaller than the genes of transcription factors, making them possibly suitable for use in clinical strategies. Therefore, we reprogrammed colon cancer cells using miR-302s and miR-369-3p or -5p. This resulted in inhibition of cell proliferation and invasion and the stimulation of the mesenchymal-to-epithelial transition phenotype in colon cancer cells. Importantly, the introduction of the ribonucleotides resulted in epigenetic reprogramming of DNA demethylation and histone modification events. Furthermore, in vivo administration of the ribonucleotides in mice elicited the induction of cancer cell apoptosis, which involves the mitochondrial Bcl2 protein family. The present study shows that the introduction of miR-302s and miR-369s could induce cellular reprogramming and modulate malignant phenotypes of human colorectal cancer, suggesting that the appropriate delivery of functional small-sized ribonucleotides may open a new avenue for therapy against human malignant tumors.

  7. Personalized Cancer Medicine: Molecular Diagnostics, Predictive biomarkers, and Drug Resistance

    Science.gov (United States)

    Gonzalez de Castro, D; Clarke, P A; Al-Lazikani, B; Workman, P

    2013-01-01

    The progressive elucidation of the molecular pathogenesis of cancer has fueled the rational development of targeted drugs for patient populations stratified by genetic characteristics. Here we discuss general challenges relating to molecular diagnostics and describe predictive biomarkers for personalized cancer medicine. We also highlight resistance mechanisms for epidermal growth factor receptor (EGFR) kinase inhibitors in lung cancer. We envisage a future requiring the use of longitudinal genome sequencing and other omics technologies alongside combinatorial treatment to overcome cellular and molecular heterogeneity and prevent resistance caused by clonal evolution. PMID:23361103

  8. Biomarkers of the Metabolic Syndrome and Breast Cancer Prognosis

    International Nuclear Information System (INIS)

    Zhu, Qiu-Li; Xu, Wang-Hong; Tao, Meng-Hua

    2010-01-01

    In spite of its public health importance, our understanding of the mechanisms of breast carcinogenesis and progress is still evolving. The metabolic syndrome (MS) is a constellation of biochemical abnormalities including visceral adiposity, hyperglycemia, hyperinsulinemia, dyslipidemia and high blood pressure. The components of the MS have all been related to late-stage disease and even to a poor prognosis of breast cancer through multiple interacting mechanisms. In this review, we aim to present a summary of recent advances in the understanding of the contribution of the MS to breast cancer with the emphasis on the role of biomarkers of the MS in the prognosis of breast cancer

  9. Biomarkers of the Metabolic Syndrome and Breast Cancer Prognosis

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Qiu-Li; Xu, Wang-Hong [Department of Epidemiology, School of Public Health, Fudan University, Shanghai 200032 (China); Tao, Meng-Hua [Department of Social and Preventive Medicine, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY 14214 (United States)

    2010-04-28

    In spite of its public health importance, our understanding of the mechanisms of breast carcinogenesis and progress is still evolving. The metabolic syndrome (MS) is a constellation of biochemical abnormalities including visceral adiposity, hyperglycemia, hyperinsulinemia, dyslipidemia and high blood pressure. The components of the MS have all been related to late-stage disease and even to a poor prognosis of breast cancer through multiple interacting mechanisms. In this review, we aim to present a summary of recent advances in the understanding of the contribution of the MS to breast cancer with the emphasis on the role of biomarkers of the MS in the prognosis of breast cancer.

  10. Epigenetic Control of Prolyl and Asparaginyl Hydroxylases in Prostate Cancer

    Science.gov (United States)

    2011-07-01

    melanoma, renal carcinoma and breast cancer cell lines. Furthermore, we show that neither HIF-1a protein levels nor hypoxic response through an HRE ...constitutively expressed gene to control for equivalent DNase digestion between the cell lines examined. HRE -Luciferase assay Cell lines ,85% confluent in 60...mm dishes were transfected with an HRE -luciferase reporter vector [19] (2.5 mg) and Renilla luciferase (1.5 mg) according to Lipofectamine 2000

  11. Gestational Exposure as Epigenetic Modifier of Breast Cancer Risk

    Science.gov (United States)

    2016-10-01

    tumor promotion in adult life is influenced by prior exposure to carcinogens in early life . The main purpose of this project is to investigate whether...development of triple- negative breast cancers (TNBC). Major findings: Preliminary data acquired through the support of this grant indicate that: 1...methylation of genes associated with the TNBC phenotype in offspring; Aim 2: To examine the combinatorial effects of gestational and postpubertal

  12. Biomarkers of Selenium Chemoprevention of Prostate Cancer

    National Research Council Canada - National Science Library

    Dong, Yan

    2003-01-01

    The purpose of the present study was to examine the mechanism of selenium growth inhibition in PC-3 human prostate cancer cells Selenium retarded cell cycle progression at multiple transition points...

  13. Exosome: emerging biomarker in breast cancer

    OpenAIRE

    Jia, Yunlu; Chen, Yongxia; Wang, Qinchuan; Jayasinghe, Ushani; Luo, Xiao; Wei, Qun; Wang, Ji; Xiong, Hanchu; Chen, Cong; Xu, Bin; Hu, Wenxian; Wang, Linbo; Zhao, Wenhe; Zhou, Jichun

    2017-01-01

    Exosomes are nano-sized membrane vesicles released by a variety of cell types, and are thought to play important roles in intercellular communications. In breast cancer, through horizontal transfer of various bioactive molecules, such as proteins and mRNAs, exosomes are emerging as local and systemic cell-to-cell mediators of oncogenic information and play an important role on cancer progression. This review outlines the current knowledge and concepts concerning the exosomes involvement in br...

  14. Epigenetic changes of DNA repair genes in cancer

    OpenAIRE

    Lahtz, Christoph; Pfeifer, Gerd P.

    2011-01-01

    ‘Every Hour Hurts, The Last One Kills'. That is an old saying about getting old. Every day, thousands of DNA damaging events take place in each cell of our body, but efficient DNA repair systems have evolved to prevent that. However, our DNA repair system and that of most other organisms are not as perfect as that of Deinococcus radiodurans, for example, which is able to repair massive amounts of DNA damage at one time. In many instances, accumulation of DNA damage has been linked to cancer, ...

  15. New Epigenetic Therapeutic Intervention for Metastatic Breast Cancer

    Science.gov (United States)

    2017-04-01

    Metastasis” 04/20/2017 Distinguished Scientist Speaker, University of Southern Alabama Mitchell Cancer Institute, Mobile , AL, “Role and Regulation...tracks for Il21 andRock2, two important genes in Th17 cell differentiation (Figure 3G ). Further, the functional dif- ferences of Brd2 and Brd4 in gene...terminal Dub3 (Fig. 2f). Consistent with this, Dub3 only stabilized the N-terminal but not the C-terminal fragments of Snail1 (Fig. 2g ). The interaction

  16. Predictive Biomarkers of Radiation Sensitivity in Rectal Cancer

    Science.gov (United States)

    Tut, Thein Ga

    Colorectal cancer (CRC) is the third most common cancer in the world. Australia, New Zealand, Canada, the United States, and parts of Europe have the highest incidence rates of CRC. China, India, South America and parts of Africa have the lowest risk of CRC. CRC is the second most common cancer in both sexes in Australia. Even though the death rates from CRC involving the colon have diminished, those arising from the rectum have revealed no improvement. The greatest obstacle in attaining a complete surgical resection of large rectal cancers is the close anatomical relation to surrounding structures, as opposed to the free serosal surfaces enfolding the colon. To assist complete resection, pre-operative radiotherapy (DXT) can be applied, but the efficacy of ionising radiation (IR) is extremely variable between individual tumours. Reliable predictive marker/s that enable patient stratification in the application of this otherwise toxic therapy is still not available. Current therapeutic management of rectal cancer can be improved with the availability of better predictive and prognostic biomarkers. Proteins such as Plk1, gammaH2AX and MMR proteins (MSH2, MSH6, MLH1 and PMS2), involved in DNA damage response (DDR) pathway may be possible biomarkers for radiation response prediction and prognostication of rectal cancer. Serine/threonine protein kinase Plk1 is overexpressed in most of cancers including CRC. Plk1 functional activity is essential in the restoration of DNA damage following IR, which causes DNA double strand break (DSB). The earliest manifestation of this reparative process is histone H2AX phosphorylation at serine 139, leading to gammaH2AX. Colorectal normal mucosa showed the lowest level of gammaH2AX with gradually increasing levels in early adenoma and then in advanced malignant colorectal tissues, leading to the possibility that gammaH2AX may be a prospective biomarker in rectal cancer management. There are numerous publications regarding DNA mismatch

  17. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

    OpenAIRE

    Shen, Hui; Fridley, Brooke L.; Song, Honglin; Lawrenson, Kate; Cunningham, Julie M.; Ramus, Susan J.; Cicek, Mine S.; Tyrer, Jonathan; Stram, Douglas; Larson, Melissa C.; Köbel, Martin; Ziogas, Argyrios; Zheng, Wei; Yang, Hannah P.; Wu, Anna H.

    2013-01-01

    HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide poly...

  18. Integrative analysis to select cancer candidate biomarkers to targeted validation

    Science.gov (United States)

    Heberle, Henry; Domingues, Romênia R.; Granato, Daniela C.; Yokoo, Sami; Canevarolo, Rafael R.; Winck, Flavia V.; Ribeiro, Ana Carolina P.; Brandão, Thaís Bianca; Filgueiras, Paulo R.; Cruz, Karen S. P.; Barbuto, José Alexandre; Poppi, Ronei J.; Minghim, Rosane; Telles, Guilherme P.; Fonseca, Felipe Paiva; Fox, Jay W.; Santos-Silva, Alan R.; Coletta, Ricardo D.; Sherman, Nicholas E.; Paes Leme, Adriana F.

    2015-01-01

    Targeted proteomics has flourished as the method of choice for prospecting for and validating potential candidate biomarkers in many diseases. However, challenges still remain due to the lack of standardized routines that can prioritize a limited number of proteins to be further validated in human samples. To help researchers identify candidate biomarkers that best characterize their samples under study, a well-designed integrative analysis pipeline, comprising MS-based discovery, feature selection methods, clustering techniques, bioinformatic analyses and targeted approaches was performed using discovery-based proteomic data from the secretomes of three classes of human cell lines (carcinoma, melanoma and non-cancerous). Three feature selection algorithms, namely, Beta-binomial, Nearest Shrunken Centroids (NSC), and Support Vector Machine-Recursive Features Elimination (SVM-RFE), indicated a panel of 137 candidate biomarkers for carcinoma and 271 for melanoma, which were differentially abundant between the tumor classes. We further tested the strength of the pipeline in selecting candidate biomarkers by immunoblotting, human tissue microarrays, label-free targeted MS and functional experiments. In conclusion, the proposed integrative analysis was able to pre-qualify and prioritize candidate biomarkers from discovery-based proteomics to targeted MS. PMID:26540631

  19. Emerging biomarkers in the diagnosis of prostate cancer

    Directory of Open Access Journals (Sweden)

    Filella X

    2018-05-01

    Full Text Available Xavier Filella, Esther Fernández-Galan, Rosa Fernández Bonifacio, Laura Foj Department of Biochemistry and Molecular Genetics (CDB, Hospital Clínic, IDIBAPS, Barcelona, Catalonia, Spain Abstract: Prostate cancer (PCa is the second most common cancer in men worldwide. A large proportion of PCa are latent, never destined to progress or affect the patients’ life. It is of utmost importance to identify which PCa are destined to progress and which would benefit from an early radical treatment. Prostate-specific antigen (PSA remains the most used test to detect PCa. Its limited specificity and an elevated rate of overdiagnosis are the main problems associated with PSA testing. New PCa biomarkers have been proposed to improve the accuracy of PSA in the management of early PCa. Commercially available biomarkers such as PCA3 score, Prostate Health Index (PHI, and the four-kallikrein panel are used with the purpose of reducing the number of unnecessary biopsies and providing information related to the aggressiveness of the tumor. The relationship with PCa aggressiveness seems to be confirmed by PHI and the four-kallikrein panel, but not by the PCA3 score. In this review, we also summarize new promising biomarkers, such as PSA glycoforms, TMPRSS2:ERG fusion gene, microRNAs, circulating tumor cells, androgen receptor variants, and PTEN gene. All these emerging biomarkers could change the management of early PCa, offering more accurate results than PSA. Nonetheless, large prospective studies comparing these new biomarkers among them are required to know their real value in PCa detection and prognosis. Keywords: prostate cancer, PSA, PHI, four-kallikrein panel, PCA3, miRNAs

  20. Redefining the impact of nutrition on breast cancer incidence: is epigenetics involved?

    Science.gov (United States)

    Teegarden, Dorothy; Romieu, Isabelle; Lelièvre, Sophie A.

    2014-01-01

    Breast cancer incidence is rising worldwide with an increase in aggressive neoplasias in young women. Possible factors involved include lifestyle changes, notably diet that is known to make an impact on gene transcription. However, among dietary factors, there is sufficient support for only greater body weight and alcohol consumption whereas numerous studies revealing an impact of specific diets and nutrients on breast cancer risk show conflicting results. Also, little information is available from middle- and low-income countries. The diversity of gene expression profiles found in breast cancers indicates that transcription control is critical for the outcome of the disease. This suggests the need for studies on nutrients that affect epigenetic mechanisms of transcription, such as DNA methylation and post-translational modifications of histones. In the present review, a new examination of the relationship between diet and breast cancer based on transcription control is proposed in light of epidemiological, animal and clinical studies. The mechanisms underlying the impact of diets on breast cancer development and factors that impede reaching clear conclusions are discussed. Understanding the interaction between nutrition and epigenetics (gene expression control via chromatin structure) is critical in light of the influence of diet during early stages of mammary gland development on breast cancer risk, suggesting a persistent effect on gene expression as shown by the influence of certain nutrients on DNA methylation. Successful development of breast cancer prevention strategies will require appropriate models, identification of biological markers for rapid assessment of preventive interventions, and coordinated worldwide research to discern the effects of diet. PMID:22853843

  1. Epigenetic modulation of cancer-germline antigen gene expression in tumorigenic human mesenchymal stem cells: implications for cancer therapy

    DEFF Research Database (Denmark)

    Gjerstorff, Morten; Burns, Jorge S; Nielsen, Ole

    2009-01-01

    Cancer-germline antigens are promising targets for cancer immunotherapy, but whether such therapies will also eliminate the primary tumor stem cell population remains undetermined. We previously showed that long-term cultures of telomerized adult human bone marrow mesenchymal stem cells can...... spontaneously evolve into tumor-initiating, mesenchymal stem cells (hMSC-TERT20), which have characteristics of clinical sarcoma cells. In this study, we used the hMSC-TERT20 tumor stem cell model to investigate the potential of cancer-germline antigens to serve as tumor stem cell targets. We found...... of cancer-germline antigens in hMSC-TERT20 cells, while their expression levels in primary human mesenchymal stem cells remained unaffected. The expression pattern of cancer-germline antigens in tumorigenic mesenchymal stem cells and sarcomas, plus their susceptibility to enhancement by epigenetic...

  2. Validation of Biomarkers for Prostate Cancer Prognosis

    Science.gov (United States)

    2013-10-01

    surgery and radiation therapy, result in well documented significant morbidities, including significant lower urinary tract symptoms such as incontinence ...and urinary urgency as well as sexual dysfunction. Furthermore, evidence from many sources suggests that most prostate cancers are relatively...pre-operative PSA (pɘ.0001). These analyses provide confidence in the clinical data because they are known factors associated with recurrence

  3. Endometrial Cancer and Hypermethylation: Regulation of DNA and MicroRNA by Epigenetics

    Directory of Open Access Journals (Sweden)

    Kouji Banno

    2012-01-01

    Full Text Available Endometrial cancer is the seventh most common cancer in women worldwide. Therefore elucidation of the pathogenesis and development of effective treatment for endometrial cancer are important. However, several aspects of the mechanism of carcinogenesis in the endometrium remain unclear. Associations with genetic variation and mutations of cancer-related genes have been shown, but these do not provide a complete explanation. Therefore, in recent years, epigenetic mechanisms that do not involve changes in DNA sequences have been examined. Studies aimed at detection of aberrant DNA hypermethylation in cancer cells present in microscopic amounts in vivo and application of the results to cancer diagnosis have also started. Breakdown of the DNA mismatch repair mechanism is thought to play a large role in the development of endometrial cancer, with changes in the expression of the hMLH1 gene being particularly important. Silencing of genes such as APC and CHFR, Sprouty 2, RASSF1A, GPR54, CDH1, and RSK4 by DNA hypermethylation, onset of Lynch syndrome due to hereditary epimutation of hMLH1 and hMSH2 mismatch repair genes, and regulation of gene expression by microRNAs may also underlie the carcinogenic mechanisms of endometrial cancer. Further understanding of these issues may permit development of new therapies.

  4. Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer.

    Science.gov (United States)

    Clermont, Pier-Luc; Crea, Francesco; Chiang, Yan Ting; Lin, Dong; Zhang, Amy; Wang, James Z L; Parolia, Abhijit; Wu, Rebecca; Xue, Hui; Wang, Yuwei; Ding, Jiarui; Thu, Kelsie L; Lam, Wan L; Shah, Sohrab P; Collins, Colin C; Wang, Yuzhuo; Helgason, Cheryl D

    2016-01-01

    While localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC). Emerging evidence suggests that aberrant epigenetic repression by the polycomb group (PcG) complexes fuels PCa progression, providing novel therapeutic opportunities. In the search for potential epigenetic drivers of CRPC, we analyzed the molecular profile of PcG members in patient-derived xenografts and clinical samples. Overall, our results identify the PcG protein and methyl-lysine reader CBX2 as a potential therapeutic target in advanced PCa. We report that CBX2 was recurrently up-regulated in metastatic CRPC and that elevated CBX2 expression was correlated with poor clinical outcome in PCa cohorts. Furthermore, CBX2 depletion abrogated cell viability and induced caspase 3-mediated apoptosis in metastatic PCa cell lines. Mechanistically explaining this phenotype, microarray analysis in CBX2-depleted cells revealed that CBX2 controls the expression of many key regulators of cell proliferation and metastasis. Taken together, this study provides the first evidence that CBX2 inhibition induces cancer cell death, positioning CBX2 as an attractive drug target in lethal CRPC.

  5. Evaluating the physiological reserves of older patients with cancer: the value of potential biomarkers of aging?

    Science.gov (United States)

    Pallis, Athanasios G; Hatse, Sigrid; Brouwers, Barbara; Pawelec, Graham; Falandry, Claire; Wedding, Ulrich; Lago, Lissandra Dal; Repetto, Lazzaro; Ring, Alistair; Wildiers, Hans

    2014-04-01

    Aging of an individual entails a progressive decline of functional reserves and loss of homeostasis that eventually lead to mortality. This process is highly individualized and is influenced by multiple genetic, epigenetic and environmental factors. This individualization and the diversity of factors influencing aging result in a significant heterogeneity among people with the same chronological age, representing a major challenge in daily oncology practice. Thus, many factors other than mere chronological age will contribute to treatment tolerance and outcome in the older patients with cancer. Clinical/comprehensive geriatric assessment can provide information on the general health status of individuals, but is far from perfect as a prognostic/predictive tool for individual patients. On the other hand, aging can also be assessed in terms of biological changes in certain tissues like the blood compartment which result from adaptive alterations due to past history of exposures, as well as intrinsic aging processes. There are major signs of 'aging' in lymphocytes (e.g. lymphocyte subset distribution, telomere length, p16INK4A expression), and also in (inflammatory) cytokine expression and gene expression patterns. These result from a combination of the above two processes, overlaying genetic predispositions which contribute significantly to the aging phenotype. These potential "aging biomarkers" might provide additional prognostic/predictive information supplementing clinical evaluation. The purpose of the current paper is to describe the most relevant potential "aging biomarkers" (markers that indicate the biological functional age of patients) which focus on the biological background, the (limited) available clinical data, and technical challenges. Despite their great potential interest, there is a need for much more (validated) clinical data before these biomarkers could be used in a routine clinical setting. This manuscript tries to provide a guideline on how

  6. Searching for new biomarkers in ovarian cancer patients

    DEFF Research Database (Denmark)

    Hentze, Julie L.; Høgdall, Claus; Kjær, Susanne K.

    2017-01-01

    , will be examined. Relevant microRNAs and DNA methylation patterns will be investigated using array technology. Patient exomes will be fully sequenced, and identified genetic variations will be validated with Next Generation Sequencing. In all cases, data will be correlated with clinical information on the patient...... of cancer and the discovery of new drugs. Moreover, biomarkers are a prerequisite for the development of precision medicine. This study will attack the ovarian cancer problem from several angles, thereby increasing the chance of successfully contributing to saving lives....

  7. Platelet RNA as a circulating biomarker trove for cancer diagnostics.

    Science.gov (United States)

    Best, M G; Vancura, A; Wurdinger, T

    2017-07-01

    Platelets are multifunctional cell fragments, circulating in blood in high abundance. Platelets assist in thrombus formation, sensing of pathogens entering the blood stream, signaling to immune cells, releasing vascular remodeling factors, and, negatively, enhancing cancer metastasis. Platelets are 'educated' by their environment, including in patients with cancer. Cancer cells appear to initiate intraplatelet signaling, resulting in splicing of platelet pre-mRNAs, and enhance secretion of cytokines. Platelets can induce leukocyte and endothelial cell modeling factors, for example, through adenine nucleotides (ATP), thereby facilitating extravasation of cancer cells. Besides releasing factors, platelets can also sequester RNAs and proteins released by cancer cells. Thus, platelets actively respond to queues from local and systemic conditions, thereby altering their transcriptome and molecular content. Platelets contain a rich repertoire of RNA species, including mRNAs, small non-coding RNAs and circular RNAs; although studies regarding the functionality of the various platelet RNA species require more attention. Recent advances in high-throughput characterization of platelet mRNAs revealed 10 to > 1000 altered mRNAs in platelets in the presence of disease. Hence, platelet RNA appears to be dynamically affected by pathological conditions, thus possibly providing opportunities to use platelet RNA as diagnostic, prognostic, predictive, or monitoring biomarkers. In this review, we cover the literature regarding the platelet RNA families, processing of platelet RNAs, and the potential application of platelet RNA as disease biomarkers. © 2017 International Society on Thrombosis and Haemostasis.

  8. Serum prognostic biomarkers in head and neck cancer patients.

    Science.gov (United States)

    Lin, Ho-Sheng; Siddiq, Fauzia; Talwar, Harvinder S; Chen, Wei; Voichita, Calin; Draghici, Sorin; Jeyapalan, Gerald; Chatterjee, Madhumita; Fribley, Andrew; Yoo, George H; Sethi, Seema; Kim, Harold; Sukari, Ammar; Folbe, Adam J; Tainsky, Michael A

    2014-08-01

    A reliable estimate of survival is important as it may impact treatment choice. The objective of this study is to identify serum autoantibody biomarkers that can be used to improve prognostication for patients affected with head and neck squamous cell carcinoma (HNSCC). Prospective cohort study. A panel of 130 serum biomarkers, previously selected for cancer detection using microarray-based serological profiling and specialized bioinformatics, were evaluated for their potential as prognostic biomarkers in a cohort of 119 HNSCC patients followed for up to 12.7 years. A biomarker was considered positive if its reactivity to the particular patient's serum was greater than one standard deviation above the mean reactivity to sera from the other 118 patients, using a leave-one-out cross-validation model. Survival curves were estimated according to the Kaplan-Meier method, and statistically significant differences in survival were examined using the log rank test. Independent prognostic biomarkers were identified following analysis using multivariate Cox proportional hazards models. Poor overall survival was associated with African Americans (hazard ratio [HR] for death = 2.61; 95% confidence interval [CI]: 1.58-4.33; P = .000), advanced stage (HR = 2.79; 95% CI: 1.40-5.57; P = .004), and recurrent disease (HR = 6.66; 95% CI: 2.54-17.44; P = .000). On multivariable Cox analysis adjusted for covariates (race and stage), six of the 130 markers evaluated were found to be independent prognosticators of overall survival. The results shown here are promising and demonstrate the potential use of serum biomarkers for prognostication in HNSCC patients. Further clinical trials to include larger samples of patients across multiple centers may be warranted. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

  9. Prolonged re-expression of the hypermethylated gene EPB41L3 using artificial transcription factors and epigenetic drugs

    NARCIS (Netherlands)

    Huisman, Christian; van der Wijst, Monique G. P.; Falahi, Fahimeh; Overkamp, Juul; Karsten, Gellert; Terpstra, Martijn M.; Kok, Klaas; van der Zee, Ate G. J.; Schuuring, Ed; Wisman, G. Bea A.; Rots, Marianne G.

    2015-01-01

    Epigenetic silencing of tumor suppressor genes (TSGs) is considered a significant event in the progression of cancer. For example, EPB41L3, a potential biomarker in cervical cancer, is often silenced by cancer-specific promoter methylation. Artificial transcription factors (ATFs) are unique tools to

  10. Current and upcoming approaches to exploit the reversibility of epigenetic mutations in breast cancer

    NARCIS (Netherlands)

    Falahi, Fahimeh; van Kruchten, Michel; Martinet, Nadine; Hospers, Geesiena; Rots, Marianne G.

    2014-01-01

    DNA methylation and histone modifications are important epigenetic modifications associated with gene (dys) regulation. The epigenetic modifications are balanced by epigenetic enzymes, so-called writers and erasers, such as DNA (de)methylases and histone (de)acetylases. Aberrant epigenetic

  11. Prognostic and predictive potential molecular biomarkers in colon cancer.

    Science.gov (United States)

    Nastase, A; Pâslaru, L; Niculescu, A M; Ionescu, M; Dumitraşcu, T; Herlea, V; Dima, S; Gheorghe, C; Lazar, V; Popescu, I

    2011-01-01

    An important objective in nowadays research is the discovery of new biomarkers that can detect colon tumours in early stages and indicate with accuracy the status of the disease. The aim of our study was to identify potential biomarkers for colon cancer onset and progression. We assessed gene expression profiles of a list of 10 candidate genes (MMP-1, MMP-3, MMP-7, DEFA 1, DEFA-5, DEFA-6, IL-8, CXCL-1, SPP-1, CTHRC-1) by quantitative real time PCR in triplets of colonic mucosa (normal, adenoma, tumoral tissue) collected from the same patient during surgery for a group of 20 patients. Additionally we performed immunohistochemistry for DEFA1-3 and SPP1. We remarked that DEFA5 and DEFA6 are key factors in adenoma formation (p<0.05). MMP7 is important in the transition from a benign to a malignant status (p <0.01) and further in metastasis being a prognostic indicator for tumor transformation and for the metastatic potential of cancer cells. IL8, irrespective of tumor stage, has a high mRNA level in adenocarcinoma (p< 0.05). The level of expression for SPP1 is correlated with tumor level. We suggest that high levels of DEFAS, DEFA6 (key elements in adenoma formation), MMP7 (marker of colon cancer onset and progression to metastasis), SPP1 (marker of progression) and IL8 could be used to diagnose an early stage colon cancer and to evaluate the prognostic of progression for colon tumors. Further, if DEFA5 and DEFA6 level of expression are low but MMP7, SPP1 and IL8 level are high we could point out that the transition from adenoma to adenocarcinoma had already occurred. Thus, DEFA5, DEFA6, MMP7, IL8 and SPP1 consist in a valuable panel of biomarkers, whose detection can be used in early detection and progressive disease and also in prognostic of colon cancer.

  12. Epigenetic inactivation of inhibitor of differentiation 4 (Id4) correlates with prostate cancer

    International Nuclear Information System (INIS)

    Sharma, Pankaj; Chinaranagari, Swathi; Patel, Divya; Carey, Jason; Chaudhary, Jaideep

    2012-01-01

    The inhibitor of DNA-binding (Id) proteins, Id1–4 are negative regulators of basic helix-loop-helix (bHLH) transcription factors. As key regulators of cell cycle and differentiation, expression of Id proteins are increasingly observed in many cancers and associated with aggressiveness of the disease. Of all the four Id proteins, the expression of Id1, Id2, and to a lesser extent, Id3 in prostate cancer and the underlying molecular mechanism is relatively well known. On the contrary, our previous results demonstrated that Id4 acts as a potential tumor suppressor in prostate cancer. In the present study, we extend these observations and demonstrate that Id4 is down-regulated in prostate cancer due to promoter hypermethylation. We used prostate cancer tissue microarrays to investigate Id4 expression. Methylation specific PCR on bisulfite treated DNA was used to determine methylation status of Id4 promoter in laser capture micro-dissected normal, stroma and prostate cancer regions. High Id4 expression was observed in the normal prostate epithelial cells. In prostate cancer, a stage-dependent decrease in Id4 expression was observed with majority of high grade cancers showing no Id4 expression. Furthermore, Id4 expression progressively decreased in prostate cancer cell line LNCaP and with no expression in androgen-insensitive LNCaP-C81 cell line. Conversely, Id4 promoter hypermethylation increased in LNCaP-C81 cells suggesting epigenetic silencing. In prostate cancer samples, loss of Id4 expression was also associated with promoter hypermethylation. Our results demonstrate loss of Id4 expression in prostate cancer due to promoter hypermethylation. The data strongly support the role of Id4 as a tumor suppressor

  13. Biomarkers for Response to Neoadjuvant Chemoradiation for Rectal Cancer

    International Nuclear Information System (INIS)

    Kuremsky, Jeffrey G.; Tepper, Joel E.; McLeod, Howard L. Phar

    2009-01-01

    Locally advanced rectal cancer (LARC) is currently treated with neoadjuvant chemoradiation. Although approximately 45% of patients respond to neoadjuvant therapy with T-level downstaging, there is no effective method of predicting which patients will respond. Molecular biomarkers have been investigated for their ability to predict outcome in LARC treated with neoadjuvant chemotherapy and radiation. A literature search using PubMed resulted in the initial assessment of 1,204 articles. Articles addressing the ability of a biomarker to predict outcome for LARC treated with neoadjuvant chemotherapy and radiation were included. Six biomarkers met the criteria for review: p53, epidermal growth factor receptor (EGFR), thymidylate synthase, Ki-67, p21, and bcl-2/bax. On the basis of composite data, p53 is unlikely to have utility as a predictor of response. Epidermal growth factor receptor has shown promise as a predictor when quantitatively evaluated in pretreatment biopsies or when EGFR polymorphisms are evaluated in germline DNA. Thymidylate synthase, when evaluated for polymorphisms in germline DNA, is promising as a predictive biomarker. Ki-67 and bcl-2 are not useful in predicting outcome. p21 needs to be further evaluated to determine its usefulness in predicting outcome. Bax requires more investigation to determine its usefulness. Epidermal growth factor receptor, thymidylate synthase, and p21 should be evaluated in larger prospective clinical trials for their ability to guide preoperative therapy choices in LARC.

  14. Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines.

    Directory of Open Access Journals (Sweden)

    Syed M Meeran

    Full Text Available BACKGROUND: Sulforaphane (SFN, an isothiocyanate found in cruciferous vegetables, is a common dietary component that has histone deacetylase inhibition activity and exciting potential in cancer prevention. The mechanisms by which SFN imparts its chemopreventive properties are of considerable interest and little is known of its preventive potential for breast cancer. PRINCIPAL FINDINGS: We found that SFN significantly inhibits the viability and proliferation of breast cancer cells in vitro while it has negligible effects on normal breast cells. Inhibition of telomerase has received considerable attention because of its high expression in cancer cells and extremely low level of expression in normal cells. SFN treatment dose- and time-dependently inhibited human telomerase reverse transcriptase (hTERT, the catalytic regulatory subunit of telomerase, in both MCF-7 and MDA-MB-231 human breast cancer cells. DNA methyltransferases (DNMTs, especially DNMT1 and DNMT3a, were also decreased in SFN-treated breast cancer cells suggesting that SFN may repress hTERT by impacting epigenetic pathways. Down-regulation of DNMTs in response to SFN induced site-specific CpG demethylation occurring primarily in the first exon of the hTERT gene thereby facilitating CTCF binding associated with hTERT repression. Chromatin immunoprecipitation (ChIP analysis of the hTERT promoter revealed that SFN increased the level of active chromatin markers acetyl-H3, acetyl-H3K9 and acetyl-H4, whereas the trimethyl-H3K9 and trimethyl-H3K27 inactive chromatin markers were decreased in a dose-dependent manner. SFN-induced hyperacetylation facilitated the binding of many hTERT repressor proteins such as MAD1 and CTCF to the hTERT regulatory region. Depletion of CTCF using siRNA reduced the SFN-induced down-regulation of hTERT mRNA transcription in these breast cancer cells. In addition, down-regulation of hTERT expression facilitated the induction of cellular apoptosis in human breast

  15. Proteomics for discovery of candidate colorectal cancer biomarkers

    Science.gov (United States)

    Álvarez-Chaver, Paula; Otero-Estévez, Olalla; Páez de la Cadena, María; Rodríguez-Berrocal, Francisco J; Martínez-Zorzano, Vicenta S

    2014-01-01

    Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in Europe and other Western countries, mainly due to the lack of well-validated clinically useful biomarkers with enough sensitivity and specificity to detect this disease at early stages. Although it is well known that the pathogenesis of CRC is a progressive accumulation of mutations in multiple genes, much less is known at the proteome level. Therefore, in the last years many proteomic studies have been conducted to find new candidate protein biomarkers for diagnosis, prognosis and as therapeutic targets for this malignancy, as well as to elucidate the molecular mechanisms of colorectal carcinogenesis. An important advantage of the proteomic approaches is the capacity to look for multiple differentially expressed proteins in a single study. This review provides an overview of the recent reports describing the different proteomic tools used for the discovery of new protein markers for CRC such as two-dimensional electrophoresis methods, quantitative mass spectrometry-based techniques or protein microarrays. Additionally, we will also focus on the diverse biological samples used for CRC biomarker discovery such as tissue, serum and faeces, besides cell lines and murine models, discussing their advantages and disadvantages, and summarize the most frequently identified candidate CRC markers. PMID:24744574

  16. Immunohistochemistry of colorectal cancer biomarker phosphorylation requires controlled tissue fixation.

    Directory of Open Access Journals (Sweden)

    Abbey P Theiss

    Full Text Available Phosphorylated signaling molecules are biomarkers of cancer pathophysiology and resistance to therapy, but because phosphoprotein analytes are often labile, poorly controlled clinical laboratory practices could prevent translation of research findings in this area from the bench to the bedside. We therefore compared multiple biomarker and phosphoprotein immunohistochemistry (IHC results in 23 clinical colorectal carcinoma samples after either a novel, rapid tissue fixation protocol or a standard tissue fixation protocol employed by clinical laboratories, and we also investigated the effect of a defined post-operative "cold" ischemia period on these IHC results. We found that a one-hour cold ischemia interval, allowed by ASCO/CAP guidelines for certain cancer biomarker assays, is highly deleterious to certain phosphoprotein analytes, specifically the phosphorylated epidermal growth factor receptor (pEGFR, but shorter ischemic intervals (less than 17 minutes facilitate preservation of phosphoproteins. Second, we found that a rapid 4-hour, two temperature, formalin fixation yielded superior staining in several cases with select markers (pEGFR, pBAD, pAKT compared to a standard overnight room temperature fixation protocol, despite taking less time. These findings indicate that the future research and clinical utilities of phosphoprotein IHC for assessing colorectal carcinoma pathophysiology absolutely depend upon attention to preanalytical factors and rigorously controlled tissue fixation protocols.

  17. Identification of prostate cancer biomarkers in urinary exosomes.

    Science.gov (United States)

    Øverbye, Anders; Skotland, Tore; Koehler, Christian J; Thiede, Bernd; Seierstad, Therese; Berge, Viktor; Sandvig, Kirsten; Llorente, Alicia

    2015-10-06

    Exosomes have recently appeared as a novel source of non-invasive cancer biomarkers since tumour-specific molecules can be found in exosomes isolated from biological fluids. We have here investigated the proteome of urinary exosomes by using mass spectrometry to identify proteins differentially expressed in prostate cancer patients compared to healthy male controls. In total, 15 control and 16 prostate cancer samples of urinary exosomes were analyzed. Importantly, 246 proteins were differentially expressed in the two groups. The majority of these proteins (221) were up-regulated in exosomes from prostate cancer patients. These proteins were analyzed according to specific criteria to create a focus list that contained 37 proteins. At 100% specificity, 17 of these proteins displayed individual sensitivities above 60%. Even though several of these proteins showed high sensitivity and specificity for prostate cancer as individual biomarkers, combining them in a multi-panel test has the potential for full differentiation of prostate cancer from non-disease controls. The highest sensitivity, 94%, was observed for transmembrane protein 256 (TM256; chromosome 17 open reading frame 61). LAMTOR proteins were also distinctly enriched with very high specificity for patient samples. TM256 and LAMTOR1 could be used to augment the sensitivity to 100%. Other prominent proteins were V-type proton ATPase 16 kDa proteolipid subunit (VATL), adipogenesis regulatory factor (ADIRF), and several Rab-class members and proteasomal proteins. In conclusion, this study clearly shows the potential of using urinary exosomes in the diagnosis and clinical management of prostate cancer.

  18. Proteomic biomarkers for ovarian cancer risk in women with polycystic ovary syndrome: a systematic review and biomarker database integration.

    Science.gov (United States)

    Galazis, Nicolas; Olaleye, Olalekan; Haoula, Zeina; Layfield, Robert; Atiomo, William

    2012-12-01

    To review and identify possible biomarkers for ovarian cancer (OC) in women with polycystic ovary syndrome (PCOS). Systematic literature searches of MEDLINE, EMBASE, and Cochrane using the search terms "proteomics," "proteomic," and "ovarian cancer" or "ovarian carcinoma." Proteomic biomarkers for OC were then integrated with an updated previously published database of all proteomic biomarkers identified to date in patients with PCOS. Academic department of obstetrics and gynecology in the United Kingdom. A total of 180 women identified in the six studies. Tissue samples from women with OC vs. tissue samples from women without OC. Proteomic biomarkers, proteomic technique used, and methodologic quality score. A panel of six biomarkers was overexpressed both in women with OC and in women with PCOS. These biomarkers include calreticulin, fibrinogen-γ, superoxide dismutase, vimentin, malate dehydrogenase, and lamin B2. These biomarkers could help improve our understanding of the links between PCOS and OC and could potentially be used to identify subgroups of women with PCOS at increased risk of OC. More studies are required to further evaluate the role these biomarkers play in women with PCOS and OC. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  19. Biosemiotic Entropy of the Genome: Mutations and Epigenetic Imbalances Resulting in Cancer

    Directory of Open Access Journals (Sweden)

    Samuel S. Shepard

    2013-01-01

    Full Text Available Biosemiotic entropy involves the deterioration of biological sign systems. The genome is a coded sign system that is connected to phenotypic outputs through the interpretive functions of the tRNA/ribosome machinery. This symbolic sign system (semiosis at the core of all biology has been termed “biosemiosis”. Layers of biosemiosis and cellular information management are analogous in varying degrees to the semiotics of computer programming, spoken, and written human languages. Biosemiotic entropy — an error or deviation from a healthy state — results from errors in copying functional information (mutations and errors in the appropriate context or quantity of gene expression (epigenetic imbalance. The concept of biosemiotic entropy is a deeply imbedded assumption in the study of cancer biology. Cells have a homeostatic, preprogrammed, ideal or healthy state that is rooted in genomics, strictly orchestrated by epigenetic regulation, and maintained by DNA repair mechanisms. Cancer is an eminent illustration of biosemiotic entropy, in which the corrosion of genetic information via substitutions, deletions, insertions, fusions, and aberrant regulation results in malignant phenotypes. However, little attention has been given to explicitly outlining the paradigm of biosemiotic entropy in the context of cancer. Herein we distill semiotic theory (from the familiar and well understood spheres of human language and computer code to draw analogies useful for understanding the operation of biological semiosis at the genetic level. We propose that the myriad checkpoints, error correcting mechanisms, and immunities are all systems whose primary role is to defend against the constant pressure of biosemiotic entropy, which malignancy must shut down in order to achieve advanced stages. In lieu of the narrower tumor suppressor/oncogene model, characterization of oncogenesis into the biosemiotic framework of sign, index, or object entropy may allow for more

  20. Evaluation of an Epigenetic Profile for the Detection of Bladder Cancer in Patients with Hematuria.

    Science.gov (United States)

    van Kessel, Kim E M; Van Neste, Leander; Lurkin, Irene; Zwarthoff, Ellen C; Van Criekinge, Wim

    2016-03-01

    Many patients enter the care cycle with gross or microscopic hematuria and undergo cystoscopy to rule out bladder cancer. Sensitivity of this invasive examination is limited, leaving many patients at risk for undetected cancer. To improve current clinical practice more sensitive and noninvasive screening methods should be applied. A total of 154 urine samples were collected from patients with hematuria, including 80 without and 74 with bladder cancer. DNA from cells in the urine was epigenetically profiled using 2 independent assays. Methylation specific polymerase chain reaction was performed on TWIST1. SNaPshot™ methylation analysis was done for different loci of OTX1 and ONECUT2. Additionally all samples were analyzed for mutation status of TERT (telomerase reverse transcriptase), PIK3CA, FGFR3 (fibroblast growth factor receptor 3), HRAS, KRAS and NRAS. The combination of TWIST1, ONECUT2 (2 loci) and OTX1 resulted in the best overall performing panel. Logistic regression analysis on these methylation markers, mutation status of FGFR3, TERT and HRAS, and patient age resulted in an accurate model with 97% sensitivity, 83% specificity and an AUC of 0.93 (95% CI 0.88-0.98). Internal validation led to an optimism corrected AUC of 0.92. With an estimated bladder cancer prevalence of 5% to 10% in a hematuria cohort the assay resulted in a 99.6% to 99.9% negative predictive value. Epigenetic profiling using TWIST1, ONECUT2 and OTX1 results in a high sensitivity and specificity. Accurate risk prediction might result in less extensive and invasive examination of patients at low risk, thereby reducing unnecessary patient burden and health care costs. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  1. MicroRNAs in prostate cancer: Functional role as biomarkers.

    Science.gov (United States)

    Kanwal, Rajnee; Plaga, Alexis R; Liu, Xiaoqi; Shukla, Girish C; Gupta, Sanjay

    2017-10-28

    MicroRNAs (miRNAs) are small endogenous non-coding molecules that alters gene expression through post-transcriptional regulation of messenger RNA. Compelling evidence suggest the role of miRNA in cancer biology having potential as diagnostic, prognostic and predictive biomarkers. This review summarizes the current knowledge on miRNA deregulated in prostate cancer and their role as oncogene, tumor suppressor and metastasis regulators. The emerging information elucidating the biological function of miRNA is promising and may lead to their potential usefulness as diagnostic/prognostic markers and development as effective therapeutic tools for management of prostate cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Circulating DNA as Potential Biomarker for Cancer Individualized Therapy

    Directory of Open Access Journals (Sweden)

    Shaorong Yu

    2013-09-01

    Full Text Available Cancer individualized therapy often requires for gene mutation analysis of tumor tissue. However, tumor tissue is not always available in clinical practice, particularly from patients with refractory and recurrence disease. Even if patients have sufficient tumor tissue for detection, as development of cancer, the gene status and drug sensitivity of tumor tissues could also change. Hence, screening mutations from primary tumor tissues becomes useless, it’s necessary to find a surrogate tumor tissue for individualized gene screening. Circulating DNA is digested rapidly from blood, which could provide real-time information of the released fragment and make the real-time detection possible. Therefore, it’s expected that circulating DNA could be a potential tumor biomarker for cancer individualized therapy. This review focuses on the biology and clinical utility of circulating DNA mainly on gene mutation detection. Besides, its current status and possible direction in this research area is summarized and discussed objectively.

  3. Oncofetal protein IMP3, a new cancer biomarker.

    Science.gov (United States)

    Gong, Yuna; Woda, Bruce A; Jiang, Zhong

    2014-05-01

    IMP3 is a member of a family of RNA-binding proteins that consists of IMP1, IMP2 and IMP3. These proteins contain 2 RNA recognition motifs and 4 K-homology domains that allow them to bind RNAs strongly and specifically. IMP3 is an oncofetal protein involved in embryogenesis and its expression is associated with a number of malignant neoplasms. IMP3 is associated with aggressive and advanced cancers and is specifically expressed in malignant tumors but is not found in adjacent benign tissues. Moreover, in vitro studies have shown that IMP3 promotes tumor cell proliferation, adhesion, and invasion. This review focuses on the studies of IMP3 expression in different cancers and emphasizes the potential utility of IMP3 in routine surgical pathology practice. We also discuss IMP3 as a prognostic biomarker for cancer patients' outcomes.

  4. Comparison of proteomic biomarker panels in urine and serum for ovarian cancer diagnosis

    DEFF Research Database (Denmark)

    Petri, Anette Lykke; Simonsen, Anja Hviid; Høgdall, Estrid

    2010-01-01

    The purposes of this study were to confirm previously found candidate epithelial ovarian cancer biomarkers in urine and to compare a paired serum biomarker panel and a urine biomarker panel from the same study cohort with regard to the receiver operating characteristic curve (ROC) area under the ...

  5. PLAC1 as a serum biomarker for breast cancer.

    Directory of Open Access Journals (Sweden)

    Hongyan Yuan

    Full Text Available Placental-specific protein 1 (PLAC1 is an X-linked trophoblast gene that is re-expressed in several malignancies, including breast cancer, and is therefore a potential biomarker to follow disease onset and progression. Sera from 117 preoperative/pretreatment breast cancer patients and 51 control subjects, including those with fibrocystic disease, were analyzed for the presence of PLAC1 protein as well as its expression by IHC in tumor biopsies in a subset of subjects. Serum PLAC1 levels exceeded the mean plus one standard deviation (mean+SD of the level in control subjects in 67% of subjects with ductal carcinoma in situ (DCIS, 67% with HER2+ tumors, 73% with triple-negative cancer and 73% with ER+/PR+ tumors. Greater sensitivity was achieved using the mean+2 SD of control PLAC1 serum values, where the false positive rate was 3% and was exceeded by 38%, 40%, 60% and 43% of subjects with DCIS, HER2+, TNBC and ER+/PR+/HER2- tumors. PLAC1 was detected in 97% of tumor biopsies, but did not correlate quantitatively with serum levels. There was no significant correlation of serum PLAC1 levels with race, age at diagnosis, body mass index (BMI or the presence of metastatic disease. It remains to be determined whether PLAC1 serum levels can serve as a diagnostic biomarker for the presence or recurrence of disease post-surgery and/or therapy.

  6. Enhancement of MS Signal Processing For Improved Cancer Biomarker Discovery

    Science.gov (United States)

    Si, Qian

    Technological advances in proteomics have shown great potential in detecting cancer at the earliest stages. One way is to use the time of flight mass spectroscopy to identify biomarkers, or early disease indicators related to the cancer. Pattern analysis of time of flight mass spectra data from blood and tissue samples gives great hope for the identification of potential biomarkers among the complex mixture of biological and chemical samples for the early cancer detection. One of the keys issues is the pre-processing of raw mass spectra data. A lot of challenges need to be addressed: unknown noise character associated with the large volume of data, high variability in the mass spectroscopy measurements, and poorly understood signal background and so on. This dissertation focuses on developing statistical algorithms and creating data mining tools for computationally improved signal processing for mass spectrometry data. I have introduced an advanced accurate estimate of the noise model and a half-supervised method of mass spectrum data processing which requires little knowledge about the data.

  7. Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity.

    NARCIS (Netherlands)

    Coolen, M.W.; Stirzaker, C.; Song, J.Z.; Statham, A.L.; Kassir, Z.; Moreno, C.S.; Young, A.N.; Varma, V.; Speed, T.P.; Cowley, M.; Lacaze, P.; Kaplan, W.; Robinson, M.D.; Clark, S. J.

    2010-01-01

    Silencing of individual genes can occur by genetic and epigenetic processes during carcinogenesis, but the underlying mechanisms remain unclear. By creating an integrated prostate cancer epigenome map using tiling arrays, we show that contiguous regions of gene suppression commonly occur through

  8. Circulating exosomal microRNAs as biomarkers of colon cancer.

    Directory of Open Access Journals (Sweden)

    Hiroko Ogata-Kawata

    Full Text Available PURPOSE: Exosomal microRNAs (miRNAs have been attracting major interest as potential diagnostic biomarkers of cancer. The aim of this study was to characterize the miRNA profiles of serum exosomes and to identify those that are altered in colorectal cancer (CRC. To evaluate their use as diagnostic biomarkers, the relationship between specific exosomal miRNA levels and pathological changes of patients, including disease stage and tumor resection, was examined. EXPERIMENTAL DESIGN: Microarray analyses of miRNAs in exosome-enriched fractions of serum samples from 88 primary CRC patients and 11 healthy controls were performed. The expression levels of miRNAs in the culture medium of five colon cancer cell lines were also compared with those in the culture medium of a normal colon-derived cell line. The expression profiles of miRNAs that were differentially expressed between CRC and control sample sets were verified using 29 paired samples from post-tumor resection patients. The sensitivities of selected miRNAs as biomarkers of CRC were evaluated and compared with those of known tumor markers (CA19-9 and CEA using a receiver operating characteristic analysis. The expression levels of selected miRNAs were also validated by quantitative real-time RT-PCR analyses of an independent set of 13 CRC patients. RESULTS: The serum exosomal levels of seven miRNAs (let-7a, miR-1229, miR-1246, miR-150, miR-21, miR-223, and miR-23a were significantly higher in primary CRC patients, even those with early stage disease, than in healthy controls, and were significantly down-regulated after surgical resection of tumors. These miRNAs were also secreted at significantly higher levels by colon cancer cell lines than by a normal colon-derived cell line. The high sensitivities of the seven selected exosomal miRNAs were confirmed by a receiver operating characteristic analysis. CONCLUSION: Exosomal miRNA signatures appear to mirror pathological changes of CRC patients and

  9. Blood-based biomarkers of aggressive prostate cancer.

    Directory of Open Access Journals (Sweden)

    Men Long Liong

    Full Text Available PURPOSE: Prostate cancer is a bimodal disease with aggressive and indolent forms. Current prostate-specific-antigen testing and digital rectal examination screening provide ambiguous results leading to both under-and over-treatment. Accurate, consistent diagnosis is crucial to risk-stratify patients and facilitate clinical decision making as to treatment versus active surveillance. Diagnosis is currently achieved by needle biopsy, a painful procedure. Thus, there is a clinical need for a minimally-invasive test to determine prostate cancer aggressiveness. A blood sample to predict Gleason score, which is known to reflect aggressiveness of the cancer, could serve as such a test. MATERIALS AND METHODS: Blood mRNA was isolated from North American and Malaysian prostate cancer patients/controls. Microarray analysis was conducted utilizing the Affymetrix U133 plus 2·0 platform. Expression profiles from 255 patients/controls generated 85 candidate biomarkers. Following quantitative real-time PCR (qRT-PCR analysis, ten disease-associated biomarkers remained for paired statistical analysis and normalization. RESULTS: Microarray analysis was conducted to identify 85 genes differentially expressed between aggressive prostate cancer (Gleason score ≥8 and controls. Expression of these genes was qRT-PCR verified. Statistical analysis yielded a final seven-gene panel evaluated as six gene-ratio duplexes. This molecular signature predicted as aggressive (ie, Gleason score ≥8 55% of G6 samples, 49% of G7(3+4, 79% of G7(4+3 and 83% of G8-10, while rejecting 98% of controls. CONCLUSION: In this study, we have developed a novel, blood-based biomarker panel which can be used as the basis of a simple blood test to identify men with aggressive prostate cancer and thereby reduce the overdiagnosis and overtreatment that currently results from diagnosis using PSA alone. We discuss possible clinical uses of the panel to identify men more likely to benefit from

  10. Integrated genetic and epigenetic analysis of bladder cancer reveals an additive diagnostic value of FGFR3 mutations and hypermethylation events

    DEFF Research Database (Denmark)

    Serizawa, Reza R; Ralfkiaer, Ulrik; Steven, Kenneth

    2011-01-01

    The bladder cancer genome harbors numerous oncogenic mutations and aberrantly methylated gene promoters. The aim of our study was to generate a profile of these alterations and investigate their use as biomarkers in urine sediments for noninvasive detection of bladder cancer. We systematically sc...... noninvasive, DNA-based detection of bladder cancer....

  11. Breast cancer cells induce stromal fibroblasts to secrete ADAMTS1 for cancer invasion through an epigenetic change.

    Directory of Open Access Journals (Sweden)

    Shiaw-Wei Tyan

    Full Text Available Microenvironment plays an important role in cancer development. We have reported that the cancer-associated stromal cells exhibit phenotypic and functional changes compared to stromal cells neighboring to normal tissues. However, the molecular mechanisms as well as the maintenance of these changes remain elusive. Here we showed that through co-culture with breast cancer cells for at least three to four passages, breast normal tissue-associated fibroblasts (NAFs gained persistent activity for promoting cancer cell invasion, partly via up-regulating ADAM metallopeptidase with thrombospondin type 1 motif, 1 (ADAMTS1. Furthermore, we demonstrated that the DNA methylation pattern in the ADAMTS1 promoter has no alteration. Instead, the loss of EZH2 binding to the ADAMTS1 promoter and the resulting decrease of promoter-associated histone H3K27 methylation may account for the up-regulation of ADAMTS1. Importantly, the lack of EZH2 binding and the H3K27 methylation on the ADAMTS1 promoter were sustained in cancer cell-precocultured NAFs after removal of cancer cells. These results suggest that cancer cells are capable of inducing stromal fibroblasts to secrete ADAMTS1 persistently for their invasion and the effect is epigenetically inheritable.

  12. Sputum-Based Molecular Biomarkers for the Early Detection of Lung Cancer: Limitations and Promise

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Connie E. [Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine. 462 First Avenue, NBV 7N24, New York, NY 10016 (United States); Tchou-Wong, Kam-Meng; Rom, William N., E-mail: william.rom@nyumc.org [Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine. 462 First Avenue, NBV 7N24, New York, NY 10016 (United States); Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987 (United States)

    2011-07-19

    Lung cancer is the leading cause of cancer deaths, with an overall survival of 15% at five years. Biomarkers that can sensitively and specifically detect lung cancer at early stage are crucial for improving this poor survival rate. Sputum has been the target for the discovery of non-invasive biomarkers for lung cancer because it contains airway epithelial cells, and molecular alterations identified in sputum are most likely to reflect tumor-associated changes or field cancerization caused by smoking in the lung. Sputum-based molecular biomarkers include morphology, allelic imbalance, promoter hypermethylation, gene mutations and, recently, differential miRNA expression. To improve the sensitivity and reproducibility of sputum-based biomarkers, we recommend standardization of processing protocols, bronchial epithelial cell enrichment, and identification of field cancerization biomarkers.

  13. 1-D grating based SPR biosensor for the detection of lung cancer biomarkers using Vroman effect

    Science.gov (United States)

    Teotia, Pradeep Kumar; Kaler, R. S.

    2018-01-01

    Grating based surface plasmon resonance waveguide biosensor have been reported for the detection of lung cancer biomarkers using Vroman effect. The proposed grating based multilayered biosensor is designed with high detection accuracy for Epidermal growth factor receptor (EGFR) and also analysed to show high detection accuracy with acceptable sensitivity for both cancer biomarkers. The introduction of periodic grating with multilayer metals generates a good resonance that make it possible for early detection of cancerous cells. Using finite difference time domain method, it is observed wavelength of biosensor get red-shifted on variations of the refractive index due to the presence of both the cancerous bio-markers. The reported detection accuracy and sensitivity of proposed biosensor is quite acceptable for both lung cancer biomarkers i.e. Carcinoembryonic antigen (CEA) and Epidermal growth factor receptor (EGFR) which further offer us label free early detection of lung cancer using these biomarkers.

  14. Epigenetic Silencing of CXCR4 Promotes Loss of Cell Adhesion in Cervical Cancer

    Directory of Open Access Journals (Sweden)

    Suresh Singh Yadav

    2014-01-01

    Full Text Available In the network of chemokine signaling pathways, recent reports have described the SDF-1α/CXCR4 axis and its role in cancer progression and metastasis. Interestingly, we found downregulation of CXCR4 at both transcript and protein level in cervical cancer cell lines and primary tumors. We also found CXCR4 promoter hypermethylation in cervical cancer cell lines and primary biopsy samples. DNA hypomethylating drug 5-AZA-2′-deoxycytidine and histone deacetylase inhibitor Trichostatin A treatments in cell lines reactivate both CXCR4 transcription and protein expression. Cell adhesion assay demonstrated that autocrine SDF-1α promotes the loss of cell adhesion while paracrine SDF-1α predominantly protects the normal cervical cells from loss of cell adhesion. Cervical cancer cell line C-33A having increased expression of CXCR4 after TSA treatment showed increased cell adhesion by paracrine source of SDF-1α in comparison to untreated C-33A. These findings demonstrate the first evidence that epigenetic silencing of CXCR4 makes the cells inefficient to respond to the paracrine source of SDF-1α leading to loss of cell adhesion, one of the key events in metastases and progression of the disease. Our results provide novel insight of SDF-1α/CXCR4 signaling in tumor microenvironment which may be promising to further delineate molecular mechanism of cervical carcinogenesis.

  15. Identification of New Serum Biomarkers for Early Breast Cancer Diagnosis and Prognosis Using Lipid Microarrays

    National Research Council Canada - National Science Library

    Du, Guangwei

    2008-01-01

    Breast cancer is the most common form of cancer among women. Compared with other serum polypeptides, autoantibodies have many appealing features as biomarkers including sensitivity, stability, and easy detection...

  16. Vasculature surrounding a nodule: A novel lung cancer biomarker.

    Science.gov (United States)

    Wang, Xiaohua; Leader, Joseph K; Wang, Renwei; Wilson, David; Herman, James; Yuan, Jian-Min; Pu, Jiantao

    2017-12-01

    To investigate whether the vessels surrounding a nodule depicted on non-contrast, low-dose computed tomography (LDCT) can discriminate benign and malignant screen detected nodules. We collected a dataset consisting of LDCT scans acquired on 100 subjects from the Pittsburgh Lung Screening study (PLuSS). Fifty subjects were diagnosed with lung cancer and 50 subjects had suspicious nodules later proven benign. For the lung cancer cases, the location of the malignant nodule in the LDCT scans was known; while for the benign cases, the largest nodule in the LDCT scan was used in the analysis. A computer algorithm was developed to identify surrounding vessels and quantify the number and volume of vessels that were connected or near the nodule. A nonparametric receiver operating characteristic (ROC) analysis was performed based on a single nodule per subject to assess the discriminability of the surrounding vessels to provide a lung cancer diagnosis. Odds ratio (OR) were computed to determine the probability of a nodule being lung cancer based on the vessel features. The areas under the ROC curves (AUCs) for vessel count and vessel volume were 0.722 (95% CI=0.616-0.811, plung cancer group 9.7 (±9.6) compared to the non-lung cancer group 4.0 (±4.3) CONCLUSION: Our preliminary results showed that malignant nodules are often surrounded by more vessels compared to benign nodules, suggesting that the surrounding vessel characteristics could serve as lung cancer biomarker for indeterminate nodules detected during LDCT lung cancer screening using only the information collected during the initial visit. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Identification of a biomarker panel for colorectal cancer diagnosis

    Directory of Open Access Journals (Sweden)

    García-Bilbao Amaia

    2012-01-01

    Full Text Available Abstract Background Malignancies arising in the large bowel cause the second largest number of deaths from cancer in the Western World. Despite progresses made during the last decades, colorectal cancer remains one of the most frequent and deadly neoplasias in the western countries. Methods A genomic study of human colorectal cancer has been carried out on a total of 31 tumoral samples, corresponding to different stages of the disease, and 33 non-tumoral samples. The study was carried out by hybridisation of the tumour samples against a reference pool of non-tumoral samples using Agilent Human 1A 60-mer oligo microarrays. The results obtained were validated by qRT-PCR. In the subsequent bioinformatics analysis, gene networks by means of Bayesian classifiers, variable selection and bootstrap resampling were built. The consensus among all the induced models produced a hierarchy of dependences and, thus, of variables. Results After an exhaustive process of pre-processing to ensure data quality--lost values imputation, probes quality, data smoothing and intraclass variability filtering--the final dataset comprised a total of 8, 104 probes. Next, a supervised classification approach and data analysis was carried out to obtain the most relevant genes. Two of them are directly involved in cancer progression and in particular in colorectal cancer. Finally, a supervised classifier was induced to classify new unseen samples. Conclusions We have developed a tentative model for the diagnosis of colorectal cancer based on a biomarker panel. Our results indicate that the gene profile described herein can discriminate between non-cancerous and cancerous samples with 94.45% accuracy using different supervised classifiers (AUC values in the range of 0.997 and 0.955.

  18. Molecular profiling of childhood cancer: Biomarkers and novel therapies.

    Science.gov (United States)

    Saletta, Federica; Wadham, Carol; Ziegler, David S; Marshall, Glenn M; Haber, Michelle; McCowage, Geoffrey; Norris, Murray D; Byrne, Jennifer A

    2014-06-01

    Technological advances including high-throughput sequencing have identified numerous tumor-specific genetic changes in pediatric and adolescent cancers that can be exploited as targets for novel therapies. This review provides a detailed overview of recent advances in the application of target-specific therapies for childhood cancers, either as single agents or in combination with other therapies. The review summarizes preclinical evidence on which clinical trials are based, early phase clinical trial results, and the incorporation of predictive biomarkers into clinical practice, according to cancer type. There is growing evidence that molecularly targeted therapies can valuably add to the arsenal available for treating childhood cancers, particularly when used in combination with other therapies. Nonetheless the introduction of molecularly targeted agents into practice remains challenging, due to the use of unselected populations in some clinical trials, inadequate methods to evaluate efficacy, and the need for improved preclinical models to both evaluate dosing and safety of combination therapies. The increasing recognition of the heterogeneity of molecular causes of cancer favors the continued development of molecularly targeted agents, and their transfer to pediatric and adolescent populations.

  19. The Janus serum bank and biomarkers of cancer

    Directory of Open Access Journals (Sweden)

    Randi Gislefoss

    2009-10-01

    Full Text Available The Janus serum bank, established in 1973, contains sera stored at –25 degrees collected from 330,000 originally healthy individuals. The number of cancer cases have increased from zero in 1973 to more than 50,000 in 2005, including invasive and non-invasive cancers. Information on cases have been obtained by coupling the Janus file against the Norwegian Cancer Registry. The sera have been used in over 70 different cancers research projects, usually in case-control studies and in collaboration with national and international research groups. The type of biomarker analysed include antibodies against Chlamydia, CMV, Epstein Barr virus, HPV and Helicobacter pylori. Leptin, long chain fatty acids, androgens and other hormones, vitamins as well as environmental toxins such as organochlorines are other types of cancer biomarkers investigated. Mutation analyses (BRCA-1 etc have been possible using PCR and the trace amounts of DNA remaining in the sera.Janus serum bank ble etablert i 1973 og inneholder sera lagret ved –25 grader, innsamlet fra 330.000 opprinnelig friske personer. Antall krefttilfeller har steget fra null i 1973 til over 50.000 i år 2005, inkludert både invasiv og ikke-invasiv kreft. Informasjon om kasus er tilgjengelig ved å koble Janus-filene mot Kreftregisterets databaser. Serumprøvene er blitt benyttet i over 70 forskjellige kreftforskningsprosjekter, som oftest i kasus-kontroll studier og i samarbeide med en rekke nasjonale og internasjonale forskningsgrupper. Mange ulike biomarkører på kreft er blitt analysert, bl.a. antistoffer mot Chlamydia, CMV, Epstein Barr virus, HPV og Helicobacter pylori. Leptin, lange fettsyrer, androgener og andre hormoner, vitaminer såvel som miljøgifter av typen organiske klorforbindelser er eksempler på andre kreftbiomarkører som er undersøkt. Det har også vært mulig å gjøre mutasjonsanalyser (BRCA-1 etc ved å bruke PCR til å amplifisere opp den spormengden DNA som finnes i serum.

  20. Validation of Candidate Serum Ovarian Cancer Biomarkers for Early Detection

    Directory of Open Access Journals (Sweden)

    Feng Su

    2007-01-01

    Full Text Available Objective: We have previously analyzed protein profi les using Surface Enhanced Laser Desorption and Ionization Time-Of-Flight Mass Spectroscopy (SELDI-TOF-MS [Kozak et al. 2003, Proc. Natl. Acad. Sci. U.S.A. 100:12343–8] and identified 3 differentially expressed serum proteins for the diagnosis of ovarian cancer (OC [Kozak et al. 2005, Proteomics, 5:4589–96], namely, apolipoprotein A-I (apoA-I, transthyretin (TTR and transferin (TF. The objective of the present study is to determine the efficacy of the three OC biomarkers for the detection of early stage (ES OC, in direct comparison to CA125.Methods: The levels of CA125, apoA-I, TTR and TF were measured in 392 serum samples [82 women with normal ovaries (N, 24 women with benign ovarian tumors (B, 85 women with ovarian tumors of low malignant potential (LMP, 126 women with early stage ovarian cancer (ESOC, and 75 women with late stage ovarian cancer (LSOC], obtained through the GOG and Cooperative Human Tissue Network. Following statistical analysis, multivariate regression models were built to evaluate the utility of the three OC markers in early detection.Results: Multiple logistic regression models (MLRM utilizing all biomarker values (CA125, TTR, TF and apoA-I from all histological subtypes (serous, mucinous, and endometrioid adenocarcinoma distinguished normal samples from LMP with 91% sensitivity (specifi city 92%, and normal samples from ESOC with a sensitivity of 89% (specifi city 92%. MLRM, utilizing values of all four markers from only the mucinous histological subtype showed that collectively, CA125, TTR, TF and apoA-I, were able to distinguish normal samples from mucinous LMP with 90% sensitivity, and further distinguished normal samples from early stage mucinous ovarian cancer with a sensitivity of 95%. In contrast, in serum samples from patients with mucinous tumors, CA125 alone was able to distinguish normal samples from LMP and early stage ovarian cancer with a sensitivity of

  1. Modulating epigenetic memory through vitamins and TET: implications for regenerative medicine and cancer treatment.

    Science.gov (United States)

    Hore, Timothy A

    2017-06-01

    Vitamins A and C represent unrelated sets of small molecules that are essential to the human diet and have recently been shown to intensify erasure of epigenetic memory in naive embryonic stem cells. These effects are driven by complementary enhancement of the ten-eleven translocation (TET) demethylases - vitamin A stimulates TET expression, whereas vitamin C potentiates TET catalytic activity. Vitamin A and C cosupplementation synergistically enhances reprogramming of differentiated cells to the naive state, but overuse may exaggerate instability of imprinted genes. As such, optimizing their use in culture media will be important for regenerative medicine and mammalian transgenics. In addition, mechanistic perception of how these vitamins interact with the epigenome may be relevant for understanding cancer and improving patient treatment.

  2. Polymer Therapeutics: Biomarkers and New Approaches for Personalized Cancer Treatment.

    Science.gov (United States)

    Atkinson, Stuart P; Andreu, Zoraida; Vicent, María J

    2018-01-23

    Polymer therapeutics (PTs) provides a potentially exciting approach for the treatment of many diseases by enhancing aqueous solubility and altering drug pharmacokinetics at both the whole organism and subcellular level leading to improved therapeutic outcomes. However, the failure of many polymer-drug conjugates in clinical trials suggests that we may need to stratify patients in order to match each patient to the right PT. In this concise review, we hope to assess potential PT-specific biomarkers for cancer treatment, with a focus on new studies, detection methods, new models and the opportunities this knowledge will bring for the development of novel PT-based anti-cancer strategies. We discuss the various "hurdles" that a given PT faces on its passage from the syringe to the tumor (and beyond), including the passage through the bloodstream, tumor targeting, tumor uptake and the intracellular release of the active agent. However, we also discuss other relevant concepts and new considerations in the field, which we hope will provide new insight into the possible applications of PT-related biomarkers.

  3. Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth.

    Science.gov (United States)

    Deng, X; Shao, G; Zhang, H-T; Li, C; Zhang, D; Cheng, L; Elzey, B D; Pili, R; Ratliff, T L; Huang, J; Hu, C-D

    2017-03-02

    Protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3. Accumulating evidence suggests that PRMT5 may function as an oncogene to drive cancer cell growth by epigenetic inactivation of several tumor suppressors. Here, we provide evidence that PRMT5 promotes prostate cancer cell growth by epigenetically activating transcription of the androgen receptor (AR) in prostate cancer cells. Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR-positive, but not AR-negative, prostate cancer cells. Significantly, knockdown of PRMT5 in AR-positive LNCaP cells completely suppresses the growth of xenograft tumors in mice. Molecular analysis reveals that PRMT5 binds to the proximal promoter region of the AR gene and contributes mainly to the enriched symmetric dimethylation of H4R3 in the same region. Mechanistically, PRMT5 is recruited to the AR promoter by its interaction with Sp1, the major transcription factor responsible for AR transcription, and forms a complex with Brg1, an ATP-dependent chromatin remodeler, on the proximal promoter region of the AR gene. Furthermore, PRMT5 expression in prostate cancer tissues is significantly higher than that in benign prostatic hyperplasia tissues, and PRMT5 expression correlates positively with AR expression at both the protein and mRNA levels. Taken together, our results identify PRMT5 as a novel epigenetic activator of AR in prostate cancer. Given that inhibiting AR transcriptional activity or androgen synthesis remains the major mechanism of action for most existing anti-androgen agents, our findings also raise an interesting possibility that targeting PRMT5 may represent a novel approach for prostate cancer treatment by eliminating AR expression.

  4. Epigenetic Mechanisms Regulating Adaptive Responses to Targeted Kinase Inhibitors in Cancer.

    Science.gov (United States)

    Angus, Steven P; Zawistowski, Jon S; Johnson, Gary L

    2018-01-06

    Although targeted inhibition of oncogenic kinase drivers has achieved remarkable patient responses in many cancers, the development of resistance has remained a significant challenge. Numerous mechanisms have been identified, including the acquisition of gatekeeper mutations, activating pathway mutations, and copy number loss or gain of the driver or alternate nodes. These changes have prompted the development of kinase inhibitors with increased selectivity, use of second-line therapeutics to overcome primary resistance, and combination treatment to forestall resistance. In addition to genomic resistance mechanisms, adaptive transcriptional and signaling responses seen in tumors are gaining appreciation as alterations that lead to a phenotypic state change-often observed as an epithelial-to-mesenchymal shift or reversion to a cancer stem cell-like phenotype underpinned by remodeling of the epigenetic landscape. This epigenomic modulation driving cell state change is multifaceted and includes modulation of repressive and activating histone modifications, DNA methylation, enhancer remodeling, and noncoding RNA species. Consequently, the combination of kinase inhibitors with drugs targeting components of the transcriptional machinery and histone-modifying enzymes has shown promise in preclinical and clinical studies. Here, we review mechanisms of resistance to kinase inhibition in cancer, with special emphasis on the rewired kinome and transcriptional signaling networks and the potential vulnerabilities that may be exploited to overcome these adaptive signaling changes.

  5. Using the epigenetic field defect to detect prostate cancer in biopsy negative patients.

    Science.gov (United States)

    Truong, Matthew; Yang, Bing; Livermore, Andrew; Wagner, Jennifer; Weeratunga, Puspha; Huang, Wei; Dhir, Rajiv; Nelson, Joel; Lin, Daniel W; Jarrard, David F

    2013-06-01

    We determined whether a novel combination of field defect DNA methylation markers could predict the presence of prostate cancer using histologically normal transrectal ultrasound guided biopsy cores. Methylation was assessed using quantitative Pyrosequencing® in a training set consisting of 65 nontumor and tumor associated prostate tissues from University of Wisconsin. A multiplex model was generated using multivariate logistic regression and externally validated in blinded fashion in a set of 47 nontumor and tumor associated biopsy specimens from University of Washington. We observed robust methylation differences in all genes at all CpGs assayed (p prostate cancer (AUC 0.774, p = 0.001) and had a negative predictive value of 0.909. Comparison between 2 separate cores in patients in this validation set revealed similar methylation defects, indicating detection of a widespread field defect. A widespread epigenetic field defect can be used to detect prostate cancer in patients with histologically negative biopsies. To our knowledge this assay is unique, in that it detects alterations in nontumor cells. With further validation this marker combination (EVX1 and FGF1) has the potential to decrease the need for repeat prostate biopsies, a procedure associated with cost and complications. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  6. Common structural and epigenetic changes in the genome of castration-resistant prostate cancer.

    Science.gov (United States)

    Friedlander, Terence W; Roy, Ritu; Tomlins, Scott A; Ngo, Vy T; Kobayashi, Yasuko; Azameera, Aruna; Rubin, Mark A; Pienta, Kenneth J; Chinnaiyan, Arul; Ittmann, Michael M; Ryan, Charles J; Paris, Pamela L

    2012-02-01

    Progression of primary prostate cancer to castration-resistant prostate cancer (CRPC) is associated with numerous genetic and epigenetic alterations that are thought to promote survival at metastatic sites. In this study, we investigated gene copy number and CpG methylation status in CRPC to gain insight into specific pathophysiologic pathways that are active in this advanced form of prostate cancer. Our analysis defined and validated 495 genes exhibiting significant differences in CRPC in gene copy number, including gains in androgen receptor (AR) and losses of PTEN and retinoblastoma 1 (RB1). Significant copy number differences existed between tumors with or without AR gene amplification, including a common loss of AR repressors in AR-unamplified tumors. Simultaneous gene methylation and allelic deletion occurred frequently in RB1 and HSD17B2, the latter of which is involved in testosterone metabolism. Lastly, genomic DNA from most CRPC was hypermethylated compared with benign prostate tissue. Our findings establish a comprehensive methylation signature that couples epigenomic and structural analyses, thereby offering insights into the genomic alterations in CRPC that are associated with a circumvention of hormonal therapy. Genes identified in this integrated genomic study point to new drug targets in CRPC, an incurable disease state which remains the chief therapeutic challenge. ©2012 AACR.

  7. Grape seed proanthocyanidins reactivate silenced tumor suppressor genes in human skin cancer cells by targeting epigenetic regulators

    International Nuclear Information System (INIS)

    Vaid, Mudit; Prasad, Ram; Singh, Tripti; Jones, Virginia; Katiyar, Santosh K.

    2012-01-01

    Grape seed proanthocyanidins (GSPs) have been shown to have anti-skin carcinogenic effects in in vitro and in vivo models. However, the precise epigenetic molecular mechanisms remain unexplored. This study was designed to investigate whether GSPs reactivate silenced tumor suppressor genes following epigenetic modifications in skin cancer cells. For this purpose, A431 and SCC13 human squamous cell carcinoma cell lines were used as in vitro models. The effects of GSPs on DNA methylation, histone modifications and tumor suppressor gene expressions were studied in these cell lines using enzyme activity assays, western blotting, dot-blot analysis and real-time polymerase chain reaction (RT-PCR). We found that treatment of A431 and SCC13 cells with GSPs decreased the levels of: (i) global DNA methylation, (ii) 5-methylcytosine, (iii) DNA methyltransferase (DNMT) activity and (iv) messenger RNA (mRNA) and protein levels of DNMT1, DNMT3a and DNMT3b in these cells. Similar effects were noted when these cancer cells were treated identically with 5-aza-2′-deoxycytidine, an inhibitor of DNA methylation. GSPs decreased histone deacetylase activity, increased levels of acetylated lysines 9 and 14 on histone H3 (H3-Lys 9 and 14) and acetylated lysines 5, 12 and 16 on histone H4, and reduced the levels of methylated H3-Lys 9. Further, GSP treatment resulted in re-expression of the mRNA and proteins of silenced tumor suppressor genes, RASSF1A, p16 INK4a and Cip1/p21. Together, this study provides a new insight into the epigenetic mechanisms of GSPs and may have significant implications for epigenetic therapy in the treatment/prevention of skin cancers in humans. -- Highlights: ►Epigenetic modulations have been shown to have a role in cancer risk. ►Proanthocyanidins decrease the levels of DNA methylation and histone deacetylation. ►Proanthocyanidins inhibit histone deacetylase activity in skin cancer cells. ►Proanthocyanidins reactivate tumor suppressor genes in skin

  8. Epigenetic repression of ROR2 has a Wnt-mediated, pro-tumourigenic role in colon cancer

    Directory of Open Access Journals (Sweden)

    López-Otín Carlos

    2010-06-01

    Full Text Available Abstract Background Wnt factors control cell differentiation through semi-independent molecular cascades known as the β-catenin-dependent (canonical and -independent (non-canonical Wnt signalling pathways. Genetic and epigenetic alteration of components of the canonical Wnt signalling pathway is one of the primary mechanisms underlying colon cancer. Despite increasing evidence of the role of the non-canonical pathways in tumourigenesis, however, the underlying molecular mechanisms are poorly understood. Results Here we report that the receptor tyrosine kinase-like orphan receptor 2 (ROR2, a transmembrane receptor for Wnt factors that activates non-canonical pathways, is frequently repressed by aberrant promoter hypermethylation in human colon cancer cell lines and primary tumours. By restoring ROR2 activity in colon cancer cells harbouring ROR2 promoter hypermethylation, we show that the role of ROR2 in colon cancer cells is mediated, at least in part, by canonical Wnt and that its epigenetic-dependent loss can be pro-tumourigenic. Conclusions Our data show the importance of epigenetic alterations of ROR2 in colon cancer, highlighting the close interconnection between canonical and non-canonical Wnt signalling pathways in this type of tumour.

  9. Biomarker Identification and Pathway Analysis by Serum Metabolomics of Lung Cancer

    Directory of Open Access Journals (Sweden)

    Yingrong Chen

    2015-01-01

    Full Text Available Lung cancer is one of the most common causes of cancer death, for which no validated tumor biomarker is sufficiently accurate to be useful for diagnosis. Additionally, the metabolic alterations associated with the disease are unclear. In this study, we investigated the construction, interaction, and pathways of potential lung cancer biomarkers using metabolomics pathway analysis based on the Kyoto Encyclopedia of Genes and Genomes database and the Human Metabolome Database to identify the top altered pathways for analysis and visualization. We constructed a diagnostic model using potential serum biomarkers from patients with lung cancer. We assessed their specificity and sensitivity according to the area under the curve of the receiver operator characteristic (ROC curves, which could be used to distinguish patients with lung cancer from normal subjects. The pathway analysis indicated that sphingolipid metabolism was the top altered pathway in lung cancer. ROC curve analysis indicated that glycerophospho-N-arachidonoyl ethanolamine (GpAEA and sphingosine were potential sensitive and specific biomarkers for lung cancer diagnosis and prognosis. Compared with the traditional lung cancer diagnostic biomarkers carcinoembryonic antigen and cytokeratin 19 fragment, GpAEA and sphingosine were as good or more appropriate for detecting lung cancer. We report our identification of potential metabolic diagnostic and prognostic biomarkers of lung cancer and clarify the metabolic alterations in lung cancer.

  10. BORIS/CTCFL mRNA isoform expression and epigenetic regulation in epithelial ovarian cancer

    Science.gov (United States)

    Link, Petra A.; Zhang, Wa; Odunsi, Kunle; Karpf, Adam R.

    2013-01-01

    Cancer germline (CG) genes are normally expressed in germ cells and aberrantly expressed in a variety of cancers; their immunogenicity has led to the widespread development of cancer vaccines targeting these antigens. BORIS/CTCFL is an autosomal CG antigen and promising cancer vaccine target. BORIS is the only known paralog of CTCF, a gene intimately involved in genomic imprinting, chromatin insulation, and nuclear regulation. We have previously shown that BORIS is expressed in epithelial ovarian cancer (EOC) and that its expression coincides with promoter and global DNA hypomethylation. Recently, 23 different BORIS mRNA variants have been described, and have been functionally grouped into six BORIS isoform families (sf1–sf6). In the present study, we have characterized the expression of BORIS isoform families in normal ovary (NO) and EOC, the latter of which were selected to include two groups with widely varying global DNA methylation status. We find selective expression of BORIS isoform families in NO, which becomes altered in EOC, primarily by the activation of BORIS sf1 in EOC. When comparing EOC samples based on methylation status, we find that BORIS sf1 and sf2 isoform families are selectively activated in globally hypomethylated tumors. In contrast, CTCF is downregulated in EOC, and the ratio of BORIS sf1, sf2, and sf6 isoform families as a function of CTCF is elevated in hypomethylated tumors. Finally, the expression of all BORIS isoform families was induced to varying extents by epigenetic modulatory drugs in EOC cell lines, particularly when DNMT and HDAC inhibitors were used in combination. PMID:23390377

  11. Delineating an Epigenetic Continuum for Initiation, Transformation and Progression to Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Kang Mei; Stephen, Josena K. [Department of Otolaryngology/Head and Neck Surgery, Henry Ford Hospital, 1 Ford Place, 1D, Detroit, MI 48202 (United States); Raju, Usha [Department of Pathology, Henry Ford Hospital, Detroit, 1 Ford Place, 1D, Detroit, MI 48202 (United States); Worsham, Maria J., E-mail: mworsha1@hfhs.org [Department of Otolaryngology/Head and Neck Surgery, Henry Ford Hospital, 1 Ford Place, 1D, Detroit, MI 48202 (United States)

    2011-03-29

    Aberrant methylation of promoter CpG islands is a hallmark of human cancers and is an early event in carcinogenesis. We examined whether promoter hypermethylation contributes to the pathogenesis of benign breast lesions along a progression continuum to invasive breast cancer. The exploratory study cohort comprised 17 breast cancer patients with multiple benign and/or in situ lesions concurrently present with invasive carcinoma within a tumor biopsy. DNA from tumor tissue, normal breast epithelium when present, benign lesions (fibroadenoma, hyperplasia, papilloma, sclerosing adenosis, apocrine metaplasia, atypical lobular hyperplasia or atypical ductal hyperplasia), and in situ lesions of lobular carcinoma and ductal carcinoma were interrogated for promoter methylation status in 22 tumor suppressor genes using the multiplex ligation-dependent probe amplification assay (MS-MLPA). Methylation specific PCR was performed to confirm hypermethylation detected by MS-MLPA. Promoter methylation was detected in 11/22 tumor suppressor genes in 16/17 cases. Hypermethylation of RASSF1 was most frequent, present in 14/17 cases, followed by APC in 12/17, and GSTP1 in 9/17 cases with establishment of an epigenetic monocloncal progression continuum to invasive breast cancer. Hypermethylated promoter regions in normal breast epithelium, benign, and premalignant lesions within the same tumor biopsy implicate RASSF1, APC, GSTP1, TIMP3, CDKN2B, CDKN2A, ESR1, CDH13, RARB, CASP8, and TP73 as early events. DNA hypermethylation underlies the pathogenesis of step-wise transformation along a monoclonal continuum from normal to preneoplasia to invasive breast cancer.

  12. Delineating an Epigenetic Continuum for Initiation, Transformation and Progression to Breast Cancer

    International Nuclear Information System (INIS)

    Chen, Kang Mei; Stephen, Josena K.; Raju, Usha; Worsham, Maria J.

    2011-01-01

    Aberrant methylation of promoter CpG islands is a hallmark of human cancers and is an early event in carcinogenesis. We examined whether promoter hypermethylation contributes to the pathogenesis of benign breast lesions along a progression continuum to invasive breast cancer. The exploratory study cohort comprised 17 breast cancer patients with multiple benign and/or in situ lesions concurrently present with invasive carcinoma within a tumor biopsy. DNA from tumor tissue, normal breast epithelium when present, benign lesions (fibroadenoma, hyperplasia, papilloma, sclerosing adenosis, apocrine metaplasia, atypical lobular hyperplasia or atypical ductal hyperplasia), and in situ lesions of lobular carcinoma and ductal carcinoma were interrogated for promoter methylation status in 22 tumor suppressor genes using the multiplex ligation-dependent probe amplification assay (MS-MLPA). Methylation specific PCR was performed to confirm hypermethylation detected by MS-MLPA. Promoter methylation was detected in 11/22 tumor suppressor genes in 16/17 cases. Hypermethylation of RASSF1 was most frequent, present in 14/17 cases, followed by APC in 12/17, and GSTP1 in 9/17 cases with establishment of an epigenetic monocloncal progression continuum to invasive breast cancer. Hypermethylated promoter regions in normal breast epithelium, benign, and premalignant lesions within the same tumor biopsy implicate RASSF1, APC, GSTP1, TIMP3, CDKN2B, CDKN2A, ESR1, CDH13, RARB, CASP8, and TP73 as early events. DNA hypermethylation underlies the pathogenesis of step-wise transformation along a monoclonal continuum from normal to preneoplasia to invasive breast cancer

  13. Sulforaphane modulates telomerase activity via epigenetic regulation in prostate cancer cell lines.

    Science.gov (United States)

    Abbas, Ata; Hall, J Adam; Patterson, William L; Ho, Emily; Hsu, Anna; Al-Mulla, Fahd; Georgel, Philippe T

    2016-02-01

    Epidemiologic studies have revealed that diets rich in sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables, are associated with a marked decrease in prostate cancer incidence. The chemo-preventive role of SFN is associated with its histone de-acetylase inhibitor activity. However, the effect of SFN on chromatin composition and dynamic folding, especially in relation to HDAC inhibitor activity, remains poorly understood. In this study, we found that SFN can inhibit the expression and activity of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, in 2 prostate cancer cell lines. This decrease in gene expression is correlated with SFN-induced changes in chromatin structure and composition. The SFN-mediated changes in levels of histone post-translational modifications, more specifically acetylation of histone H3 lysine 18 and di-methylation of histone H3 lysine 4, 2 modifications linked with high risk of prostate cancer recurrence, were associated with regulatory elements within the hTERT promoter region. Chromatin condensation may also play a role in SFN-mediated hTERT repression, since expression and recruitment of MeCP2, a known chromatin compactor, were altered in SFN treated prostate cancer cells. Chromatin immuno-precipitation (ChIP) of MeCP2 showed enrichment over regions of the hTERT promoter with increased nucleosome density. These combined results strongly support a role for SFN in the mediation of epigenetic events leading to the repression of hTERT in prostate cancer cells. This ability of SFN to modify chromatin composition and structure associated with target gene expression provides a new model by which dietary phytochemicals may exert their chemoprevention activity.

  14. Epigenome-Wide Tumor DNA Methylation Profiling Identifies Novel Prognostic Biomarkers of Metastatic-Lethal Progression in Men Diagnosed with Clinically Localized Prostate Cancer.

    Science.gov (United States)

    Zhao, Shanshan; Geybels, Milan S; Leonardson, Amy; Rubicz, Rohina; Kolb, Suzanne; Yan, Qingxiang; Klotzle, Brandy; Bibikova, Marina; Hurtado-Coll, Antonio; Troyer, Dean; Lance, Raymond; Lin, Daniel W; Wright, Jonathan L; Ostrander, Elaine A; Fan, Jian-Bing; Feng, Ziding; Stanford, Janet L

    2017-01-01

    Aside from Gleason sum, few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential. Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of prostate cancer patients followed prospectively for at least 5 years. Metastasis was confirmed by positive bone scan, MRI, CT, or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from nonrecurrent tumors, and which were complementary to Gleason sum. Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P prostate cancer include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset, the AUC for Gleason sum alone (0.82) significantly increased with the addition of four individual CpGs (range, 0.86-0.89; all P epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. Clin Cancer Res; 23(1); 311-9. ©2016 AACR. ©2016 American Association for Cancer Research.

  15. Clinical Use of Cancer Biomarkers in Epithelial Ovarian Cancer

    DEFF Research Database (Denmark)

    Söletormos, Georg; Duffy, Michael J; Othman Abu Hassan, Suher

    2016-01-01

    OBJECTIVE: To present an update of the European Group on Tumor Markers guidelines for serum markers in epithelial ovarian cancer. METHODS: Systematic literature survey from 2008 to 2013. The articles were evaluated by level of evidence and strength of recommendation. RESULTS: Because of its low s...

  16. Lipid Biomarkers Identified for Liver Cancer | Center for Cancer Research

    Science.gov (United States)

    Hepatocellular carcinoma (HCC) is an aggressive cancer of the liver with poor prognosis and growing incidence in developed countries. Pathology and genetic profiles of HCC are heterogeneous, suggesting that it can begin growing in different cell types. Although human tumors such as HCC have been profiled in-depth by genomics-based studies, not much is known about their overall

  17. Cancer biomarkers defined by autoantibody signatures to aberrant O-glycopeptide epitopes

    DEFF Research Database (Denmark)

    Wandall, Hans H; Blixt, Ola; Tarp, Mads A

    2010-01-01

    Autoantibodies to cancer antigens hold promise as biomarkers for early detection of cancer. Proteins that are aberrantly processed in cancer cells are likely to present autoantibody targets. The extracellular mucin MUC1 is overexpressed and aberrantly glycosylated in many cancers; thus, we evalua...

  18. Defining the steps that lead to cancer: replicative telomere erosion, aneuploidy and an epigenetic maturation arrest of tissue stem cells.

    Science.gov (United States)

    Stindl, Reinhard

    2008-01-01

    Recently, an influential sequencing study found that more than 1700 genes had non-silent mutations in either a breast or colorectal cancer, out of just 11 breast and 11 colorectal tumor samples. This is not surprising given the fact that genomic instability is the hallmark of cancer cells. The plethora of genomic alterations found in every carcinoma does not obey the 'law of genotype-phenotype correlation', since the same histological subtype of cancer harbors different gene mutations and chromosomal aberrations in every patient. In an attempt to make sense out of the observed genetic and chromosomal chaos in cancer, I propose a cascade model. According to this model, tissue regeneration depends on the proliferation and serial activation of stem cells. Replicative telomere erosion limits the proliferative life span of adult stem cells and results in the Hayflick limit (M1). However, local tissue exhaustion or old age might promote the activation of M1-deficient tissue stem cells. Extended proliferation of these cells leads to telomere-driven chromosomal instability and aneuploidy (abnormal balance of chromosomes and/or chromosome material). Several of the aforementioned steps have been already described in the literature. However, in contrast to common theories, it is proposed here that the genomic damage blocks the epigenetic differentiation switch. As a result of aneuploidy, differentiation-specific genes cannot be activated by modification of methylation patterns. Consequently, the phenotype of cancer tissue is largely determined by the epigenetic maturation arrest of tissue stem cells, which in addition enables a fraction of cancer cells to proliferate, invade and metastasize, as normal adult stem cells do. The new model combines genetic and epigenetic alterations of cancer cells in one causative cascade and offers an explanation for why identical histologic cancer types harbor a confusing variety of chromosomal and gene aberrations. The Viennese Cascade, as

  19. Prostacyclin synthase expression and epigenetic regulation in nonsmall cell lung cancer.

    LENUS (Irish Health Repository)

    Cathcart, Mary-Clare

    2012-02-01

    BACKGROUND: Prostacyclin synthase (PGIS) metabolizes prostaglandin H(2), into prostacyclin. This study aimed to determine the expression profile of PGIS in nonsmall cell lung cancer (NSCLC) and examine potential mechanisms involved in PGIS regulation. METHODS: PGIS expression was examined in human NSCLC and matched controls by reverse transcriptase polymerase chain reaction (RT-PCR), Western analysis, and immunohistochemistry. A 204-patient NSCLC tissue microarray was stained for PGIS and cyclooxygenase 2 (COX2) expression. Staining intensity was correlated with clinical parameters. Epigenetic mechanisms underpinning PGIS promoter expression were examined using RT-PCR, methylation-specific PCR, and chromatin immunoprecipitation analysis. RESULTS: PGIS expression was reduced\\/absent in human NSCLC protein samples (P < .0001), but not mRNA relative to matched controls. PGIS tissue expression was higher in squamous cell carcinoma (P = .004) and in male patients (P < .05). No significant correlation of PGIS or COX2 expression with overall patient survival was observed, although COX2 was prognostic for short-term (2-year) survival (P < .001). PGIS mRNA expression was regulated by DNA CpG methylation and histone acetylation in NSCLC cell lines, with chromatin remodeling taking place directly at the PGIS gene. PGIS mRNA expression was increased by both demethylation agents and histone deacetylase inhibitors. Protein levels were unaffected by demethylation agents, whereas PGIS protein stability was negatively affected by histone deacetylase inhibitors. CONCLUSIONS: PGIS protein expression is reduced in NSCLC, and does not correlate with overall patient survival. PGIS expression is regulated through epigenetic mechanisms. Differences in expression patterns between mRNA and protein levels suggest that PGIS expression and protein stability are regulated post-translationally. PGIS protein stability may have an important therapeutic role in NSCLC.

  20. Metabolome analysis for discovering biomarkers of gastroenterological cancer.

    Science.gov (United States)

    Suzuki, Makoto; Nishiumi, Shin; Matsubara, Atsuki; Azuma, Takeshi; Yoshida, Masaru

    2014-09-01

    Improvements in analytical technologies have made it possible to rapidly determine the concentrations of thousands of metabolites in any biological sample, which has resulted in metabolome analysis being applied to various types of research, such as clinical, cell biology, and plant/food science studies. The metabolome represents all of the end products and by-products of the numerous complex metabolic pathways operating in a biological system. Thus, metabolome analysis allows one to survey the global changes in an organism's metabolic profile and gain a holistic understanding of the changes that occur in organisms during various biological processes, e.g., during disease development. In clinical metabolomic studies, there is a strong possibility that differences in the metabolic profiles of human specimens reflect disease-specific states. Recently, metabolome analysis of biofluids, e.g., blood, urine, or saliva, has been increasingly used for biomarker discovery and disease diagnosis. Mass spectrometry-based techniques have been extensively used for metabolome analysis because they exhibit high selectivity and sensitivity during the identification and quantification of metabolites. Here, we describe metabolome analysis using liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, and capillary electrophoresis-mass spectrometry. Furthermore, the findings of studies that attempted to discover biomarkers of gastroenterological cancer are also outlined. Finally, we discuss metabolome analysis-based disease diagnosis. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Biomarkers for Anti-Angiogenic Therapy in Cancer

    Directory of Open Access Journals (Sweden)

    Markus Wehland

    2013-04-01

    Full Text Available Angiogenesis, the development of new vessels from existing vasculature, plays a central role in tumor growth, survival, and progression. On the molecular level it is controlled by a number of pro- and anti-angiogenic cytokines, among which the vascular endothelial growth factors (VEGFs, together with their related VEGF-receptors, have an exceptional position. Therefore, the blockade of VEGF signaling in order to inhibit angiogenesis was deemed an attractive approach for cancer therapy and drugs interfering with the VEGF-ligands, the VEGF receptors, and the intracellular VEGF-mediated signal transduction were developed. Although promising in pre-clinical trials, VEGF-inhibition proved to be problematic in the clinical context. One major drawback was the generally high variability in patient response to anti-angiogenic drugs and the rapid development of therapy resistance, so that, in total, only moderate effects on progression-free and overall survival were observed. Biomarkers predicting the response to VEGF-inhibition might attenuate this problem and help to further individualize drug and dosage determination. Although up to now no definitive biomarker has been identified for this purpose, several candidates are currently under investigation. This review aims to give an overview of the recent developments in this field, focusing on the most prevalent tumor species.

  2. Clinical proteomics: Applications for prostate cancer biomarker discovery and detection.

    Science.gov (United States)

    Petricoin, Emanuel F; Ornstein, David K; Liotta, Lance A

    2004-01-01

    The science of proteomics comprises much more than simply generating lists of proteins that change in expression as a cause of or consequence of pathophysiology. The goal of proteomics should be to characterize the information flow through the intercellular protein circuitry that communicates with the extracellular microenvironment and then ultimately to the serum/plasma macroenvironment. Serum proteomic pattern diagnostics is a new type of proteomic concept in which patterns of ion signatures generated from high dimensional mass spectrometry data are used as diagnostic classifiers. This recent approach has exciting potential for clinical utility of diagnostic patterns because low molecular weight metabolites, peptides, and protein fragments may have higher accuracy than traditional biomarkers of cancer detection. Intriguingly, we now have discovered that this diagnostic information exists in a bound state, complexed with circulating highly abundant carrier proteins. These diagnostic fragments may one day be harvested by circulating nanoparticles, designed to absorb, enrich, and amplify the repertoire of diagnostic biomarkers generated-even at the critical, initial stages of carcinogenesis. Copyright 2004 Elsevier Inc.

  3. New insights in oncology: Epi-genetics and cancer stem cells; Nouvelles perspectives en oncologie: epigenetique et cellules souches cancereuses

    Energy Technology Data Exchange (ETDEWEB)

    Krutovskikh, V.; Partensky, C. [Centre international de recherche sur le cancer, 150, cours Albert-Thomas, 69372 Lyon cedex 08 (France)

    2011-12-15

    Cancer is a multi-etiologic, multistage disease with a prevalent genetic component, which happens when a large number of genes, critical for cell growth, death, differentiation, migration, and metabolic plasticity are altered irreversibly, so as to either 'gain' (oncogenes) or 'lose' (tumour suppressors) their function. Recent discoveries have revealed the previously underestimated etiologic importance of multiple epigenetic, that is to say, reversible factors (histone modifications, DNA methylation, non-coding RNA) involved in the transcriptional and post-transcriptional regulation of proteins, indispensable for the control of cancerous phenotype. Stable alterations of epigenetic machinery ('epi-mutations') turn out to play a critical role at different steps of carcinogenesis. In addition, due to substantial recent progress in stem cell biology, the new concept of cancer stem cells has emerged. This, along with newly discovered epigenetic cancer mechanisms, gives rise to a hope to overcome radio- and chemo-resistance and to eradicate otherwise incurable neoplasms. (authors)

  4. The role of pancreatic cancer-derived exosomes in cancer progress and their potential application as biomarkers.

    Science.gov (United States)

    Jin, H; Wu, Y; Tan, X

    2017-08-01

    Pancreatic cancer is one of the most deadly cancers, with dismal prognosis due to its poor early detection rate and high metastatic rate. Thus, elucidation of the molecular mechanisms accounting for its metastasis and discovery of competent biomarkers is required. Exosomes are multivesicular body-derived small extracellular vesicles released by various cell types that serve as important message carriers during intercellular communication. They are also known to play critical roles during cancer-genesis, cancer-related immune reactions, and metastasis. They also possess promising potential as novel biomarkers for cancer early detection. Therefore, extensive studies on pancreatic cancer-derived exosomes are currently being performed because they hold the promising potential of elevating the overall survival rate of patients with pancreatic cancer. In the present review, we focus on the role of exosomes in pancreatic cancer-related immune reactions, metastasis, and complications, and on their potential application as pancreatic cancer biomarkers.

  5. Comparative analysis of 14-3-3 isoform expression and epigenetic alterations in colorectal cancer

    International Nuclear Information System (INIS)

    Young, Gavin M.; Radhakrishnan, Vijayababu M.; Centuori, Sara M.; Gomes, Cecil J.; Martinez, Jesse D.

    2015-01-01

    The 14-3-3 family is a group of intracellular proteins found in all eukaryotic organisms. Humans have seven isoforms that serve as scaffolds to promote interactions of regulatory phospho-proteins involved in many vital cellular processes and previous studies have shown that disturbances in native 14-3-3 levels can contribute significantly to the development of various cancers. DNA and RNA was extracted from frozen tissue samples collected by the Human Cooperative Tissue Network. RNA samples were reverse transcribed and subjected to qRT-PCR analysis using fluorescently labelled probes. Genomic DNA was treated with bisulfite and cloned into bacterial vectors for subsequent high-resolution sequencing. Mammalian NIH3T3 cells were transformed with 14-3-3 eta and Ras expression vectors synthesized from cDNA. Colonies were counted and transforming capability assessed after 21 days of growth. Cell lysates were analyzed by western blot to verify protein expression. Here we examined normal and cancerous 14-3-3 expression levels of all seven isoforms in a cohort of sporadic colorectal adenocarcinomas and in a group of tumors and their matched normals using qRT-PCR analysis. We found a statistically significant decrease in the levels of 14-3-3 sigma, eta, and zeta observed among adenocarcinomas compared to normal tissue. A parallel analysis of microarray data from the TCGA dataset confirmed that expression of sigma and eta were down-regulated in colon tumors. To explore the mechanisms behind 14-3-3 expression changes, we examined the methylation status of the sigma, eta, and zeta gene promoters in selected samples. Our data identified novel CpG methylation sites in the eta promoter consistent with epigenetic silencing of both 14-3-3 sigma and eta isoforms during colon tumorigenesis. Because epigenetic silencing is the hallmark of a tumor suppressor we tested eta in focus formation assays and found that it is capable of suppressing ras-induced transformation of NIH3T3 cells. To

  6. Epigenetic Alteration by DNA Promoter Hypermethylation of Genes Related to Transforming Growth Factor-β (TGF-β) Signaling in Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Khin, Sann Sanda [Kobe University Graduate School of Medicine, Division of Diagnostic Molecular Pathology, Kobe 650-0017 (Japan); Pathology Research Unit, Department of Medical Research (Central Myanmar), Naypyitaw, Union of (Myanmar); Kitazawa, Riko [Kobe University Graduate School of Medicine, Division of Diagnostic Molecular Pathology, Kobe 650-0017 (Japan); Ehime University Graduate School of Medicine, Toon 791-0295, Ehime (Japan); Kondo, Takeshi; Idei, Yuka; Fujimoto, Masayo [Kobe University Graduate School of Medicine, Division of Diagnostic Molecular Pathology, Kobe 650-0017 (Japan); Haraguchi, Ryuma [Ehime University Graduate School of Medicine, Toon 791-0295, Ehime (Japan); Mori, Kiyoshi [Kobe University Graduate School of Medicine, Division of Diagnostic Molecular Pathology, Kobe 650-0017 (Japan); Kitazawa, Sohei, E-mail: kitazawa@m.ehime-u.ac.jp [Kobe University Graduate School of Medicine, Division of Diagnostic Molecular Pathology, Kobe 650-0017 (Japan); Ehime University Graduate School of Medicine, Toon 791-0295, Ehime (Japan)

    2011-03-03

    Epigenetic alterations in cancer, especially DNA methylation and histone modification, exert a significant effect on the deregulated expression of cancer-related genes and lay an epigenetic pathway to carcinogenesis and tumor progression. Global hypomethylation and local hypermethylation of CpG islands in the promoter region, which result in silencing tumor suppressor genes, constitute general and major epigenetic modification, the hallmark of the neoplastic epigenome. Additionally, methylation-induced gene silencing commonly affects a number of genes and increases with cancer progression. Indeed, cancers with a high degree of methylation (CpG island methylator phenotype/CIMP) do exist and represent a distinct subset of certain cancers including colorectal, bladder and kidney. On the other hand, signals from the microenvironment, especially those from transforming growth factor-β (TGF-β), induce targeted de novo epigenetic alterations of cancer-related genes. While TGF-β signaling has been implicated in two opposite roles in cancer, namely tumor suppression and tumor promotion, its deregulation is also partly induced by epigenetic alteration itself. Although the epigenetic pathway to carcinogenesis and cancer progression has such reciprocal complexity, the important issue is to identify genes or signaling pathways that are commonly silenced in various cancers in order to find early diagnostic and therapeutic targets. In this review, we focus on the epigenetic alteration by DNA methylation and its role in molecular modulations of the TGF-β signaling pathway that cause or underlie altered cancer-related gene expression in both phases of early carcinogenesis and late cancer progression.

  7. Epigenetic Alteration by DNA Promoter Hypermethylation of Genes Related to Transforming Growth Factor-β (TGF-β) Signaling in Cancer

    International Nuclear Information System (INIS)

    Khin, Sann Sanda; Kitazawa, Riko; Kondo, Takeshi; Idei, Yuka; Fujimoto, Masayo; Haraguchi, Ryuma; Mori, Kiyoshi; Kitazawa, Sohei

    2011-01-01

    Epigenetic alterations in cancer, especially DNA methylation and histone modification, exert a significant effect on the deregulated expression of cancer-related genes and lay an epigenetic pathway to carcinogenesis and tumor progression. Global hypomethylation and local hypermethylation of CpG islands in the promoter region, which result in silencing tumor suppressor genes, constitute general and major epigenetic modification, the hallmark of the neoplastic epigenome. Additionally, methylation-induced gene silencing commonly affects a number of genes and increases with cancer progression. Indeed, cancers with a high degree of methylation (CpG island methylator phenotype/CIMP) do exist and represent a distinct subset of certain cancers including colorectal, bladder and kidney. On the other hand, signals from the microenvironment, especially those from transforming growth factor-β (TGF-β), induce targeted de novo epigenetic alterations of cancer-related genes. While TGF-β signaling has been implicated in two opposite roles in cancer, namely tumor suppression and tumor promotion, its deregulation is also partly induced by epigenetic alteration itself. Although the epigenetic pathway to carcinogenesis and cancer progression has such reciprocal complexity, the important issue is to identify genes or signaling pathways that are commonly silenced in various cancers in order to find early diagnostic and therapeutic targets. In this review, we focus on the epigenetic alteration by DNA methylation and its role in molecular modulations of the TGF-β signaling pathway that cause or underlie altered cancer-related gene expression in both phases of early carcinogenesis and late cancer progression

  8. Epigenetic Alteration by DNA Promoter Hypermethylation of Genes Related to Transforming Growth Factor-β (TGF-β Signaling in Cancer

    Directory of Open Access Journals (Sweden)

    Kiyoshi Mori

    2011-03-01

    Full Text Available Epigenetic alterations in cancer, especially DNA methylation and histone modification, exert a significant effect on the deregulated expression of cancer-related genes and lay an epigenetic pathway to carcinogenesis and tumor progression. Global hypomethylation and local hypermethylation of CpG islands in the promoter region, which result in silencing tumor suppressor genes, constitute general and major epigenetic modification, the hallmark of the neoplastic epigenome. Additionally, methylation-induced gene silencing commonly affects a number of genes and increases with cancer progression. Indeed, cancers with a high degree of methylation (CpG island methylator phenotype/CIMP do exist and represent a distinct subset of certain cancers including colorectal, bladder and kidney. On the other hand, signals from the microenvironment, especially those from transforming growth factor-β (TGF-β, induce targeted de novo epigenetic alterations of cancer-related genes. While TGF-β signaling has been implicated in two opposite roles in cancer, namely tumor suppression and tumor promotion, its deregulation is also partly induced by epigenetic alteration itself. Although the epigenetic pathway to carcinogenesis and cancer progression has such reciprocal complexity, the important issue is to identify genes or signaling pathways that are commonly silenced in various cancers in order to find early diagnostic and therapeutic targets. In this review, we focus on the epigenetic alteration by DNA methylation and its role in molecular modulations of the TGF-β signaling pathway that cause or underlie altered cancer-related gene expression in both phases of early carcinogenesis and late cancer progression.

  9. Oral Microbiome: A New Biomarker Reservoir for Oral and Oropharyngeal Cancers

    OpenAIRE

    Lim, Yenkai; Totsika, Makrina; Morrison, Mark; Punyadeera, Chamindie

    2017-01-01

    Current biomarkers (DNA, RNA and protein) for oral cavity and oropharyngeal cancers demonstrate biological variations between individuals, rendering them impractical for clinical translation. Whilst these biomarkers originate from the host, there is not much information in the literature about the influence of oral microbiota on cancer pathogenesis, especially in oral cancers. Oral microbiotas are known to participate in disease initiation and progression not only limited to the oral cavity, ...

  10. microRNA Biomarkers to Generate Sensitivity to Abiraterone-Resistant Prostate Cancer

    Science.gov (United States)

    2017-09-01

    CYP17A1 inhibition with abiraterone in castration- resistant prostate cancer : induction of steroidogenesis and androgen receptor splice variants...AWARD NUMBER: W81XWH-15-1-0353 TITLE: microRNA Biomarkers to Generate Sensitivity to Abiraterone-Resistant Prostate Cancer PRINCIPAL...TITLE AND SUBTITLE microRNA Biomarkers to Generate Sensitivity to Abiraterone- Resistant Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER

  11. The Thoc1 Ribonucleoprotein as a Novel Biomarker for Prostate Cancer Treatment Assignment

    Science.gov (United States)

    2017-10-01

    for prostate cancer , the work may impact development of diagnostic /prognostic products based on pThoc1. The presence of the THO ribonucleoprotin...AWARD NUMBER: W81XWH-14-1-0475 TITLE: The Thoc1 Ribonucleoprotein as a Novel Biomarker for Prostate Cancer Treatment Assignment PRINCIPAL...15Sept 2016 - 14Sep2017 4. TITLE AND SUBTITLE The Thoc1 Ribonucleoprotein as a Novel Biomarker for Prostate 5a. CONTRACT NUMBER Cancer Treatment

  12. Breast cancer biomarkers predict weight loss after gastric bypass surgery

    Directory of Open Access Journals (Sweden)

    Sauter Edward R

    2012-01-01

    Full Text Available Abstract Background Obesity has long been associated with postmenopausal breast cancer risk and more recently with premenopausal breast cancer risk. We previously observed that nipple aspirate fluid (n levels of prostate specific antigen (PSA were associated with obesity. Serum (s levels of adiponectin are lower in women with higher body mass index (BMI and with breast cancer. We conducted a prospective study of obese women who underwent gastric bypass surgery to determine: 1 change in n- and s-adiponectin and nPSA after surgery and 2 if biomarker change is related to change in BMI. Samples (30-s, 28-n and BMI were obtained from women 0, 3, 6 and 12 months after surgery. Findings There was a significant increase after surgery in pre- but not postmenopausal women at all time points in s-adiponectin and at 3 and 6 months in n-adiponectin. Low n-PSA and high s-adiponectin values were highly correlated with decrease in BMI from baseline. Conclusions Adiponectin increases locally in the breast and systemically in premenopausal women after gastric bypass. s-adiponectin in pre- and nPSA in postmenopausal women correlated with greater weight loss. This study provides preliminary evidence for biologic markers to predict weight loss after gastric bypass surgery.

  13. Tumor interstitial fluid - a treasure trove of cancer biomarkers.

    Science.gov (United States)

    Gromov, Pavel; Gromova, Irina; Olsen, Charlotta J; Timmermans-Wielenga, Vera; Talman, Mai-Lis; Serizawa, Reza R; Moreira, José M A

    2013-11-01

    Tumor interstitial fluid (TIF) is a proximal fluid that, in addition to the set of blood soluble phase-borne proteins, holds a subset of aberrantly externalized components, mainly proteins, released by tumor cells and tumor microenvironment through various mechanisms, which include classical secretion, non-classical secretion, secretion via exosomes and membrane protein shedding. Consequently, the interstitial aqueous phase of solid tumors is a highly promising resource for the discovery of molecules associated with pathological changes in tissues. Firstly, it allows one to delve deeper into the regulatory mechanisms and functions of secretion-related processes in tumor development. Secondly, the anomalous secretion of molecules that is innate to tumors and the tumor microenvironment, being associated with cancer progression, offers a valuable source for biomarker discovery and possible targets for therapeutic intervention. Here we provide an overview of the features of tumor-associated interstitial fluids, based on recent and updated information obtained mainly from our studies of breast cancer. Data from the study of interstitial fluids recovered from several other types of cancer are also discussed. This article is a part of a Special Issue entitled: The Updated Secretome. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Epigenetic down-regulated DDX10 promotes cell proliferation through Akt/NF-κB pathway in ovarian cancer

    Energy Technology Data Exchange (ETDEWEB)

    Gai, Muhuizi; Bo, Qifang; Qi, Lixia, E-mail: lixiaqi_dph@sina.com

    2016-01-22

    Ovarian cancer contributes to the majority of ovarian cancer, while the molecular mechanisms remain elusive. Recently, some DEAD box protein 1 has been reported play a tumor suppressor role in ovarian cancer progression. However, the functions of DEAD box protein (DDX) members in ovarian cancer development remain largely unknown. In current study, we retrieved GEO databases and surprisingly found that DDX10 is significantly down-regulated in ovarian cancer tissues compared with normal ovary. These findings suggest that DDX10 might also play a suppressive role in ovarian cancer. We then validated the down-regulated expression pattern of DDX10 in fresh ovarian cancer tissues. Furthermore, both loss- and gain-functions assays reveal that the down-regulated DDX10 could promote ovarian cancer proliferation in vitro and the xenograft subcutaneous tumor formation assays confirmed these findings in vivo. In addition, we found that DDX10 is epigenetic silenced by miR-155-5p in ovarian cancer. Moreover, we further preliminary illustrated that down-regulated DDX10 promotes ovarian cancer cell proliferation through Akt/NF-κB pathway. Taken together, in current study, we found a novel tumor suppressor, DDX10, is epigenetic silenced by miR-155-5p in ovarian cancer, and the down-regulated expression pattern of DDX10 promotes ovarian cancer proliferation through Akt/NF-κB pathway. Our findings shed the light that DDX families might be a novel for ovarian cancer treatment. - Highlights: • A novel DEAD box protein, DDX10 is significantly down-regulated in ovarian cancer tissues. • Down-regulated DDX10 promotes ovarian cancer cell proliferation and growth both in vitro and in vivo. • miR-155-5p is highly expressed in ovarian cancer tissues and epigenetically targets DDX10. • DDX10 and miR-155-5p regulates Akt/p65 axis in ovarian cancer cells.

  15. Epigenetic down-regulated DDX10 promotes cell proliferation through Akt/NF-κB pathway in ovarian cancer

    International Nuclear Information System (INIS)

    Gai, Muhuizi; Bo, Qifang; Qi, Lixia

    2016-01-01

    Ovarian cancer contributes to the majority of ovarian cancer, while the molecular mechanisms remain elusive. Recently, some DEAD box protein 1 has been reported play a tumor suppressor role in ovarian cancer progression. However, the functions of DEAD box protein (DDX) members in ovarian cancer development remain largely unknown. In current study, we retrieved GEO databases and surprisingly found that DDX10 is significantly down-regulated in ovarian cancer tissues compared with normal ovary. These findings suggest that DDX10 might also play a suppressive role in ovarian cancer. We then validated the down-regulated expression pattern of DDX10 in fresh ovarian cancer tissues. Furthermore, both loss- and gain-functions assays reveal that the down-regulated DDX10 could promote ovarian cancer proliferation in vitro and the xenograft subcutaneous tumor formation assays confirmed these findings in vivo. In addition, we found that DDX10 is epigenetic silenced by miR-155-5p in ovarian cancer. Moreover, we further preliminary illustrated that down-regulated DDX10 promotes ovarian cancer cell proliferation through Akt/NF-κB pathway. Taken together, in current study, we found a novel tumor suppressor, DDX10, is epigenetic silenced by miR-155-5p in ovarian cancer, and the down-regulated expression pattern of DDX10 promotes ovarian cancer proliferation through Akt/NF-κB pathway. Our findings shed the light that DDX families might be a novel for ovarian cancer treatment. - Highlights: • A novel DEAD box protein, DDX10 is significantly down-regulated in ovarian cancer tissues. • Down-regulated DDX10 promotes ovarian cancer cell proliferation and growth both in vitro and in vivo. • miR-155-5p is highly expressed in ovarian cancer tissues and epigenetically targets DDX10. • DDX10 and miR-155-5p regulates Akt/p65 axis in ovarian cancer cells.

  16. Circulating biomarkers in cancer care: What possible use?

    Directory of Open Access Journals (Sweden)

    Rob J. Jones

    2017-04-01

    Full Text Available The practice of the physician has changed greatly in the last 100 years. Yet, the fundamental role remains constant: it is the physician's function to make a diagnosis, assess prognosis, choose and deliver the most effective treatment and then to assess the adequacy of that treatment (both in terms of effectiveness and safety. Whereas our predecessors were almost entirely reliant on clinical history and examination findings in conducting these assessments, the 21st century physician is aided by a plethora of blood tests, imaging investigations, electrophysiological recordings and morphological and molecular analyses of tissue samples. For many patients, the totality of these newer tests contributes relatively little to their journey, whilst, for some, key tests can dictate the direction of travel and, sometimes, the ultimate destination. Keywords: Prostate, Cancer, Biomarker

  17. Epigenetic Modulation with HDAC Inhibitor CG200745 Induces Anti-Proliferation in Non-Small Cell Lung Cancer Cells

    OpenAIRE

    Chun, Sung-Min; Lee, Ji-Young; Choi, Jene; Lee, Je-Hwan; Hwang, Jung Jin; Kim, Chung-Soo; Suh, Young-Ah; Jang, Se Jin

    2015-01-01

    Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes. Hence, chemical approaches targeting histone-modifying enzymes have emerged onto the main stage of anticancer drug discovery. Here, we investigated the therapeutic potentials and mechanistic roles of the recently developed histone deacetylase inhibitor, CG200745, in non-small cell lung cancer cells. Treatment with CG200745 increased the global level of his...

  18. Putative Biomarkers and Targets of Estrogen Receptor Negative Human Breast Cancer

    Directory of Open Access Journals (Sweden)

    Stephen W. Byers

    2011-07-01

    Full Text Available Breast cancer is a progressive and potentially fatal disease that affects women of all ages. Like all progressive diseases, early and reliable diagnosis is the key for successful treatment and annihilation. Biomarkers serve as indicators of pathological, physiological, or pharmacological processes. Her2/neu, CA15.3, estrogen receptor (ER, progesterone receptor (PR, and cytokeratins are biomarkers that have been approved by the Food and Drug Administration for disease diagnosis, prognosis, and therapy selection. The structural and functional complexity of protein biomarkers and the heterogeneity of the breast cancer pathology present challenges to the scientific community. Here we review estrogen receptor-related putative breast cancer biomarkers, including those of putative breast cancer stem cells, a minor population of estrogen receptor negative tumor cells that retain the stem cell property of self renewal. We also review a few promising cytoskeleton targets for ER alpha negative breast cancer.

  19. GSNFS: Gene subnetwork biomarker identification of lung cancer expression data.

    Science.gov (United States)

    Doungpan, Narumol; Engchuan, Worrawat; Chan, Jonathan H; Meechai, Asawin

    2016-12-05

    Gene expression has been used to identify disease gene biomarkers, but there are ongoing challenges. Single gene or gene-set biomarkers are inadequate to provide sufficient understanding of complex disease mechanisms and the relationship among those genes. Network-based methods have thus been considered for inferring the interaction within a group of genes to further study the disease mechanism. Recently, the Gene-Network-based Feature Set (GNFS), which is capable of handling case-control and multiclass expression for gene biomarker identification, has been proposed, partly taking into account of network topology. However, its performance relies on a greedy search for building subnetworks and thus requires further improvement. In this work, we establish a new approach named Gene Sub-Network-based Feature Selection (GSNFS) by implementing the GNFS framework with two proposed searching and scoring algorithms, namely gene-set-based (GS) search and parent-node-based (PN) search, to identify subnetworks. An additional dataset is used to validate the results. The two proposed searching algorithms of the GSNFS method for subnetwork expansion are concerned with the degree of connectivity and the scoring scheme for building subnetworks and their topology. For each iteration of expansion, the neighbour genes of a current subnetwork, whose expression data improved the overall subnetwork score, is recruited. While the GS search calculated the subnetwork score using an activity score of a current subnetwork and the gene expression values of its neighbours, the PN search uses the expression value of the corresponding parent of each neighbour gene. Four lung cancer expression datasets were used for subnetwork identification. In addition, using pathway data and protein-protein interaction as network data in order to consider the interaction among significant genes were discussed. Classification was performed to compare the performance of the identified gene subnetworks with three

  20. Early life exposure to famine and colorectal cancer risk: a role for epigenetic mechanisms.

    Directory of Open Access Journals (Sweden)

    Laura A E Hughes

    Full Text Available BACKGROUND: Exposure to energy restriction during childhood and adolescence is associated with a lower risk of developing colorectal cancer (CRC. Epigenetic dysregulation during this critical period of growth and development may be a mechanism to explain such observations. Within the Netherlands Cohort Study on diet and cancer, we investigated the association between early life energy restriction and risk of subsequent CRC characterized by the (promoter CpG island methylation phenotype (CIMP. METHODOLOGY/PRINCIPAL FINDINGS: Information on diet and risk factors was collected by baseline questionnaire (n = 120,856. Three indicators of exposure were assessed: place of residence during the Hunger Winter (1944-45 and World War II years (1940-44, and father's employment status during the Economic Depression (1932-40. Methylation specific PCR (MSP on DNA from paraffin embedded tumor tissue was performed to determine CIMP status according to the Weisenberger markers. After 7.3 years of follow-up, 603 cases and 4631 sub-cohort members were available for analysis. Cox regression was used to calculate hazard ratios (HR and 95% confidence intervals for CIMP+ (27.7% and CIMP- (72.3% tumors according to the three time periods of energy restriction, adjusted for age and gender. Individuals exposed to severe famine during the Hunger Winter had a decreased risk of developing a tumor characterized by CIMP compared to those not exposed (HR 0.65, 95%CI: 0.45-0.92. Further categorizing individuals by an index of '0-1' '2-3' or '4-7' genes methylated in the promoter region suggested that exposure to the Hunger Winter was associated with the degree of promoter hypermethylation ('0-1 genes methylated' HR = 1.01, 95%CI:0.74-1.37; '2-3 genes methylated' HR = 0.83, 95% CI:0.61-1.15; '4-7 genes methylated' HR = 0.72, 95% CI:0.49-1.04. No associations were observed with respect to the Economic Depression and WWII years. CONCLUSIONS: This is the first study indicating that

  1. Implementation of External Quality Assurance Trials for Immunohistochemically Determined Breast Cancer Biomarkers in Germany

    OpenAIRE

    von Wasielewski, Reinhard; Krusche, Claudia A.; Rüschoff, Joseph; Fisseler-Eckhoff, Anette; Kreipe, Hans

    2008-01-01

    Besides typing and grading of breast cancer, Pathologists are involved in the determination of biomarkers, such as steroid hormone receptors and HER2, which are of utmost importance in adjuvant therapy. There have been concerns with regard to security and reproducibility of the biomarker assays done on tissue sections applying either immunohistochemistry or in-situ hybridisation. In order to assure the quality of these biomarker assays, a number of measures are required, among them external p...

  2. Regulation of the ITGA2 gene by epigenetic mechanisms in prostate cancer.

    Science.gov (United States)

    Chin, Suyin Paulynn; Marthick, James R; West, Alison C; Short, Annabel K; Chuckowree, Jyoti; Polanowski, Andrea M; Thomson, Russell J; Holloway, Adele F; Dickinson, Joanne L

    2015-05-01

    Integrin alpha2 beta1 (α2 β1 ) plays an integral role in tumour cell invasion, metastasis and angiogenesis, and altered expression of the receptor has been linked to tumour prognosis in several solid tumours. However, the relationship is complex, with both increased and decreased expression associated with different stages of tumour metastases in several tumour types. The ITGA2 gene, which codes for the α2 subunit, was examined to investigate whether a large CpG island associated with its promoter region is involved in the differential expression of ITGA2 observed in prostate cancer. Bisulphite sequencing of the ITGA2 promoter was used to assess methylation in formalin-fixed paraffin-embedded (FFPE) prostate tumour specimens and prostate cancer cell lines, PC3, 22Rv1 and LNCaP. Changes in ITGA2 mRNA expression were measured using quantitative PCR. ITGA2 functionality was interrogated using cell migration scratch assays and siRNA knockdown experiments. Bisulphite sequencing revealed strikingly decreased methylation at key CpG sites within the promoter of tumour samples, when compared with normal prostate tissue. Altered methylation of this CpG island is also associated with differences in expression in the non-invasive LNCaP, and the highly metastatic PC3 and 22Rv1 prostate cancer cell lines. Further bisulphite sequencing confirmed that selected CpGs were highly methylated in LNCaP cells, whilst only low levels of methylation were observed in PC3 and 22Rv1 cells, correlating with ITGA2 transcript levels. Examination of the increased expression of ITGA2 was shown to influence migratory potential via scratch assay in PC3, 22Rv1 and LNCaP cells, and was confirmed by siRNA knockdown experiments. Taken together, our data supports the assertion that epigenetic modification of the ITGA2 promoter is a mechanism by which ITGA2 expression is regulated. © 2015 Wiley Periodicals, Inc.

  3. Combination effect of epigenetic regulation and ionizing radiation in colorectal cancer cells.

    Directory of Open Access Journals (Sweden)

    Joong-Gook Kim

    Full Text Available Exposure of cells to ionizing radiation (IR induces, not only, activation of multiple signaling pathways that play critical roles in cell fate determination, but also alteration of molecular pathways involved in cell death or survival. Recently, DNA methylation has been established as a critical epigenetic process involved in the regulation of gene expression in cancer cells, suggesting that DNA methylation inhibition may be an effective cancer treatment strategy. Because alterations of gene expression by DNA methylation have been considered to influence radioresponsiveness, we investigated the effect of a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5-aza-dC, on radiosensitivity. In addition, we investigated the underlying cellular mechanisms of combination treatments of ionizing irradiation (IR and 5-aza-dC in human colon cancer cells. Colon cancer cell lines were initially tested for radiation sensitivity by IR in vitro and were treated with two different doses of 5-aza-dC. Survival of these cell lines was measured using MTT (3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide and clonogenic assays. The effects of 5-aza-dC along with irradiation on cell growth, cell cycle distribution, apoptosis, and apoptosis-related gene expression were examined. Combination irradiation treatment with 5-aza-dC significantly decreased growth activity compared with irradiation treatment alone or with 5-aza-dC treatment alone. The percentage of HCT116 cells in the sub-G1 phase and their apoptotic rate was increased when cells were treated with irradiation in combination with 5-aza-dC compared with either treatment alone. These observations were strongly supported by increased caspase activity, increased comet tails using comet assays, and increased protein levels of apoptosis-associated molecules (caspase 3/9, cleaved PARP. Our data demonstrated that 5-aza-dC enhanced radiosensitivity in colon cancer cells, and the combination effects of 5

  4. lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer

    NARCIS (Netherlands)

    Wang, Zehua; Yang, Bo; Zhang, Min; Guo, Weiwei; Wu, Zhiyuan; Wang, Yue; Jia, Lin; Li, Song; Caesar-Johnson, Samantha J.; Demchok, John A.; Felau, Ina; Kasapi, Melpomeni; Ferguson, Martin L.; Hutter, Carolyn M.; Sofia, Heidi J.; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean C.; Zhang, Jiashan (Julia); Chudamani, Sudha; Liu, Jia; Lolla, Laxmi; Naresh, Rashi; Pihl, Todd; Sun, Qiang; Wan, Yunhu; Wu, Ye; Cho, Juok; DeFreitas, Timothy; Frazer, Scott; Gehlenborg, Nils; Getz, Gad; Heiman, David I.; Kim, Jaegil; Lawrence, Michael S.; Lin, Pei; Meier, Sam; Noble, Michael S.; Saksena, Gordon; Voet, Doug; Zhang, Hailei; Bernard, Brady; Chambwe, Nyasha; Dhankani, Varsha; Knijnenburg, Theo; Kramer, Roger; Leinonen, Kalle; Liu, Yuexin; Miller, Michael; Reynolds, Sheila; Shmulevich, Ilya; Thorsson, Vesteinn; Zhang, Wei; Akbani, Rehan; Broom, Bradley M.; Hegde, Apurva M.; Ju, Zhenlin; Kanchi, Rupa S.; Korkut, Anil; Li, Jun; Liang, Han; Ling, Shiyun; Liu, Wenbin; Lu, Yiling; Mills, Gordon B.; Ng, Kwok Shing; Rao, Arvind; Ryan, Michael; Wang, Jing; Weinstein, John N.; Zhang, Jiexin; Abeshouse, Adam; Armenia, Joshua; Chakravarty, Debyani; Chatila, Walid K.; Bruijn, Inode; Gao, Jianjiong; Gross, Benjamin E.; Heins, Zachary J.; Kundra, Ritika; La, Konnor; Ladanyi, Marc; Luna, Augustin; Nissan, Moriah G.; Ochoa, Angelica; Phillips, Sarah M.; Reznik, Ed; Sanchez-Vega, Francisco; Sander, Chris; Schultz, Nikolaus; Sheridan, Robert; Sumer, S. Onur; Sun, Yichao; Taylor, Barry S.; Wang, Jioajiao; Zhang, Hongxin; Anur, Pavana; Peto, Myron; Spellman, Paul; Benz, Christopher; Stuart, Joshua M.; Wong, Christopher K.; Yau, Christina; Hayes, D. Neil; Parker, Joel S.; Wilkerson, Matthew D.; Ally, Adrian; Balasundaram, Miruna; Bowlby, Reanne; Brooks, Denise; Carlsen, Rebecca; Chuah, Eric; Dhalla, Noreen; Holt, Robert; Jones, Steven J.M.; Kasaian, Katayoon; Lee, Darlene; Ma, Yussanne; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Mungall, Andrew J.; Mungall, Karen; Robertson, A. Gordon; Sadeghi, Sara; Schein, Jacqueline E.; Sipahimalani, Payal; Tam, Angela; Thiessen, Nina; Tse, Kane; Wong, Tina; Berger, Ashton C.; Beroukhim, Rameen; Cherniack, Andrew D.; Cibulskis, Carrie; Gabriel, Stacey B.; Gao, Galen F.; Ha, Gavin; Meyerson, Matthew; Schumacher, Steven E.; Shih, Juliann; Kucherlapati, Melanie H.; Kucherlapati, Raju S.; Baylin, Stephen; Cope, Leslie; Danilova, Ludmila; Bootwalla, Moiz S.; Lai, Phillip H.; Maglinte, Dennis T.; Van Den Berg, David J.; Weisenberger, Daniel J.; Auman, J. Todd; Balu, Saianand; Bodenheimer, Tom; Fan, Cheng; Hoadley, Katherine A.; Hoyle, Alan P.; Jefferys, Stuart R.; Jones, Corbin D.; Meng, Shaowu; Mieczkowski, Piotr A.; Mose, Lisle E.; Perou, Amy H.; Perou, Charles M.; Roach, Jeffrey; Shi, Yan; Simons, Janae V.; Skelly, Tara; Soloway, Matthew G.; Tan, Donghui; Veluvolu, Umadevi; Fan, Huihui; Hinoue, Toshinori; Laird, Peter W.; Shen, Hui; Zhou, Wanding; Bellair, Michelle; Chang, Kyle; Covington, Kyle; Creighton, Chad J.; Dinh, Huyen; Doddapaneni, Harsha Vardhan; Donehower, Lawrence A.; Drummond, Jennifer; Gibbs, Richard A.; Glenn, Robert; Hale, Walker; Han, Yi; Hu, Jianhong; Korchina, Viktoriya; Lee, Sandra; Lewis, Lora; Li, Wei; Liu, Xiuping; Morgan, Margaret; Morton, Donna; Muzny, Donna; Santibanez, Jireh; Sheth, Margi; Shinbrot, Eve; Wang, Linghua; Wang, Min; Wheeler, David A.; Xi, Liu; Zhao, Fengmei; Hess, Julian; Appelbaum, Elizabeth L.; Bailey, Matthew; Cordes, Matthew G.; Ding, Li; Fronick, Catrina C.; Fulton, Lucinda A.; Fulton, Robert S.; Kandoth, Cyriac; Mardis, Elaine R.; McLellan, Michael D.; Miller, Christopher A.; Schmidt, Heather K.; Wilson, Richard K.; Crain, Daniel; Curley, Erin; Gardner, Johanna; Lau, Kevin; Mallery, David; Morris, Scott; Paulauskis, Joseph; Penny, Robert; Shelton, Candace; Shelton, Troy; Sherman, Mark; Thompson, Eric; Yena, Peggy; Bowen, Jay; Gastier-Foster, Julie M.; Gerken, Mark; Leraas, Kristen M.; Lichtenberg, Tara M.; Ramirez, Nilsa C.; Wise, Lisa; Zmuda, Erik; Corcoran, Niall; Costello, Tony; Hovens, Christopher; Carvalho, Andre L.; de Carvalho, Ana C.; Fregnani, José H.; Longatto-Filho, Adhemar; Reis, Rui M.; Scapulatempo-Neto, Cristovam; Silveira, Henrique C.S.; Vidal, Daniel O.; Burnette, Andrew; Eschbacher, Jennifer; Hermes, Beth; Noss, Ardene; Singh, Rosy; Anderson, Matthew L.; Castro, Patricia D.; Ittmann, Michael; Huntsman, David; Kohl, Bernard; Le, Xuan; Thorp, Richard; Andry, Chris; Duffy, Elizabeth R.; Lyadov, Vladimir; Paklina, Oxana; Setdikova, Galiya; Shabunin, Alexey; Tavobilov, Mikhail; McPherson, Christopher; Warnick, Ronald; Berkowitz, Ross; Cramer, Daniel; Feltmate, Colleen; Horowitz, Neil; Kibel, Adam; Muto, Michael; Raut, Chandrajit P.; Malykh, Andrei; Barnholtz-Sloan, Jill S.; Barrett, Wendi; Devine, Karen; Fulop, Jordonna; Ostrom, Quinn T.; Shimmel, Kristen; Wolinsky, Yingli; Sloan, Andrew E.; De Rose, Agostino; Giuliante, Felice; Goodman, Marc; Karlan, Beth Y.; Hagedorn, Curt H.; Eckman, John; Harr, Jodi; Myers, Jerome; Tucker, Kelinda; Zach, Leigh Anne; Deyarmin, Brenda; Hu, Hai; Kvecher, Leonid; Larson, Caroline; Mural, Richard J.; Somiari, Stella; Vicha, Ales; Zelinka, Tomas; Bennett, Joseph; Iacocca, Mary; Rabeno, Brenda; Swanson, Patricia; Latour, Mathieu; Lacombe, Louis; Têtu, Bernard; Bergeron, Alain; McGraw, Mary; Staugaitis, Susan M.; Chabot, John; Hibshoosh, Hanina; Sepulveda, Antonia; Su, Tao; Wang, Timothy; Potapova, Olga; Voronina, Olga; Desjardins, Laurence; Mariani, Odette; Roman-Roman, Sergio; Sastre, Xavier; Stern, Marc Henri; Cheng, Feixiong; Signoretti, Sabina; Berchuck, Andrew; Bigner, Darell; Lipp, Eric; Marks, Jeffrey; McCall, Shannon; McLendon, Roger; Secord, Angeles; Sharp, Alexis; Behera, Madhusmita; Brat, Daniel J.; Chen, Amy; Delman, Keith; Force, Seth; Khuri, Fadlo; Magliocca, Kelly; Maithel, Shishir; Olson, Jeffrey J.; Owonikoko, Taofeek; Pickens, Alan; Ramalingam, Suresh; Shin, Dong M.; Sica, Gabriel; Van Meir, Erwin G.; Zhang, Hongzheng; Eijckenboom, Wil; Gillis, Ad; Korpershoek, Esther; Looijenga, Leendert; Oosterhuis, Wolter; Stoop, Hans; van Kessel, Kim E.; Zwarthoff, Ellen C.; Calatozzolo, Chiara; Cuppini, Lucia; Cuzzubbo, Stefania; DiMeco, Francesco; Finocchiaro, Gaetano; Mattei, Luca; Perin, Alessandro; Pollo, Bianca; Chen, Chu; Houck, John; Lohavanichbutr, Pawadee; Hartmann, Arndt; Stoehr, Christine; Stoehr, Robert; Taubert, Helge; Wach, Sven; Wullich, Bernd; Kycler, Witold; Murawa, Dawid; Wiznerowicz, Maciej; Chung, Ki; Edenfield, W. Jeffrey; Martin, Julie; Baudin, Eric; Bubley, Glenn; Bueno, Raphael; De Rienzo, Assunta; Richards, William G.; Kalkanis, Steven; Mikkelsen, Tom; Noushmehr, Houtan; Scarpace, Lisa; Girard, Nicolas; Aymerich, Marta; Campo, Elias; Giné, Eva; Guillermo, Armando López; Van Bang, Nguyen; Hanh, Phan Thi; Phu, Bui Duc; Tang, Yufang; Colman, Howard; Evason, Kimberley; Dottino, Peter R.; Martignetti, John A.; Gabra, Hani; Juhl, Hartmut; Akeredolu, Teniola; Stepa, Serghei; Hoon, Dave; Ahn, Keunsoo; Kang, Koo Jeong; Beuschlein, Felix; Breggia, Anne; Birrer, Michael; Bell, Debra; Borad, Mitesh; Bryce, Alan H.; Castle, Erik; Chandan, Vishal; Cheville, John; Copland, John A.; Farnell, Michael; Flotte, Thomas; Giama, Nasra; Ho, Thai; Kendrick, Michael; Kocher, Jean Pierre; Kopp, Karla; Moser, Catherine; Nagorney, David; O'Brien, Daniel; O'Neill, Brian Patrick; Patel, Tushar; Petersen, Gloria; Que, Florencia; Rivera, Michael; Roberts, Lewis; Smallridge, Robert; Smyrk, Thomas; Stanton, Melissa; Thompson, R. Houston; Torbenson, Michael; Yang, Ju Dong; Zhang, Lizhi; Brimo, Fadi; Ajani, Jaffer A.; Gonzalez, Ana Maria Angulo; Behrens, Carmen; Bondaruk, Jolanta; Broaddus, Russell; Czerniak, Bogdan; Esmaeli, Bita; Fujimoto, Junya; Gershenwald, Jeffrey; Guo, Charles; Lazar, Alexander J.; Logothetis, Christopher; Meric-Bernstam, Funda; Moran, Cesar; Ramondetta, Lois; Rice, David; Sood, Anil; Tamboli, Pheroze; Thompson, Timothy; Troncoso, Patricia; Tsao, Anne; Wistuba, Ignacio; Carter, Candace; Haydu, Lauren; Hersey, Peter; Jakrot, Valerie; Kakavand, Hojabr; Kefford, Richard; Lee, Kenneth; Long, Georgina; Mann, Graham; Quinn, Michael; Saw, Robyn; Scolyer, Richard; Shannon, Kerwin; Spillane, Andrew; Stretch, Jonathan; Synott, Maria; Thompson, John; Wilmott, James; Al-Ahmadie, Hikmat; Chan, Timothy A.; Ghossein, Ronald; Gopalan, Anuradha; Levine, Douglas A.; Reuter, Victor; Singer, Samuel; Singh, Bhuvanesh; Tien, Nguyen Viet; Broudy, Thomas; Mirsaidi, Cyrus; Nair, Praveen; Drwiega, Paul; Miller, Judy; Smith, Jennifer; Zaren, Howard; Park, Joong Won; Hung, Nguyen Phi; Kebebew, Electron; Linehan, W. Marston; Metwalli, Adam R.; Pacak, Karel; Pinto, Peter A.; Schiffman, Mark; Schmidt, Laura S.; Vocke, Cathy D.; Wentzensen, Nicolas; Worrell, Robert; Yang, Hannah; Moncrieff, Marc; Goparaju, Chandra; Melamed, Jonathan; Pass, Harvey; Botnariuc, Natalia; Caraman, Irina; Cernat, Mircea; Chemencedji, Inga; Clipca, Adrian; Doruc, Serghei; Gorincioi, Ghenadie; Mura, Sergiu; Pirtac, Maria; Stancul, Irina; Tcaciuc, Diana; Albert, Monique; Alexopoulou, Iakovina; Arnaout, Angel; Bartlett, John; Engel, Jay; Gilbert, Sebastien; Parfitt, Jeremy; Sekhon, Harman; Thomas, George; Rassl, Doris M.; Rintoul, Robert C.; Bifulco, Carlo; Tamakawa, Raina; Urba, Walter; Hayward, Nicholas; Timmers, Henri; Antenucci, Anna; Facciolo, Francesco; Grazi, Gianluca; Marino, Mirella; Merola, Roberta; de Krijger, Ronald; Gimenez-Roqueplo, Anne Paule; Piché, Alain; Chevalier, Simone; McKercher, Ginette; Birsoy, Kivanc; Barnett, Gene; Brewer, Cathy; Farver, Carol; Naska, Theresa; Pennell, Nathan A.; Raymond, Daniel; Schilero, Cathy; Smolenski, Kathy; Williams, Felicia; Morrison, Carl; Borgia, Jeffrey A.; Liptay, Michael J.; Pool, Mark; Seder, Christopher W.; Junker, Kerstin; Omberg, Larsson; Dinkin, Mikhail; Manikhas, George; Alvaro, Domenico; Bragazzi, Maria Consiglia; Cardinale, Vincenzo; Carpino, Guido; Gaudio, Eugenio; Chesla, David; Cottingham, Sandra; Dubina, Michael; Moiseenko, Fedor; Dhanasekaran, Renumathy; Becker, Karl Friedrich; Janssen, Klaus Peter; Slotta-Huspenina, Julia; Abdel-Rahman, Mohamed H.; Aziz, Dina; Bell, Sue; Cebulla, Colleen M.; Davis, Amy; Duell, Rebecca; Elder, J. Bradley; Hilty, Joe; Kumar, Bahavna; Lang, James; Lehman, Norman L.; Mandt, Randy; Nguyen, Phuong; Pilarski, Robert; Rai, Karan; Schoenfield, Lynn; Senecal, Kelly; Wakely, Paul; Hansen, Paul; Lechan, Ronald; Powers, James; Tischler, Arthur; Grizzle, William E.; Sexton, Katherine C.; Kastl, Alison; Henderson, Joel; Porten, Sima; Waldmann, Jens; Fassnacht, Martin; Asa, Sylvia L.; Schadendorf, Dirk; Couce, Marta; Graefen, Markus; Huland, Hartwig; Sauter, Guido; Schlomm, Thorsten; Simon, Ronald; Tennstedt, Pierre; Olabode, Oluwole; Nelson, Mark; Bathe, Oliver; Carroll, Peter R.; Chan, June M.; Disaia, Philip; Glenn, Pat; Kelley, Robin K.; Landen, Charles N.; Phillips, Joanna; Prados, Michael; Simko, Jeffry; Smith-McCune, Karen; VandenBerg, Scott; Roggin, Kevin; Fehrenbach, Ashley; Kendler, Ady; Sifri, Suzanne; Steele, Ruth; Jimeno, Antonio; Carey, Francis; Forgie, Ian; Mannelli, Massimo; Carney, Michael; Hernandez, Brenda; Campos, Benito; Herold-Mende, Christel; Jungk, Christin; Unterberg, Andreas; von Deimling, Andreas; Bossler, Aaron; Galbraith, Joseph; Jacobus, Laura; Knudson, Michael; Knutson, Tina; Ma, Deqin; Milhem, Mohammed; Sigmund, Rita; Godwin, Andrew K.; Madan, Rashna; Rosenthal, Howard G.; Adebamowo, Clement; Adebamowo, Sally N.; Boussioutas, Alex; Beer, David; Giordano, Thomas; Mes-Masson, Anne Marie; Saad, Fred; Bocklage, Therese; Landrum, Lisa; Mannel, Robert; Moore, Kathleen; Moxley, Katherine; Postier, Russel; Walker, Joan; Zuna, Rosemary; Feldman, Michael; Valdivieso, Federico; Dhir, Rajiv; Luketich, James; Pinero, Edna M.Mora; Quintero-Aguilo, Mario; Carlotti, Carlos Gilberto; Dos Santos, Jose Sebastião; Kemp, Rafael; Sankarankuty, Ajith; Tirapelli, Daniela; Catto, James; Agnew, Kathy; Swisher, Elizabeth; Creaney, Jenette; Robinson, Bruce; Shelley, Carl Simon; Godwin, Eryn M.; Kendall, Sara; Shipman, Cassaundra; Bradford, Carol; Carey, Thomas; Haddad, Andrea; Moyer, Jeffey; Peterson, Lisa; Prince, Mark; Rozek, Laura; Wolf, Gregory; Bowman, Rayleen; Fong, Kwun M.; Yang, Ian; Korst, Robert; Rathmell, W. Kimryn; Fantacone-Campbell, J. Leigh; Hooke, Jeffrey A.; Kovatich, Albert J.; Shriver, Craig D.; DiPersio, John; Drake, Bettina; Govindan, Ramaswamy; Heath, Sharon; Ley, Timothy; Van Tine, Brian; Westervelt, Peter; Rubin, Mark A.; Lee, Jung Il; Aredes, Natália D.; Mariamidze, Armaz; Xie, Wen; Yang, Da

    2018-01-01

    We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1

  5. RNA Biomarkers: Frontier of Precision Medicine for Cancer

    Directory of Open Access Journals (Sweden)

    Xiaochen Xi

    2017-02-01

    Full Text Available As an essential part of central dogma, RNA delivers genetic and regulatory information and reflects cellular states. Based on high‐throughput sequencing technologies, cumulating data show that various RNA molecules are able to serve as biomarkers for the diagnosis and prognosis of various diseases, for instance, cancer. In particular, detectable in various bio‐fluids, such as serum, saliva and urine, extracellular RNAs (exRNAs are emerging as non‐invasive biomarkers for earlier cancer diagnosis, tumor progression monitor, and prediction of therapy response. In this review, we summarize the latest studies on various types of RNA biomarkers, especially extracellular RNAs, in cancer diagnosis and prognosis, and illustrate several well‐known RNA biomarkers of clinical utility. In addition, we describe and discuss general procedures and issues in investigating exRNA biomarkers, and perspectives on utility of exRNAs in precision medicine.

  6. Multimodal lung cancer screening using the ITALUNG biomarker panel and low dose computed tomography. Results of the ITALUNG biomarker study.

    Science.gov (United States)

    Carozzi, Francesca Maria; Bisanzi, Simonetta; Carrozzi, Laura; Falaschi, Fabio; Lopes Pegna, Andrea; Mascalchi, Mario; Picozzi, Giulia; Peluso, Marco; Sani, Cristina; Greco, Luana; Ocello, Cristina; Paci, Eugenio

    2017-07-01

    Asymptomatic high-risk subjects, randomized in the intervention arm of the ITALUNG trial (1,406 screened for lung cancer), were enrolled for the ITALUNG biomarker study (n = 1,356), in which samples of blood and sputum were analyzed for plasma DNA quantification (cut off 5 ng/ml), loss of heterozygosity and microsatellite instability. The ITALUNG biomarker panel (IBP) was considered positive if at least one of the two biomarkers included in the panel was positive. Subjects with and without lung cancer diagnosis at the end of the screening cycle with LDCT (n = 517) were evaluated. Out of 18 baseline screen detected lung cancer cases, 17 were IBP positive (94%). Repeat screen-detected lung cancer cases were 18 and 12 of them positive at baseline IBP test (66%). Interval cancer cases (2-years) and biomarker tests after a suspect Non Calcific Nodule follow-up were investigated. The single test versus multimodal screening measures of accuracy were compared in a simulation within the screened ITALUNG intervention arm, considering screen-detected and interval cancer cases. Sensitivity was 90% at baseline screening. Specificity was 71 and 61% for LDCT and IBP as baseline single test, and improved at 89% with multimodal, combined screening. The positive predictive value was 4.3% for LDCT at baseline and 10.6% for multimodal screening. Multimodal screening could improve the screening efficiency at baseline and strategies for future implementation are discussed. If IBP was used as primary screening test, the LDCT burden might decrease of about 60%. © 2017 UICC.

  7. Integrated analysis of epigenomic and genomic changes by DNA methylation dependent mechanisms provides potential novel biomarkers for prostate cancer.

    Science.gov (United States)

    White-Al Habeeb, Nicole M A; Ho, Linh T; Olkhov-Mitsel, Ekaterina; Kron, Ken; Pethe, Vaijayanti; Lehman, Melanie; Jovanovic, Lidija; Fleshner, Neil; van der Kwast, Theodorus; Nelson, Colleen C; Bapat, Bharati

    2014-09-15

    Epigenetic silencing mediated by CpG methylation is a common feature of many cancers. Characterizing aberrant DNA methylation changes associated with tumor progression may identify potential prognostic markers for prostate cancer (PCa). We treated two PCa cell lines, 22Rv1 and DU-145 with the demethylating agent 5-Aza 2'-deoxycitidine (DAC) and global methylation status was analyzed by performing methylation-sensitive restriction enzyme based differential methylation hybridization strategy followed by genome-wide CpG methylation array profiling. In addition, we examined gene expression changes using a custom microarray. Gene Set Enrichment Analysis (GSEA) identified the most significantly dysregulated pathways. In addition, we assessed methylation status of candidate genes that showed reduced CpG methylation and increased gene expression after DAC treatment, in Gleason score (GS) 8 vs. GS6 patients using three independent cohorts of patients; the publically available The Cancer Genome Atlas (TCGA) dataset, and two separate patient cohorts. Our analysis, by integrating methylation and gene expression in PCa cell lines, combined with patient tumor data, identified novel potential biomarkers for PCa patients. These markers may help elucidate the pathogenesis of PCa and represent potential prognostic markers for PCa patients.

  8. Improved prediction of breast cancer outcome by identifying heterogeneous biomarkers.

    Science.gov (United States)

    Choi, Jonghwan; Park, Sanghyun; Yoon, Youngmi; Ahn, Jaegyoon

    2017-11-15

    Identification of genes that can be used to predict prognosis in patients with cancer is important in that it can lead to improved therapy, and can also promote our understanding of tumor progression on the molecular level. One of the common but fundamental problems that render identification of prognostic genes and prediction of cancer outcomes difficult is the heterogeneity of patient samples. To reduce the effect of sample heterogeneity, we clustered data samples using K-means algorithm and applied modified PageRank to functional interaction (FI) networks weighted using gene expression values of samples in each cluster. Hub genes among resulting prioritized genes were selected as biomarkers to predict the prognosis of samples. This process outperformed traditional feature selection methods as well as several network-based prognostic gene selection methods when applied to Random Forest. We were able to find many cluster-specific prognostic genes for each dataset. Functional study showed that distinct biological processes were enriched in each cluster, which seems to reflect different aspect of tumor progression or oncogenesis among distinct patient groups. Taken together, these results provide support for the hypothesis that our approach can effectively identify heterogeneous prognostic genes, and these are complementary to each other, improving prediction accuracy. https://github.com/mathcom/CPR. jgahn@inu.ac.kr. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  9. Proteomic profiling of exosomes leads to the identification of novel biomarkers for prostate cancer

    NARCIS (Netherlands)

    D. Duijvesz (Diederick); K.E. Burnum-Johnson (Kristin); M.A. Gritsenko (Marina); A.M. Hoogland (Marije); M.S. Vredenbregt-van den Berg (Mirella); R. Willemsen (Rob); T.M. Luider (Theo); L. Paša-Tolić (Ljiljana); G.W. Jenster (Guido)

    2013-01-01

    textabstractBackground: Current markers for prostate cancer, such as PSA lack specificity. Therefore, novel biomarkers are needed. Unfortunately, the complexity of body fluids often hampers biomarker discovery. An attractive alternative approach is the isolation of small vesicles, i.e. exosomes,

  10. Epigenetic Signature: A New Player as Predictor of Clinically Significant Prostate Cancer (PCa) in Patients on Active Surveillance (AS).

    Science.gov (United States)

    Ferro, Matteo; Ungaro, Paola; Cimmino, Amelia; Lucarelli, Giuseppe; Busetto, Gian Maria; Cantiello, Francesco; Damiano, Rocco; Terracciano, Daniela

    2017-05-27

    Widespread prostate-specific antigen (PSA) testing notably increased the number of prostate cancer (PCa) diagnoses. However, about 30% of these patients have low-risk tumors that are not lethal and remain asymptomatic during their lifetime. Overtreatment of such patients may reduce quality of life and increase healthcare costs. Active surveillance (AS) has become an accepted alternative to immediate treatment in selected men with low-risk PCa. Despite much progress in recent years toward identifying the best candidates for AS in recent years, the greatest risk remains the possibility of misclassification of the cancer or missing a high-risk cancer. This is particularly worrisome in men with a life expectancy of greater than 10-15 years. The Prostate Cancer Research International Active Surveillance (PRIAS) study showed that, in addition to age and PSA at diagnosis, both PSA density (PSA-D) and the number of positive cores at diagnosis (two compared with one) are the strongest predictors for reclassification biopsy or switching to deferred treatment. However, there is still no consensus upon guidelines for placing patients on AS. Each institution has its own protocol for AS that is based on PRIAS criteria. Many different variables have been proposed as tools to enrol patients in AS: PSA-D, the percentage of freePSA, and the extent of cancer on biopsy (number of positive cores or percentage of core involvement). More recently, the Prostate Health Index (PHI), the 4 Kallikrein (4K) score, and other patient factors, such as age, race, and family history, have been investigated as tools able to predict clinically significant PCa. Recently, some reports suggested that epigenetic mapping differs significantly between cancer patients and healthy subjects. These findings indicated as future prospect the use of epigenetic markers to identify PCa patients with low-grade disease, who are likely candidates for AS. This review explores literature data about the potential of

  11. Clinical utility of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study.

    Science.gov (United States)

    Stewart, Grant D; Van Neste, Leander; Delvenne, Philippe; Delrée, Paul; Delga, Agnès; McNeill, S Alan; O'Donnell, Marie; Clark, James; Van Criekinge, Wim; Bigley, Joseph; Harrison, David J

    2013-03-01

    Concern about possible false-negative prostate biopsy histopathology findings often leads to rebiopsy. A quantitative methylation specific polymerase chain reaction assay panel, including GSTP1, APC and RASSF1, could increase the sensitivity of detecting cancer over that of pathological review alone, leading to a high negative predictive value and a decrease in unnecessary repeat biopsies. The MATLOC study blindly tested archived prostate biopsy needle core tissue samples of 498 subjects from the United Kingdom and Belgium with histopathologically negative prostate biopsies, followed by positive (cases) or negative (controls) repeat biopsy within 30 months. Clinical performance of the epigenetic marker panel, emphasizing negative predictive value, was assessed and cross-validated. Multivariate logistic regression was used to evaluate all risk factors. The epigenetic assay performed on the first negative biopsies of this retrospective review cohort resulted in a negative predictive value of 90% (95% CI 87-93). In a multivariate model correcting for patient age, prostate specific antigen, digital rectal examination and first biopsy histopathological characteristics the epigenetic assay was a significant independent predictor of patient outcome (OR 3.17, 95% CI 1.81-5.53). A multiplex quantitative methylation specific polymerase chain reaction assay determining the methylation status of GSTP1, APC and RASSF1 was strongly associated with repeat biopsy outcome up to 30 months after initial negative biopsy in men with suspicion of prostate cancer. Adding this epigenetic assay could improve the prostate cancer diagnostic process and decrease unnecessary repeat biopsies. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  12. MicroRNAs as potential biomarkers in adrenocortical cancer: progress and challenges

    Directory of Open Access Journals (Sweden)

    Nadia eCHERRADI

    2016-01-01

    Full Text Available Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited therapeutic options. Over the last decade, pan-genomic analyses of genetic and epigenetic alterations and genome-wide expression profile studies allowed major advances in the understanding of the molecular genetics of adrenocortical carcinoma. Besides the well-known dysfunctional molecular pathways in adrenocortical tumors such as the IGF2 pathway, the Wnt pathway and TP53, high-throughput technologies enabled a more comprehensive genomic characterization of adrenocortical cancer. Integration of expression profile data with exome sequencing, SNP array analysis, methylation and microRNA profiling led to the identification of subgroups of malignant tumors with distinct molecular alterations and clinical outcomes. MicroRNAs post-transcriptionally silence their target gene expression either by degrading mRNA or by inhibiting translation. Although our knowledge of the contribution of deregulated microRNAs to the pathogenesis of adrenocortical carcinoma is still in its infancy, recent studies support their relevance in gene expression alterations in these tumors. Some microRNAs have been shown to carry potential diagnostic and prognostic values while others may be good candidates for therapeutic interventions. With the emergence of disease-specific blood-borne microRNAs signatures, analyses of small cohorts of patients with adrenocortical carcinoma suggest that circulating microRNAs represent promising non-invasive biomarkers of malignancy or recurrence. However, some technical challenges still remain, and most of the microRNAs reported in the literature have not yet been validated in sufficiently powered and longitudinal studies. In this review, we discuss the current knowledge regarding the deregulation of tumor-associated and circulating microRNAs in adrenocortical carcinoma patients, while emphasizing their potential significance in adrenocortical carcinoma pathogenic

  13. A network-based biomarker approach for molecular investigation and diagnosis of lung cancer

    Directory of Open Access Journals (Sweden)

    Chen Bor-Sen

    2011-01-01

    Full Text Available Abstract Background Lung cancer is the leading cause of cancer deaths worldwide. Many studies have investigated the carcinogenic process and identified the biomarkers for signature classification. However, based on the research dedicated to this field, there is no highly sensitive network-based method for carcinogenesis characterization and diagnosis from the systems perspective. Methods In this study, a systems biology approach integrating microarray gene expression profiles and protein-protein interaction information was proposed to develop a network-based biomarker for molecular investigation into the network mechanism of lung carcinogenesis and diagnosis of lung cancer. The network-based biomarker consists of two protein association networks constructed for cancer samples and non-cancer samples. Results Based on the network-based biomarker, a total of 40 significant proteins in lung carcinogenesis were identified with carcinogenesis relevance values (CRVs. In addition, the network-based biomarker, acting as the screening test, proved to be effective in diagnosing smokers with signs of lung cancer. Conclusions A network-based biomarker using constructed protein association networks is a useful tool to highlight the pathways and mechanisms of the lung carcinogenic process and, more importantly, provides potential therapeutic targets to combat cancer.

  14. Prognostic Biomarkers Used for Localised Prostate Cancer Management: A Systematic Review.

    Science.gov (United States)

    Lamy, Pierre-Jean; Allory, Yves; Gauchez, Anne-Sophie; Asselain, Bernard; Beuzeboc, Philippe; de Cremoux, Patricia; Fontugne, Jacqueline; Georges, Agnès; Hennequin, Christophe; Lehmann-Che, Jacqueline; Massard, Christophe; Millet, Ingrid; Murez, Thibaut; Schlageter, Marie-Hélène; Rouvière, Olivier; Kassab-Chahmi, Diana; Rozet, François; Descotes, Jean-Luc; Rébillard, Xavier

    2017-03-07

    Prostate cancer stratification is based on tumour size, pretreatment PSA level, and Gleason score, but it remains imperfect. Current research focuses on the discovery and validation of novel prognostic biomarkers to improve the identification of patients at risk of aggressive cancer or of tumour relapse. This systematic review by the Intergroupe Coopérateur Francophone de Recherche en Onco-urologie (ICFuro) analysed new evidence on the analytical validity and clinical validity and utility of six prognostic biomarkers (PHI, 4Kscore, MiPS, GPS, Prolaris, Decipher). All available data for the six biomarkers published between January 2002 and April 2015 were systematically searched and reviewed. The main endpoints were aggressive prostate cancer prediction, additional value compared to classical prognostic parameters, and clinical benefit for patients with localised prostate cancer. The preanalytical and analytical validations were heterogeneous for all tests and often not adequate for the molecular signatures. Each biomarker was studied for specific indications (candidates for a first or second biopsy, and potential candidates for active surveillance, radical prostatectomy, or adjuvant treatment) for which the level of evidence (LOE) was variable. PHI and 4Kscore were the biomarkers with the highest LOE for discriminating aggressive and indolent tumours in different indications. Blood biomarkers (PHI and 4Kscore) have the highest LOE for the prediction of more aggressive prostate cancer and could help clinicians to manage patients with localised prostate cancer. The other biomarkers show a potential prognostic value; however, they should be evaluated in additional studies to confirm their clinical validity. We reviewed studies assessing the value of six prognostic biomarkers for prostate cancer. On the basis of the available evidence, some biomarkers could help in discriminating between aggressive and non-aggressive tumours with an additional value compared to the

  15. Peroxisome Proliferator-Activated Receptor Gamma in Obesity and Colorectal Cancer: the Role of Epigenetics.

    Science.gov (United States)

    Motawi, T K; Shaker, O G; Ismail, M F; Sayed, N H

    2017-09-06

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that is deregulated in obesity. PPARγ exerts diverse antineoplastic effects. Attempting to determine the clinical relevance of the epigenetic mechanisms controlling the expression PPARγ and susceptibility to colorectal cancer (CRC) in obese subjects, this study investigated the role of some microRNAs and DNA methylation on the deregulation of PPARγ. Seventy CRC patients (34 obese and 36 lean), 22 obese and 24 lean healthy controls were included. MicroRNA levels were measured in serum. PPARγ promoter methylation was evaluated in peripheral blood mononuclear cells (PBMC). PPARγ level was evaluated by measuring mRNA level in PBMC and protein level in serum. The tested microRNAs (miR-27b, 130b and 138) were significantly upregulated in obese and CRC patients. Obese and CRC patients had significantly low levels of PPARγ. A significant negative correlation was found between PPARγ levels and the studied microRNAs. There was a significant PPARγ promoter hypermethylation in CRC patients that correlated to low PPARγ levels. Our results suggest that upregulation of microRNAs 27b, 130b and 138 is associated with susceptibility to CRC in obese subjects through PPARγ downregulation. Hypermethylation of PPARγ gene promoter is associated with CRC through suppression of PPARγ regardless of BMI.

  16. Bone remodeling and regulating biomarkers in women at the time of breast cancer diagnosis.

    Science.gov (United States)

    Yao, Song; Zhang, Yali; Tang, Li; Roh, Janise M; Laurent, Cecile A; Hong, Chi-Chen; Hahn, Theresa; Lo, Joan C; Ambrosone, Christine B; Kushi, Lawrence H; Kwan, Marilyn L

    2017-02-01

    The majority of breast cancer patients receive endocrine therapy, including aromatase inhibitors known to cause increased bone resorption. Bone-related biomarkers at the time of breast cancer diagnosis may predict future risk of osteoporosis and fracture after endocrine therapy. In a large population of 2,401 female breast cancer patients who later underwent endocrine therapy, we measured two bone remodeling biomarkers, TRAP5b and BAP, and two bone regulating biomarkers, RANKL and OPG, in serum samples collected at the time of breast cancer diagnosis. We analyzed these biomarkers and their ratios with patients' demographic, lifestyle, clinical tumor characteristics, as well as bone health history. The presence of bone metastases, prior bisphosphonate (BP) treatment, and blood collection after chemotherapy had a significant impact on biomarker levels. After excluding these cases and controlling for blood collection time, several factors, including age, race/ethnicity, body mass index, physical activity, alcohol consumption, smoking, and hormonal replacement therapy, were significantly associated with bone biomarkers, while vitamin D or calcium supplements and tumor characteristics were not. When prior BP users were included in, recent history of osteoporosis and fracture was also associated. Our findings support further investigation of these biomarkers with bone health outcomes after endocrine therapy initiation in women with breast cancer.

  17. Novel robust biomarkers for human bladder cancer based on activation of intracellular signaling pathways

    OpenAIRE

    Lezhnina, Ksenia; Kovalchuk, Olga; Zhavoronkov, Alexander A.; Korzinkin, Mikhail B.; Zabolotneva, Anastasia A.; Shegay, Peter V.; Sokov, Dmitry G.; Gaifullin, Nurshat M.; Rusakov, Igor G.; Aliper, Alexander M.; Roumiantsev, Sergey A.; Alekseev, Boris Y.; Borisov, Nikolay M.; Buzdin, Anton A.

    2014-01-01

    We recently proposed a new bioinformatic algorithm called OncoFinder for quantifying the activation of intracellular signaling pathways. It was proved advantageous for minimizing errors of high-throughput gene expression analyses and showed strong potential for identifying new biomarkers. Here, for the first time, we applied OncoFinder for normal and cancerous tissues of the human bladder to identify biomarkers of bladder cancer. Using Illumina HT12v4 microarrays, we profiled gene expression ...

  18. Molecular Characterization of H.pylori Strains and Biomarkers in Gastric Cancer

    Science.gov (United States)

    2017-07-01

    AWARD NUMBER: W81XWH-16-1-0274 TITLE: Molecular Characterization of H.pylori Strains and Biomarkers in Gastric Cancer PRINCIPAL INVESTIGATOR...SUBTITLE Molecular Characterization of H.pylori Strains and Biomarkers in Gastric Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0274 5c...organoid technology via collaboration with Dr. Mary Estes (Baylor College of Medicine ) and her lab, via one-on-one visits, has guided Dr. Alex Peniche with

  19. Cancer Chemoprevention by Traditional Chinese Herbal Medicine and Dietary Phytochemicals: Targeting Nrf2-Mediated Oxidative Stress/Anti-Inflammatory Responses, Epigenetics, and Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Jong Hun Lee

    2013-01-01

    Full Text Available Excessive oxidative stress induced by reactive oxygen species (ROS, reactive nitrogen species (RNS, and reactive metabolites of carcinogens alters cellular homeostasis, leading to genetic/epigenetic changes, genomic instability, neoplastic transformation, and cancer initiation/progression. As a protective mechanism against oxidative stress, antioxidant/detoxifying enzymes reduce these reactive species and protect normal cells from endo-/exogenous oxidative damage. The transcription factor nuclear factor-erythroid 2 p45 (NF-E2-related factor 2 (Nrf2, a master regulator of the antioxidative stress response, plays a critical role in the expression of many cytoprotective enzymes, including NAD(PH:quinine oxidoreductase (NQO1, heme oxygenase-1 (HO-1, UDP-glucuronosyltransferase (UGT, and glutathione S-transferase (GST. Recent studies demonstrated that many dietary phytochemicals derived from various vegetables, fruits, spices, and herbal medicines induce Nrf2-mediated antioxidant/detoxifying enzymes, restore aberrant epigenetic alterations, and eliminate cancer stem cells (CSCs. The Nrf2-mediated antioxidant response prevents many age-related diseases, including cancer. Owing to their fundamental contribution to carcinogenesis, epigenetic modifications and CSCs are novel targets of dietary phytochemicals and traditional Chinese herbal medicine (TCHM. In this review, we summarize cancer chemoprevention by dietary phytochemicals, including TCHM, which have great potential as a safer and more effective strategy for preventing cancer.

  20. Some aspects of cancer biomarkers and their clinical application in solid tumors – revisited

    Directory of Open Access Journals (Sweden)

    Isaac D

    2017-07-01

    Full Text Available Cancer biomarkers can be used for a variety of purposes related to screening, prediction, stratification, detection, diagnosis, prognosis, treatment design, and monitoring of a therapeutic response. One of the most important characteristics of a given biomarker includes ease of collection allowing for a non-invasive approach and frequent sampling. Such samples may be obtained from serum or plasma, sputum, bronchoalveolar lavage, saliva, nipple discharge, pleural, or peritoneal effusions. Validation of different biomarkers is considered a mandatory method for useful evaluation. In this review, we highlight the clinical applicability of some cancer biomarkers, as well as future approaches for their development and collection, which may help guide clinicians and researchers. The role of liquid biopsies will also be summarized. Further studies using liquid biopsies are needed to elucidate the significance of various sources of biomarkers suitable for clinical application.

  1. Improving accuracy of breast cancer biomarker testing in India

    Directory of Open Access Journals (Sweden)

    Tanuja Shet

    2017-01-01

    Full Text Available There is a global mandate even in countries with low resources to improve the accuracy of testing biomarkers in breast cancer viz. oestrogen receptor (ER, progesterone receptor (PR and human epidermal growth factor receptor 2 (HER2neu given their critical impact in the management of patients. The steps taken include compulsory participation in an external quality assurance (EQA programme, centralized testing, and regular performance audits for laboratories. This review addresses the status of ER/PR and HER2neu testing in India and possible reasons for the delay in development of guidelines and mandate for testing in the country. The chief cause of erroneous ER and PR testing in India continues to be easily correctable issues such as fixation and antigen retrieval, while for HER2neu testing, it is the use of low-cost non-validated antibodies and interpretative errors. These deficiencies can however, be rectified by (i distributing the accountability and responsibility to surgeons and oncologist, (ii certification of centres for testing in oncology, and (iii initiation of a national EQA system (EQAS programme that will help with economical solutions and identifying the centres of excellence and instill a system for reprimand of poorly performing laboratories.

  2. Cancer therapy trials employing level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1

    DEFF Research Database (Denmark)

    Schmitt, Manfred; Harbeck, Nadia; Brünner, Nils

    2011-01-01

    Clinical research on cancer biomarkers is essential in understanding recent discoveries in cancer biology and heterogeneity of the cancer disease. However, there are only a few examples of clinically useful studies that have identified cancer biomarkers with clinical benefit. Urokinase-type plasm...

  3. Epigenetic regulation of APC in the molecular pathogenesis of gallbladder cancer

    Directory of Open Access Journals (Sweden)

    Dinesh Singh Tekcham

    2016-01-01

    Interpretation & conclusions: The present findings indicate epigenetic silencing of APC in advanced GBC. The methylation pattern, followed by expression analysis of APC may be suggested for diagnostic, prognostic and therapeutic purposes in GBC in future.

  4. LSD1 dual function in mediating epigenetic corruption of the vitamin D signaling in prostate cancer.

    Science.gov (United States)

    Battaglia, Sebastiano; Karasik, Ellen; Gillard, Bryan; Williams, Jennifer; Winchester, Trisha; Moser, Michael T; Smiraglia, Dominic J; Foster, Barbara A

    2017-01-01

    Lysine-specific demethylase 1A (LSD1) is a key regulator of the androgen (AR) and estrogen receptors (ER), and LSD1 levels correlate with tumor aggressiveness. Here, we demonstrate that LSD1 regulates vitamin D receptor (VDR) activity and is a mediator of 1,25(OH) 2 -D 3 (vitamin D) action in prostate cancer (PCa). Athymic nude mice were xenografted with CWR22 cells and monitored weekly after testosterone pellet removal. Expression of LSD1 and VDR (IHC) were correlated with tumor growth using log-rank test. TRAMP tumors and prostates from wild-type (WT) mice were used to evaluate VDR and LSD1 expression via IHC and western blotting. The presence of VDR and LSD1 in the same transcriptional complex was evaluated via immunoprecipitation (IP) using nuclear cell lysate. The effect of LSD1 and 1,25(OH) 2 -D 3 on cell viability was evaluated in C4-2 and BC1A cells via trypan blue exclusion. The role of LSD1 in VDR-mediated gene transcription was evaluated for Cdkn1a , E2f1 , Cyp24a1 , and S100g via qRT-PCR-TaqMan and via chromatin immunoprecipitation assay. Methylation of Cdkn1a TSS was measured via bisulfite sequencing, and methylation of a panel of cancer-related genes was quantified using methyl arrays. The Cancer Genome Atlas data were retrieved to identify genes whose status correlates with LSD1 and DNA methyltransferase 1 (DNMT1). Results were correlated with patients' survival data from two separate cohorts of primary and metastatic PCa. LSD1 and VDR protein levels are elevated in PCa tumors and correlate with faster tumor growth in xenograft mouse models. Knockdown of LSD1 reduces PCa cell viability, and gene expression data suggest a dual coregulatory role of LSD1 for VDR, acting as a coactivator and corepressor in a locus-specific manner. LSD1 modulates VDR-dependent transcription by mediating the recruitment of VDR and DNMT1 at the TSS of VDR-targeted genes and modulates the epigenetic status of transcribed genes by altering H3K4me2 and H3K9Ac and DNA

  5. Breast Cancer Biomarkers Based on Nipple and Fine Needle Aspirates

    National Research Council Canada - National Science Library

    Torosian, Michael

    2000-01-01

    .... These biomarkers include: cytology, DNA index, cell cycle parameters, proliferation index, epidermal growth factor receptor overexpression, p53 and RAS hotspot mutations and hypermethylation of specific gene products...

  6. The Role of Chromosomal Instability and Epigenetics in Colorectal Cancers Lacking β-Catenin/TCF Regulated Transcription

    Directory of Open Access Journals (Sweden)

    Wael M. Abdel-Rahman

    2016-01-01

    Full Text Available All colorectal cancer cell lines except RKO displayed active β-catenin/TCF regulated transcription. This feature of RKO was noted in familial colon cancers; hence our aim was to dissect its carcinogenic mechanism. MFISH and CGH revealed distinct instability of chromosome structure in RKO. Gene expression microarray of RKO versus 7 colon cancer lines (with active Wnt signaling and 3 normal specimens revealed 611 differentially expressed genes. The majority of the tested gene loci were susceptible to LOH in primary tumors with various β-catenin localizations as a surrogate marker for β-catenin activation. The immunohistochemistry of selected genes (IFI16, RGS4, MCTP1, DGKI, OBCAM/OPCML, and GLIPR1 confirmed that they were differentially expressed in clinical specimens. Since epigenetic mechanisms can contribute to expression changes, selected target genes were evaluated for promoter methylation in patient specimens from sporadic and hereditary colorectal cancers. CMTM3, DGKI, and OPCML were frequently hypermethylated in both groups, whereas KLK10, EPCAM, and DLC1 displayed subgroup specificity. The overall fraction of hypermethylated genes was higher in tumors with membranous β-catenin. We identified novel genes in colorectal carcinogenesis that might be useful in personalized tumor profiling. Tumors with inactive Wnt signaling are a heterogeneous group displaying interaction of chromosomal instability, Wnt signaling, and epigenetics.

  7. Reinventing clinical trials: a review of innovative biomarker trial designs in cancer therapies.

    Science.gov (United States)

    Lin, Ja-An; He, Pei

    2015-06-01

    Recently, new clinical trial designs involving biomarkers have been studied and proposed in cancer clinical research, in the hope of incorporating the rapid growing basic research into clinical practices. Journal articles related to various biomarkers and their role in cancer clinical trial, articles and books about statistical issues in trial design, and regulatory website, documents, and guidance for submission of targeted cancer therapies. The drug development process involves four phases. The confirmatory Phase III is essential in regulatory approval of a special treatment. Regulatory agency has restrictions on confirmatory trials 'using adaptive designs'. No rule of thumb to pick the most appropriate design for biomarker-related trials. Statistical issues to solve in new designs. Regulatory acceptance of the 'newly proposed trial designs'. Biomarker-related trial designs that can resolve the statistical issues and satisfy the regulatory requirement. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  8. MicroRNA: a new and promising potential biomarker for diagnosis and prognosis of ovarian cancer

    International Nuclear Information System (INIS)

    Pal, Manish K.; Jaiswar, Shyam P.; Dwivedi, Vinaya N.; Tripathi, Amit K.; Dwivedi, Ashish; Sankhwar, Pushplata

    2015-01-01

    Epithelial ovarian cancer (EOC) is the leading cause of death among all gynecological malignancies. Despite the technological and medical advances over the past four decades, such as the development of several biological markers (mRNA and proteins biomarkers), the mortality rate of ovarian cancer remains a challenge because of its late diagnosis, which is specifically attributed to low specificities and sensitivities. Under this compulsive scenario, recent advances in expression biology have shifted in identifying and developing specific and sensitive biomarkers, such as microRNAs (miRNAs) for cancer diagnosis and prognosis. MiRNAs are a novel class of small non-coding RNAs that deregulate gene expression at the posttranscriptional level, either by translational repression or by mRNA degradation. These mechanisms may be involved in a complex cascade of cellular events associated with the pathophysiology of many types of cancer. MiRNAs are easily detectable in tissue and blood samples of cancer patients. Therefore, miRNAs hold good promise as potential biomarkers in ovarian cancer. In this review, we attempted to provide a comprehensive profile of key miRNAs involved in ovarian carcinoma to establish miRNAs as more reliable non-invasive clinical biomarkers for early detection of ovarian cancer compared with protein and DNA biomarkers

  9. Physical Activity, Biomarkers, and Disease Outcomes in Cancer Survivors: A Systematic Review

    Science.gov (United States)

    Friedenreich, Christine M.; Courneya, Kerry S.; Siddiqi, Sameer M.; McTiernan, Anne; Alfano, Catherine M.

    2012-01-01

    Background Cancer survivors often seek information about how lifestyle factors, such as physical activity, may influence their prognosis. We systematically reviewed studies that examined relationships between physical activity and mortality (cancer-specific and all-cause) and/or cancer biomarkers. Methods We identified 45 articles published from January 1950 to August 2011 through MEDLINE database searches that were related to physical activity, cancer survival, and biomarkers potentially relevant to cancer survival. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement to guide this review. Study characteristics, mortality outcomes, and biomarker-relevant and subgroup results were abstracted for each article that met the inclusion criteria (ie, research articles that included participants with a cancer diagnosis, mortality outcomes, and an assessment of physical activity). Results There was consistent evidence from 27 observational studies that physical activity is associated with reduced all-cause, breast cancer–specific, and colon cancer–specific mortality. There is currently insufficient evidence regarding the association between physical activity and mortality for survivors of other cancers. Randomized controlled trials of exercise that included biomarker endpoints suggest that exercise may result in beneficial changes in the circulating level of insulin, insulin-related pathways, inflammation, and, possibly, immunity; however, the evidence is still preliminary. Conclusions Future research directions identified include the need for more observational studies on additional types of cancer with larger sample sizes; the need to examine whether the association between physical activity and mortality varies by tumor, clinical, or risk factor characteristics; and the need for research on the biological mechanisms involved in the association between physical activity and survival after a cancer diagnosis. Future randomized

  10. Current Stem Cell Biomarkers and Their Functional Mechanisms in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Kaile Zhang

    2016-07-01

    Full Text Available Currently there is little effective treatment available for castration resistant prostate cancer, which is responsible for the majority of prostate cancer related deaths. Emerging evidence suggested that cancer stem cells might play an important role in resistance to traditional cancer therapies, and the studies of cancer stem cells (including specific isolation and targeting on those cells might benefit the discovery of novel treatment of prostate cancer, especially castration resistant disease. In this review, we summarized major biomarkers for prostate cancer stem cells, as well as their functional mechanisms and potential application in clinical diagnosis and treatment of patients.

  11. Search for Breast Cancer Biomarkers in Fractionated Serum Samples by Protein Profiling With SELDI-TOF MS

    NARCIS (Netherlands)

    Opstal - van Winden, A.W.J.; Beijnen, J.H.; de Loof, A.; van Heerde, W.L.; Vermeulen, R.; Peeters, P.H.M.; van Gils, C.H.

    2012-01-01

    BackgroundMany high-abundant acute phase reactants have been previously detected as potential breast cancer biomar-kers. However, they are unlikely to be specific for breast cancer. Cancer-specific biomarkers are thought to be among the lower abundant proteins.MethodsWe aimed to detect lower

  12. Comprehensive serum profiling for the discovery of epithelial ovarian cancer biomarkers.

    Directory of Open Access Journals (Sweden)

    Ping Yip

    Full Text Available FDA-cleared ovarian cancer biomarkers are limited to CA-125 and HE4 for monitoring and recurrence and OVA1, a multivariate panel consisting of CA-125 and four additional biomarkers, for referring patients to a specialist. Due to relatively poor performance of these tests, more accurate and broadly applicable biomarkers are needed. We evaluated the dysregulation of 259 candidate cancer markers in serum samples from 499 patients. Sera were collected prospectively at 11 monitored sites under a single well-defined protocol. All stages of ovarian cancer and common benign gynecological conditions were represented. To ensure consistency and comparability of biomarker comparisons, all measurements were performed on a single platform, at a single site, using a panel of rigorously calibrated, qualified, high-throughput, multiplexed immunoassays and all analyses were conducted using the same software. Each marker was evaluated independently for its ability to differentiate ovarian cancer from benign conditions. A total of 175 markers were dysregulated in the cancer samples. HE4 (AUC=0.933 and CA-125 (AUC=0.907 were the most informative biomarkers, followed by IL-2 receptor α, α1-antitrypsin, C-reactive protein, YKL-40, cellular fibronectin, CA-72-4 and prostasin (AUC>0.800. To improve the discrimination between cancer and benign conditions, a simple multivariate combination of markers was explored using logistic regression. When combined into a single panel, the nine most informative individual biomarkers yielded an AUC value of 0.950, significantly higher than obtained when combining the markers in the OVA1 panel (AUC 0.912. Additionally, at a threshold sensitivity of 90%, the combination of the top 9 markers gave 88.9% specificity compared to 63.4% specificity for the OVA1 markers. Although a blinded validation study has not yet been performed, these results indicate that alternative biomarker combinations might lead to significant improvements in the

  13. Receiver Operating Characteristic (ROC to Determine Cut-Off Points of Biomarkers in Lung Cancer Patients

    Directory of Open Access Journals (Sweden)

    Heidi L. Weiss

    2004-01-01

    Full Text Available The role of biomarkers in disease prognosis continues to be an important investigation in many cancer studies. In order for these biomarkers to have practical application in clinical decision making regarding patient treatment and follow-up, it is common to dichotomize patients into those with low vs. high expression levels. In this study, receiver operating characteristic (ROC curves, area under the curve (AUC of the ROC, sensitivity, specificity, as well as likelihood ratios were calculated to determine levels of growth factor biomarkers that best differentiate lung cancer cases versus control subjects. Selected cut-off points for p185erbB-2 and EGFR membrane appear to have good discriminating power to differentiate control tissues versus uninvolved tissues from patients with lung cancer (AUC = 89% and 90%, respectively; while AUC increased to at least 90% for selected cut-off points for p185erbB-2 membrane, EGFR membrane, and FASE when comparing between control versus carcinoma tissues from lung cancer cases. Using data from control subjects compared to patients with lung cancer, we presented a simple and intuitive approach to determine dichotomized levels of biomarkers and validated the value of these biomarkers as surrogate endpoints for cancer outcome.

  14. ROLE OF DNA METHYLATION AS A DIAGNOSTIC BIOMARKER OF SPORADIC BREAST CANCER

    Directory of Open Access Journals (Sweden)

    Wirsma Arif Harahap

    2017-02-01

    Full Text Available The initiation and progression of breast cancer have been recognized for many years to be secondary to the accumulation of genetic mutations which lead to aberrant cellular function. Genetic mutations, either inherited or sporadic, may result in the activation of oncogenes and the inactivation of tumor suppressor genes. The more recent discovery that reversible alterations in histone proteins and deoxyribonucleic acid (DNA can also lead to tumorigenesis has introduced a novel term to the field of cancer research: epigenetics.  Epigenetics refers to the study of heritable changes in gene regulation that do not involve a change in the DNA sequence. The most often studied in epigenetics of breast cancer is DNA methylation. That a promoter methylation result in transcription blockade supports the notion that cellular inhibition takes place. Compared to normal tissues, hypermethylation occurs from double to triple in cancerous ones. DNA methylation plays a crucial role in oncogenesis and is one of the hallmarks of cancer. Detection of aberrantly methylated CpG islands in promoter region of several genes in DNA sample derived from nipple aspirates, serum, or cancer tissue associated with down regulation of expression or loss of function of these genes has been associated with early stages of breast cancer, where  hypermethylation of CpG island points to poorer prognosis in breast cancer.  DNA methylation has been identified as signature for TNBC. Methylation of BRCA1 gene is frequently demonstrated in young, estrogen receptor-negative breast cancer patients. Methylation of specific genes is known to differ across race and socioeconomic status. BRCA1 methylation in premenopausal women with sporadic breast cancer in West Sumatra region has been higher than in Western women. DNA methylation may be used to enhance current breast cancer classification. There is such a distinction between methylation and gene expression profiles of breast cancer that not

  15. Biomarker Discovery in Human Prostate Cancer: an Update in Metabolomics Studies

    Directory of Open Access Journals (Sweden)

    Ana Rita Lima

    2016-08-01

    Full Text Available Prostate cancer (PCa is the most frequently diagnosed cancer and the second leading cause of cancer death among men in Western countries. Current screening techniques are based on the measurement of serum prostate specific antigen (PSA levels and digital rectal examination. A decisive diagnosis of PCa is based on prostate biopsies; however, this approach can lead to false-positive and false-negative results. Therefore, it is important to discover new biomarkers for the diagnosis of PCa, preferably noninvasive ones. Metabolomics is an approach that allows the analysis of the entire metabolic profile of a biological system. As neoplastic cells have a unique metabolic phenotype related to cancer development and progression, the identification of dysfunctional metabolic pathways using metabolomics can be used to discover cancer biomarkers and therapeutic targets. In this study, we review several metabolomics studies performed in prostatic fluid, blood plasma/serum, urine, tissues and immortalized cultured cell lines with the objective of discovering alterations in the metabolic phenotype of PCa and thus discovering new biomarkers for the diagnosis of PCa. Encouraging results using metabolomics have been reported for PCa, with sarcosine being one of the most promising biomarkers identified to date. However, the use of sarcosine as a PCa biomarker in the clinic remains a controversial issue within the scientific community. Beyond sarcosine, other metabolites are considered to be biomarkers for PCa, but they still need clinical validation. Despite the lack of metabolomics biomarkers reaching clinical practice, metabolomics proved to be a powerful tool in the discovery of new biomarkers for PCa detection.

  16. Validated biomarkers: The key to precision treatment in patients with breast cancer.

    Science.gov (United States)

    Duffy, Michael J; O'Donovan, Norma; McDermott, Enda; Crown, John

    2016-10-01

    Recent DNA sequencing and gene expression studies have shown that at a molecular level, almost every case of breast cancer is unique and different from other breast cancers. For optimum management therefore, every patient should receive treatment that is guided by the molecular composition of their tumor, i.e., precision treatment. While such a scenario is still some distance into the future, biomarkers are beginning to play an important role in preparing the way for precision treatment. In particular, biomarkers are increasingly being used for predicting patient outcome and informing as to the most appropriate type of systemic therapy to be administered. Mandatory biomarkers for every newly diagnosed case of breast cancer are estrogen receptors and progesterone receptors in selecting patients for endocrine treatment and HER2 for identifying patients likely to benefit from anti-HER2 therapy. Amongst the best validated prognostic biomarker tests are uPA/PAI-1, MammaPrint and Oncotype DX. Although currently, there are no biomarkers available for predicting response to specific forms of chemotherapy, uPA/PAI-1 and Oncotype DX can aid the identification of lymph node-negative patients that are most likely to benefit from adjuvant chemotherapy, in general. In order to accelerate progress towards precision treatment for women with breast cancer, we need additional predictive biomarkers, especially for enhancing the positive predictive value for endocrine and anti-HER2 therapies, as well as biomarkers for predicting response to specific forms of chemotherapy. The ultimate biomarker test for achieving the goal of precision treatment for patients with breast cancer will likely require a combination of gene sequencing and transcriptomic analysis of every patient's tumor. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Advancement of Phenotype Transformation of Cancer-associated Fibroblasts: 
from Genetic Alterations to Epigenetic Modification

    Directory of Open Access Journals (Sweden)

    Dali CHEN

    2015-02-01

    Full Text Available In the field of human cancer research, even though the vast majority attentions were paid to tumor cells as “the seeds”, the roles of tumor microenvironments as “the soil” are gradually explored in recent years. As a dominant compartment of tumor microenvironments, cancer-associated fibroblasts (CAFs were discovered to correlated with tumorigenesis, tumor progression and prognosis. And the exploration of the mechanisms of CAF phenotype transformation would conducive to the further understand of the CAFs function in human cancers. As we known that CAFs have four main origins, including epithelial cells, endothelial cells, mesenchymal stem cells (MSCs and local mesenchymal cells. However, researchers found that all these origins finally conduct similiar phenotypes from intrinsic to extrinsic ones. Thus, what and how a mechanism can conduct the phenotype transformation of CAFs with different origins? Two viewpoints are proposed to try to answer the quetsion, involving genetic alterations and epigenetic modifications. This review will systematically summarize the advancement of mechanisms of CAF phenotype transformations in the aspect of genentic and epigenetic modifications.

  18. Epigenetic modulation with HDAC inhibitor CG200745 induces anti-proliferation in non-small cell lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Sung-Min Chun

    Full Text Available Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes. Hence, chemical approaches targeting histone-modifying enzymes have emerged onto the main stage of anticancer drug discovery. Here, we investigated the therapeutic potentials and mechanistic roles of the recently developed histone deacetylase inhibitor, CG200745, in non-small cell lung cancer cells. Treatment with CG200745 increased the global level of histone acetylation, resulting in the inhibition of cell proliferation. ChIP-on-chip analysis with an H4K16ac antibody showed altered H4K16 acetylation on genes critical for cell growth inhibition, although decreased at the transcription start site of a subset of genes. Altered H4K16ac was associated with changes in mRNA expression of the corresponding genes, which were further validated in quantitative RT-PCR and western blotting assays. Our results demonstrated that CG200745 causes NSCLC cell growth inhibition through epigenetic modification of critical genes in cancer cell survival, providing pivotal clues as a promising chemotherapeutics against lung cancer.

  19. Epigenetic modulation with HDAC inhibitor CG200745 induces anti-proliferation in non-small cell lung cancer cells.

    Science.gov (United States)

    Chun, Sung-Min; Lee, Ji-Young; Choi, Jene; Lee, Je-Hwan; Hwang, Jung Jin; Kim, Chung-Soo; Suh, Young-Ah; Jang, Se Jin

    2015-01-01

    Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes. Hence, chemical approaches targeting histone-modifying enzymes have emerged onto the main stage of anticancer drug discovery. Here, we investigated the therapeutic potentials and mechanistic roles of the recently developed histone deacetylase inhibitor, CG200745, in non-small cell lung cancer cells. Treatment with CG200745 increased the global level of histone acetylation, resulting in the inhibition of cell proliferation. ChIP-on-chip analysis with an H4K16ac antibody showed altered H4K16 acetylation on genes critical for cell growth inhibition, although decreased at the transcription start site of a subset of genes. Altered H4K16ac was associated with changes in mRNA expression of the corresponding genes, which were further validated in quantitative RT-PCR and western blotting assays. Our results demonstrated that CG200745 causes NSCLC cell growth inhibition through epigenetic modification of critical genes in cancer cell survival, providing pivotal clues as a promising chemotherapeutics against lung cancer.

  20. Further Development of an Exhaled microRNA Biomarker of Lung Cancer Risk

    Science.gov (United States)

    2017-08-01

    AWARD NUMBER: W81XWH-16-1-0328 TITLE: Further Development of an Exhaled microRNA Biomarker of Lung Cancer Risk PRINCIPAL INVESTIGATOR: Dr...4. TITLE AND SUBTITLE Further Development of an Exhaled microRNA Biomarker of Lung Cancer Risk 5b. GRANT NUMBER W81XWH 16-1-0328 5c. PROGRAM...devise a non-invasive airway based exhaled microRNA metric for lung cancer risk, initial work to be tested in a case control study. We expanded the

  1. Rapid point-of-care breath test for biomarkers of breast cancer and abnormal mammograms.

    Directory of Open Access Journals (Sweden)

    Michael Phillips

    Full Text Available BACKGROUND: Previous studies have reported volatile organic compounds (VOCs in breath as biomarkers of breast cancer and abnormal mammograms, apparently resulting from increased oxidative stress and cytochrome p450 induction. We evaluated a six-minute point-of-care breath test for VOC biomarkers in women screened for breast cancer at centers in the USA and the Netherlands. METHODS: 244 women had a screening mammogram (93/37 normal/abnormal or a breast biopsy (cancer/no cancer 35/79. A mobile point-of-care system collected and concentrated breath and air VOCs for analysis with gas chromatography and surface acoustic wave detection. Chromatograms were segmented into a time series of alveolar gradients (breath minus room air. Segmental alveolar gradients were ranked as candidate biomarkers by C-statistic value (area under curve [AUC] of receiver operating characteristic [ROC] curve. Multivariate predictive algorithms were constructed employing significant biomarkers identified with multiple Monte Carlo simulations and cross validated with a leave-one-out (LOO procedure. RESULTS: Performance of breath biomarker algorithms was determined in three groups: breast cancer on biopsy versus normal screening mammograms (81.8% sensitivity, 70.0% specificity, accuracy 79% (73% on LOO [C-statistic value], negative predictive value 99.9%; normal versus abnormal screening mammograms (86.5% sensitivity, 66.7% specificity, accuracy 83%, 62% on LOO; and cancer versus no cancer on breast biopsy (75.8% sensitivity, 74.0% specificity, accuracy 78%, 67% on LOO. CONCLUSIONS: A pilot study of a six-minute point-of-care breath test for volatile biomarkers accurately identified women with breast cancer and with abnormal mammograms. Breath testing could potentially reduce the number of needless mammograms without loss of diagnostic sensitivity.

  2. Immunohistochemistry for predictive biomarkers in non-small cell lung cancer.

    Science.gov (United States)

    Mino-Kenudson, Mari

    2017-10-01

    In the era of targeted therapy, predictive biomarker testing has become increasingly important for non-small cell lung cancer. Of multiple predictive biomarker testing methods, immunohistochemistry (IHC) is widely available and technically less challenging, can provide clinically meaningful results with a rapid turn-around-time and is more cost efficient than molecular platforms. In fact, several IHC assays for predictive biomarkers have already been implemented in routine pathology practice. In this review, we will discuss: (I) the details of anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) IHC assays including the performance of multiple antibody clones, pros and cons of IHC platforms and various scoring systems to design an optimal algorithm for predictive biomarker testing; (II) issues associated with programmed death-ligand 1 (PD-L1) IHC assays; (III) appropriate pre-analytical tissue handling and selection of optimal tissue samples for predictive biomarker IHC.

  3. Adiposity, mediating biomarkers and risk of colon cancer in the european prospective investigation into cancer and nutrition study

    NARCIS (Netherlands)

    Aleksandrova, K.; Drogan, D.; Boeing, H.; Jenab, M.; Bueno de Mesquita, H.B.; Duijnhoven, van F.J.B.

    2014-01-01

    Adiposity is a risk factor for colon cancer, but underlying mechanisms are not well understood. We evaluated the extent to which 11 biomarkers with inflammatory and metabolic actions mediate the association of adiposity measures, waist circumference (WC) and body mass index (BMI), with colon cancer

  4. MicroRNA-196a is a putative diagnostic biomarker and therapeutic target for laryngeal cancer.

    Directory of Open Access Journals (Sweden)

    Koichiro Saito

    Full Text Available BACKGROUND: MicroRNA (miRNA is an emerging subclass of small non-coding RNAs that regulates gene expression and has a pivotal role for many physiological processes including cancer development. Recent reports revealed the role of miRNAs as ideal biomarkers and therapeutic targets due to their tissue- or disease-specific nature. Head and neck cancer (HNC is a major cause of cancer-related mortality and morbidity, and laryngeal cancer has the highest incidence in it. However, the molecular mechanisms involved in laryngeal cancer development remain to be known and highly sensitive biomarkers and novel promising therapy is necessary. METHODOLOGY/PRINCIPAL FINDINGS: To explore laryngeal cancer-specific miRNAs, RNA from 5 laryngeal surgical specimens including cancer and non-cancer tissues were hybridized to microarray carrying 723 human miRNAs. The resultant differentially expressed miRNAs were further tested by using quantitative real time PCR (qRT-PCR on 43 laryngeal tissue samples including cancers, noncancerous counterparts, benign diseases and precancerous dysplasias. Significant expressional differences between matched pairs were reproduced in miR-133b, miR-455-5p, and miR-196a, among which miR-196a being the most promising cancer biomarker as validated by qRT-PCR analyses on additional 84 tissue samples. Deep sequencing analysis revealed both quantitative and qualitative deviation of miR-196a isomiR expression in laryngeal cancer. In situ hybridization confirmed laryngeal cancer-specific expression of miR-196a in both cancer and cancer stroma cells. Finally, inhibition of miR-196a counteracted cancer cell proliferation in both laryngeal cancer-derived cells and mouse xenograft model. CONCLUSIONS/SIGNIFICANCE: Our study provided the possibilities that miR-196a might be very useful in diagnosing and treating laryngeal cancer.

  5. The Present and Future of Biomarkers in Prostate Cancer: Proteomics, Genomics, and Immunology Advancements

    Directory of Open Access Journals (Sweden)

    Pierre-Olivier Gaudreau

    2016-01-01

    Full Text Available Prostate cancer (PC is the second most common form of cancer in men worldwide. Biomarkers have emerged as essential tools for treatment and assessment since the variability of disease behavior, the cost and diversity of treatments, and the related impairment of quality of life have given rise to a need for a personalized approach. High-throughput technology platforms in proteomics and genomics have accelerated the development of biomarkers. Furthermore, recent successes of several new agents in PC, including immunotherapy, have stimulated the search for predictors of response and resistance and have improved the understanding of the biological mechanisms at work. This review provides an overview of currently established biomarkers in PC, as well as a selection of the most promising biomarkers within these particular fields of development.

  6. Diagnostic and Prognostic MicroRNA Biomarkers for Prostate Cancer in Cell-free Urine

    DEFF Research Database (Denmark)

    Fredsøe, Jacob Christian; Rasmussen, Anne Karin; Thomsen, Anni Rønfeldt

    2017-01-01

    Background: Widespread use of prostate-specific antigen (PSA) testing for prostate cancer (PC) detection has led to extensive overdiagnosis and overtreatment. Urine-based microRNA (miRNA) biomarkers could be useful in PC diagnosis and prognosis. Objective: To train and validate urine-based micro......RNA (miRNA) biomarkers that may assist in PC diagnosis and prognosis. Design, setting, and participants: We profiled the expression levels of 92 miRNAs via reverse transcriptase–poymerase chain reaction in cell-free urine samples from 29 patients with benign prostatic hyperplasia (BPH) and 215 patients...... could help in primary diagnosis of PC and guide treatment decisions. Further validation studies are warranted. Patient summary: Using two large patient cohorts, we searched for novel prostate cancer biomarkers in urine. We found two new sets of microRNA biomarkers in urine that could accurately predict...

  7. Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers.

    Science.gov (United States)

    Borges, Álvaro H; Silverberg, Michael J; Wentworth, Deborah; Grulich, Andrew E; Fätkenheuer, Gerd; Mitsuyasu, Ronald; Tambussi, Giuseppe; Sabin, Caroline A; Neaton, James D; Lundgren, Jens D

    2013-06-01

    To investigate the relationship between inflammatory [interleukin-6 (IL-6) and C-reactive protein (CRP)] and coagulation (D-dimer) biomarkers and cancer risk during HIV infection. A prospective cohort. HIV-infected patients on continuous antiretroviral therapy (ART) in the control arms of three randomized trials (N=5023) were included in an analysis of predictors of cancer (any type, infection-related or infection-unrelated). Hazard ratios for IL-6, CRP and D-dimer levels (log2-transformed) were calculated using Cox models stratified by trial and adjusted for demographics and CD4+ cell counts and adjusted also for all biomarkers simultaneously. To assess the possibility that biomarker levels were elevated at entry due to undiagnosed cancer, analyses were repeated excluding early cancer events (i.e. diagnosed during first 2 years of follow-up). During approximately 24,000 person-years of follow-up (PYFU), 172 patients developed cancer (70 infection-related; 102 infection-unrelated). The risk of developing cancer was associated with higher levels (per doubling) of IL-6 (hazard ratio 1.38, Passociated with cancer risk when all biomarkers were considered simultaneously. Results for infection-related and infection-unrelated cancers were similar to results for any cancer. Hazard ratios excluding 69 early cancer events were 1.31 (P=0.007), 1.14 (P=0.02) and 1.07 (P=0.49) for IL-6, CRP and D-dimer, respectively. Activated inflammation and coagulation pathways are associated with increased cancer risk during HIV infection. This association was stronger for IL-6 and persisted after excluding early cancer. Trials of interventions may be warranted to assess whether cancer risk can be reduced by lowering IL-6 levels in HIV-positive individuals.

  8. Lung Cancer Serum Biomarker Discovery Using Label Free LC-MS/MS

    Science.gov (United States)

    Zeng, Xuemei; Hood, Brian L.; Zhao, Ting; Conrads, Thomas P.; Sun, Mai; Gopalakrishnan, Vanathi; Grover, Himanshu; Day, Roger S.; Weissfeld, Joel L.; Wilson, David O.; Siegfried, Jill M.; Bigbee, William L.

    2011-01-01

    Introduction Lung cancer remains the leading cause of cancer-related death with poor survival due to the late stage at which lung cancer is typically diagnosed. Given the clinical burden from lung cancer, and the relatively favorable survival associated with early stage lung cancer, biomarkers for early detection of lung cancer are of important potential clinical benefit. Methods We performed a global lung cancer serum biomarker discovery study using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in a set of pooled non-small cell lung cancer (NSCLC) case sera and matched controls. Immunoaffinity subtraction was used to deplete the top most abundant serum proteins; the remaining serum proteins were subjected to trypsin digestion and analyzed in triplicate by LC-MS/MS. The tandem mass spectrum data were searched against the human proteome database and the resultant spectral counting data were used to estimate the relative abundance of proteins across the case/control serum pools. The spectral counting derived abundances of some candidate biomarker proteins were confirmed with multiple reaction monitoring MS assays. Results A list of 49 differentially abundant candidate proteins was compiled by applying a negative binomial regression model to the spectral counting data (pbiomarkers with statistically significant differential abundance across the lung cancer case/control pools which, when validated, could improve lung cancer early detection. PMID:21304412

  9. Mass Spectrometry-Based Proteomics in Molecular Diagnostics: Discovery of Cancer Biomarkers Using Tissue Culture

    Science.gov (United States)

    Paul, Debasish; Kumar, Avinash; Gajbhiye, Akshada; Santra, Manas K.; Srikanth, Rapole

    2013-01-01

    Accurate diagnosis and proper monitoring of cancer patients remain a key obstacle for successful cancer treatment and prevention. Therein comes the need for biomarker discovery, which is crucial to the current oncological and other clinical practices having the potential to impact the diagnosis and prognosis. In fact, most of the biomarkers have been discovered utilizing the proteomics-based approaches. Although high-throughput mass spectrometry-based proteomic approaches like SILAC, 2D-DIGE, and iTRAQ are filling up the pitfalls of the conventional techniques, still serum proteomics importunately poses hurdle in overcoming a wide range of protein concentrations, and also the availability of patient tissue samples is a limitation for the biomarker discovery. Thus, researchers have looked for alternatives, and profiling of candidate biomarkers through tissue culture of tumor cell lines comes up as a promising option. It is a rich source of tumor cell-derived proteins, thereby, representing a wide array of potential biomarkers. Interestingly, most of the clinical biomarkers in use today (CA 125, CA 15.3, CA 19.9, and PSA) were discovered through tissue culture-based system and tissue extracts. This paper tries to emphasize the tissue culture-based discovery of candidate biomarkers through various mass spectrometry-based proteomic approaches. PMID:23586059

  10. Mass Spectrometry-Based Proteomics in Molecular Diagnostics: Discovery of Cancer Biomarkers Using Tissue Culture

    Directory of Open Access Journals (Sweden)

    Debasish Paul

    2013-01-01

    Full Text Available Accurate diagnosis and proper monitoring of cancer patients remain a key obstacle for successful cancer treatment and prevention. Therein comes the need for biomarker discovery, which is crucial to the current oncological and other clinical practices having the potential to impact the diagnosis and prognosis. In fact, most of the biomarkers have been discovered utilizing the proteomics-based approaches. Although high-throughput mass spectrometry-based proteomic approaches like SILAC, 2D-DIGE, and iTRAQ are filling up the pitfalls of the conventional techniques, still serum proteomics importunately poses hurdle in overcoming a wide range of protein concentrations, and also the availability of patient tissue samples is a limitation for the biomarker discovery. Thus, researchers have looked for alternatives, and profiling of candidate biomarkers through tissue culture of tumor cell lines comes up as a promising option. It is a rich source of tumor cell-derived proteins, thereby, representing a wide array of potential biomarkers. Interestingly, most of the clinical biomarkers in use today (CA 125, CA 15.3, CA 19.9, and PSA were discovered through tissue culture-based system and tissue extracts. This paper tries to emphasize the tissue culture-based discovery of candidate biomarkers through various mass spectrometry-based proteomic approaches.

  11. Exosomal proteins as prognostic biomarkers in non-small cell lung cancer

    DEFF Research Database (Denmark)

    Sandfeld-Paulsen, B; Aggerholm-Pedersen, N; Bæk, R

    2016-01-01

    BACKGROUND: Use of exosomes as biomarkers in non-small cell lung cancer (NSCLC) is an intriguing approach in the liquid-biopsy era. Exosomes are nano-sized vesicles with membrane-bound proteins that reflect their originating cell. Prognostic biomarkers are needed to improve patient selection...... Bonferroni correction. Results were adjusted for clinico-pathological characteristics, stage, histology, age, sex and performance status. CONCLUSION: We illustrate the promising aspects associated with the use of exosomal membrane-bound proteins as a biomarker and demonstrate that they are a strong...

  12. REG4 Is Highly Expressed in Mucinous Ovarian Cancer: A Potential Novel Serum Biomarker.

    Directory of Open Access Journals (Sweden)

    Laura Lehtinen

    Full Text Available Preoperative diagnostics of ovarian neoplasms rely on ultrasound imaging and the serum biomarkers CA125 and HE4. However, these markers may be elevated in non-neoplastic conditions and may fail to identify most non-serous epithelial cancer subtypes. The objective of this study was to identify histotype-specific serum biomarkers for mucinous ovarian cancer. The candidate genes with mucinous histotype specific expression profile were identified from publicly available gene-expression databases and further in silico data mining was performed utilizing the MediSapiens database. Candidate biomarker validation was done using qRT-PCR, western blotting and immunohistochemical staining of tumor tissue microarrays. The expression level of the candidate gene in serum was compared to the serum CA125 and HE4 levels in a patient cohort of prospectively collected advanced ovarian cancer. Database searches identified REG4 as a potential biomarker with specificity for the mucinous ovarian cancer subtype. The specific expression within epithelial ovarian tumors was further confirmed by mRNA analysis. Immunohistochemical staining of ovarian tumor tissue arrays showed distinctive cytoplasmic expression pattern only in mucinous carcinomas and suggested differential expression between benign and malignant mucinous neoplasms. Finally, an ELISA based serum biomarker assay demonstrated increased expression only in patients with mucinous ovarian cancer. This study identifies REG4 as a potential serum biomarker for histotype-specific detection of mucinous ovarian cancer and suggests serum REG4 measurement as a non-invasive diagnostic tool for postoperative follow-up of patients with mucinous ovarian cancer.

  13. Biomarkers for Early Detection of Clinically Relevant Prostate Cancer: A Multi-Institutional Validation Trial

    Science.gov (United States)

    2015-10-01

    provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently ...biomarker platforms in our multi-center, prospectively accrued prostate cancer active surveillance cohort – the Canary Prostate Active Surveillance...prostate cancers currently diagnosed are low risk tumors for which there is substantial evidence that the cancer will not cause harm if left untreated

  14. Urinary long noncoding RNAs in nonmuscle-invasive bladder cancer: new architects in cancer prognostic biomarkers.

    Science.gov (United States)

    Terracciano, Daniela; Ferro, Matteo; Terreri, Sara; Lucarelli, Giuseppe; D'Elia, Carolina; Musi, Gennaro; de Cobelli, Ottavio; Mirone, Vincenzo; Cimmino, Amelia

    2017-06-01

    Several reports over the last 10 years provided evidence that long noncoding RNAs (lncRNAs) are often altered in bladder cancers. lncRNAs are longer than 200 nucleotides and function as important regulators of gene expression, interacting with the major pathways of cell growth, proliferation, differentiation, and survival. A large number of lncRNAs has oncogenic function and is more expressed in tumor compared with normal tissues. Their overexpression may be associated with tumor formation, progression, and metastasis in a variety of tumors including bladder cancer. Although lncRNAs have been shown to have critical regulatory roles in cancer biology, the biological functions and prognostic values in nonmuscle-invasive bladder cancer remain largely unknown. Nevertheless, a growing body of evidence suggests that several lncRNAs expression profiles in bladder malignancies are associated with poor prognosis, and they can be detected in biological fluids, such as urines. Here, we review current progress in the biology and the implication of lncRNAs associated with bladder cancer, and we discuss their potential use as diagnosis and prognosis biomarkers in bladder malignancies with a focus on their role in high-risk nonmuscle-invasive tumors. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Identification, validation, and clinical implementation of tumor-associated biomarkers to improve therapy concepts, survival, and quality of life of cancer patients: tasks of the Receptor and Biomarker Group of the European Organization for Research and Treatment of Cancer.

    NARCIS (Netherlands)

    Schmitt, M.; Harbeck, N.; Daidone, M.G.; Brynner, N.; Duffy, M.J.; Foekens, J.A.; Sweep, C.G.J.

    2004-01-01

    Guiding principles are provided and discussed on how to inform the physician scientist and cancer researcher about quality control systems to enable a consistent assessment of the clinical value of tumor-associated biomarkers. Next to cancer research itself, the Receptor and Biomarker Group of the

  16. Is Glioblastoma an Epigenetic Malignancy?

    International Nuclear Information System (INIS)

    Maleszewska, Marta; Kaminska, Bozena

    2013-01-01

    Epigenetic modifications control gene expression by regulating the access of nuclear proteins to their target DNA and have been implicated in both normal cell differentiation and oncogenic transformation. Epigenetic abnormalities can occur both as a cause and as a consequence of cancer. Oncogenic transformation can deeply alter the epigenetic information enclosed in the pattern of DNA methylation or histone modifications. In addition, in some cancers epigenetic dysfunctions can drive oncogenic transformation. Growing evidence emphasizes the interplay between metabolic disturbances, epigenomic changes and cancer, i.e., mutations in the metabolic enzymes SDH, FH, and IDH may contribute to cancer development. Epigenetic-based mechanisms are reversible and the possibility of “resetting” the abnormal cancer epigenome by applying pharmacological or genetic strategies is an attractive, novel approach. Gliomas are incurable with all current therapeutic approaches and new strategies are urgently needed. Increasing evidence suggests the role of epigenetic events in development and/or progression of gliomas. In this review, we summarize current data on the occurrence and significance of mutations in the epigenetic and metabolic enzymes in pathobiology of gliomas. We discuss emerging therapies targeting specific epigenetic modifications or chromatin modifying enzymes either alone or in combination with other treatment regimens

  17. Epigenetic changes in cancer as potential targets for prophylaxis and maintenance therapy

    DEFF Research Database (Denmark)

    Grønbæk, Karin Elmegård; Treppendahl, M.; Asmar, F.

    2008-01-01

    (vorinostat) have been approved for clinical use by the US Food and Drug Administration and have reached clinical phase III trials elsewhere. The prospect that epigenetic alterations may play an essential role in renewing and maintaining the malignant clone has opened up new perspectives for the use...

  18. MIP-Based Sensors: Promising New Tools for Cancer Biomarker Determination

    Directory of Open Access Journals (Sweden)

    Giulia Selvolini

    2017-03-01

    Full Text Available Detecting cancer disease at an early stage is one of the most important issues for increasing the survival rate of patients. Cancer biomarker detection helps to provide a diagnosis before the disease becomes incurable in later stages. Biomarkers can also be used to evaluate the progression of therapies and surgery treatments. In recent years, molecularly imprinted polymer (MIP based sensors have been intensely investigated as promising analytical devices in several fields, including clinical analysis, offering desired portability, fast response, specificity, and low cost. The aim of this review is to provide readers with an overview on recent important achievements in MIP-based sensors coupled to various transducers (e.g., electrochemical, optical, and piezoelectric for the determination of cancer biomarkers by selected publications from 2012 to 2016.

  19. An integrative multi-dimensional genetic and epigenetic strategy to identify aberrant genes and pathways in cancer

    Directory of Open Access Journals (Sweden)

    Lockwood William W

    2010-05-01

    Full Text Available Abstract Background Genomics has substantially changed our approach to cancer research. Gene expression profiling, for example, has been utilized to delineate subtypes of cancer, and facilitated derivation of predictive and prognostic signatures. The emergence of technologies for the high resolution and genome-wide description of genetic and epigenetic features has enabled the identification of a multitude of causal DNA events in tumors. This has afforded the potential for large scale integration of genome and transcriptome data generated from a variety of technology platforms to acquire a better understanding of cancer. Results Here we show how multi-dimensional genomics data analysis would enable the deciphering of mechanisms that disrupt regulatory/signaling cascades and downstream effects. Since not all gene expression changes observed in a tumor are causal to cancer development, we demonstrate an approach based on multiple concerted disruption (MCD analysis of genes that facilitates the rational deduction of aberrant genes and pathways, which otherwise would be overlooked in single genomic dimension investigations. Conclusions Notably, this is the first comprehensive study of breast cancer cells by parallel integrative genome wide analyses of DNA copy number, LOH, and DNA methylation status to interpret changes in gene expression pattern. Our findings demonstrate the power of a multi-dimensional approach to elucidate events which would escape conventional single dimensional analysis and as such, reduce the cohort sample size for cancer gene discovery.

  20. Hypomethylated Fgf3 is a potential biomarker for early detection of oral cancer in mice treated with the tobacco carcinogen dibenzo[def,p]chrysene.

    Directory of Open Access Journals (Sweden)

    Yuan-Wan Sun

    Full Text Available Genetic and epigenetic alterations observed at end stage OSCC formation could be considered as a consequence of cancer development and thus changes in normal or premalignant tissues which had been exposed to oral carcinogens such as Dibenzo[def,p]chrysene (DBP may better serve as predictive biomarkers of disease development. Many types of DNA damage can induce epigenetic changes which can occur early and in the absence of evident morphological abnormalities. Therefore we used ERRBS to generate genome-scale, single-base resolution DNA methylomes from histologically normal oral tissues of mice treated with DBP under experimental conditions known to induce maximum DNA damage which is essential for the development of OSCC induced by DBP in mice. After genome-wide correction, 30 and 48 differentially methylated sites (DMS were identified between vehicle control and DBP treated mice using 25% and 10% differences in methylation, respectively. RT-PCR was further performed to examine the expressions of nine selected genes. Among them, Fgf3, a gene frequently amplified in head and neck cancer, showed most prominent and significant gene expression change (2.4× increases, despite the hypomethylation of Fgf3 was identified at >10kb upstream of transcription start site. No difference was observed in protein expression between normal oral tissues treated with DBP or vehicle as examined by immunohistochemistry. Collectively, our results indicate that Fgf3 hypomethylation and gene overexpression, but not protein expression, occurred in the early stage of oral carcinogenesis induced by DBP. Thus, Fgf3 hypomethylation may serve as a potential biomarker for early detection of OSCC.

  1. Direct detection of cancer biomarkers in blood using a "place n play" modular polydimethylsiloxane pump.

    Science.gov (United States)

    Zhang, Honglian; Li, Gang; Liao, Lingying; Mao, Hongju; Jin, Qinghui; Zhao, Jianlong

    2013-01-01

    Cancer biomarkers have significant potential as reliable tools for the early detection of the disease and for monitoring its recurrence. However, most current methods for biomarker detection have technical difficulties (such as sample preparation and specific detector requirements) which limit their application in point of care diagnostics. We developed an extremely simple, power-free microfluidic system for direct detection of cancer biomarkers in microliter volumes of whole blood. CEA and CYFRA21-1 were chosen as model cancer biomarkers. The system automatically extracted blood plasma from less than 3 μl of whole blood and performed a multiplex sample-to-answer assay (nano-ELISA (enzyme-linked immunosorbent assay) technique) without the use of external power or extra components. By taking advantage of the nano-ELISA technique, this microfluidic system detected CEA at a concentration of 50 pg/ml and CYFRA21-1 at a concentration of 60 pg/ml within 60 min. The combination of PnP polydimethylsiloxane (PDMS) pump and nano-ELISA technique in a single microchip system shows great promise for the detection of cancer biomarkers in a drop of blood.

  2. Epigenetic Pathways in Human Disease: The Impact of DNA Methylation on Stress-Related Pathogenesis and Current Challenges in Biomarker Development

    Directory of Open Access Journals (Sweden)

    M. Austin Argentieri

    2017-04-01

    Full Text Available HPA axis genes implicated in glucocorticoid regulation play an important role in regulating the physiological impact of social and environmental stress, and have become a focal point for investigating the role of glucocorticoid regulation in the etiology of disease. We conducted a systematic review to critically assess the full range of clinical associations that have been reported in relation to DNA methylation of CRH, CRH-R1/2, CRH-BP, AVP, POMC, ACTH, ACTH-R, NR3C1, FKBP5, and HSD11β1/2 genes in adults. A total of 32 studies were identified. There is prospective evidence for an association between HSD11β2 methylation and hypertension, and functional evidence of an association between NR3C1 methylation and both small cell lung cancer (SCLC and breast cancer. Strong associations have been reported between FKBP5 and NR3C1 methylation and PTSD, and biologically-plausible associations have been reported between FKBP5 methylation and Alzheimer's Disease. Mixed associations between NR3C1 methylation and mental health outcomes have been reported according to different social and environmental exposures, and according to varying gene regions investigated. We conclude by highlighting key challenges and future research directions that will need to be addressed in order to develop both clinically meaningful prognostic biomarkers and an evidence base that can inform public policy practice.

  3. Importance of dose-schedule of 5-aza-2'-deoxycytidine for epigenetic therapy of cancer

    International Nuclear Information System (INIS)

    Lemaire, Maryse; Chabot, Guy G; Raynal, Noël JM; Momparler, Louise F; Hurtubise, Annie; Bernstein, Mark L; Momparler, Richard L

    2008-01-01

    The inactivation of tumor suppressor genes (TSGs) by aberrant DNA methylation plays an important role in the development of malignancy. Since this epigenetic change is reversible, it is a potential target for chemotherapeutic intervention using an inhibitor of DNA methylation, such as 5-aza-2'-deoxycytidine (DAC). Although clinical studies show that DAC has activity against hematological malignancies, the optimal dose-schedule of this epigenetic agent still needs to be established. Clonogenic assays were performed on leukemic and tumor cell lines to evaluate the in vitro antineoplastic activity of DAC. The reactivation of TSGs and inhibition of DNA methylation by DAC were investigated by reverse transcriptase-PCR and Line-1 assays. The in vivo antineoplastic activity of DAC administered as an i.v. infusion was evaluated in mice with murine L1210 leukemia by measurement of survival time, and in mice bearing murine EMT6 mammary tumor by excision of tumor after chemotherapy for an in vitro clonogenic assay. Increasing the DAC concentration and duration of exposure produced a greater loss of clonogenicity for both human leukemic and tumor cell lines. The reactivation of the TSGs (p57KIP2 in HL-60 leukemic cells and p16CDKN2A in Calu-6 lung carcinoma cells) and the inhibition of global DNA methylation in HL-60 leukemic cells increased with DAC concentration. In mice with L1210 leukemia and in mice bearing EMT6 tumors, the antineoplastic action of DAC also increased with the dose. The plasma level of DAC that produced a very potent antineoplastic effect in mice with leukemia or solid tumors was > 200 ng/ml (> 1 μM). We have shown that intensification of the DAC dose markedly increased its antineoplastic activity in mouse models of cancer. Our data also show that there is a good correlation between the concentrations of DAC that reduce in vitro clonogenicity, reactivate TSGs and inhibit DNA methylation. These results suggest that the antineoplastic action of DAC is

  4. Recursive SVM biomarker selection for early detection of breast cancer in peripheral blood.

    Science.gov (United States)

    Zhang, Fan; Kaufman, Howard L; Deng, Youping; Drabier, Renee

    2013-01-01

    Breast cancer is worldwide the second most common type of cancer after lung cancer. Traditional mammography and Tissue Microarray has been studied for early cancer detection and cancer prediction. However, there is a need for more reliable diagnostic tools for early detection of breast cancer. This can be a challenge due to a number of factors and logistics. First, obtaining tissue biopsies can be difficult. Second, mammography may not detect small tumors, and is often unsatisfactory for younger women who typically have dense breast tissue. Lastly, breast cancer is not a single homogeneous disease but consists of multiple disease states, each arising from a distinct molecular mechanism and having a distinct clinical progression path which makes the disease difficult to detect and predict in early stages. In the paper, we present a Support Vector Machine based on Recursive Feature Elimination and Cross Validation (SVM-RFE-CV) algorithm for early detection of breast cancer in peripheral blood and show how to use SVM-RFE-CV to model the classification and prediction problem of early detection of breast cancer in peripheral blood.The training set which consists of 32 health and 33 cancer samples and the testing set consisting of 31 health and 34 cancer samples were randomly separated from a dataset of peripheral blood of breast cancer that is downloaded from Gene Express Omnibus. First, we identified the 42 differentially expressed biomarkers between "normal" and "cancer". Then, with the SVM-RFE-CV we extracted 15 biomarkers that yield zero cross validation score. Lastly, we compared the classification and prediction performance of SVM-RFE-CV with that of SVM and SVM Recursive Feature Elimination (SVM-RFE). We found that 1) the SVM-RFE-CV is suitable for analyzing noisy high-throughput microarray data, 2) it outperforms SVM-RFE in the robustness to noise and in the ability to recover informative features, and 3) it can improve the prediction performance (Area Under

  5. Long-term exposure to estrogen enhances chemotherapeutic efficacy potentially through epigenetic mechanism in human breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Yu-Wei Chang

    Full Text Available Chemotherapy is the most common clinical option for treatment of breast cancer. However, the efficacy of chemotherapy depends on the age of breast cancer patients. Breast tissues are estrogen responsive and the levels of ovarian estrogen vary among the breast cancer patients primarily between pre- and post-menopausal age. Whether this age-dependent variation in estrogen levels influences the chemotherapeutic efficacy in breast cancer patients is not known. Therefore, the objective of this study was to evaluate the effects of natural estrogen 17 beta-estradiol (E2 on the efficacy of chemotherapeutic drugs in breast cancer cells. Estrogen responsive MCF-7 and T47D breast cancer cells were long-term exposed to 100 pg/ml estrogen, and using these cells the efficacy of chemotherapeutic drugs doxorubicin and cisplatin were determined. The result of cell viability and cell cycle analysis revealed increased sensitivities of doxorubicin and cisplatin in estrogen-exposed MCF-7 and T47D cells as compared to their respective control cells. Gene expression analysis of cell cycle, anti-apoptosis, DNA repair, and drug transporter genes further confirmed the increased efficacy of chemotherapeutic drugs in estrogen-exposed cells at molecular level. To further understand the role of epigenetic mechanism in enhanced chemotherapeutic efficacy by estrogen, cells were pre-treated with epigenetic drugs, 5-aza-2-deoxycytidine and Trichostatin A prior to doxorubicin and cisplatin treatments. The 5-aza-2 deoxycytidine pre-treatment significantly decreased the estrogen-induced efficacy of doxorubicin and cisplatin, suggesting the role of estrogen-induced hypermethylation in enhanced sensitivity of these drugs in estrogen-exposed cells. In summary, the results of this study revealed that sensitivity to chemotherapy depends on the levels of estrogen in breast cancer cells. Findings of this study will have clinical implications in selecting the chemotherapy strategies for

  6. Strategies to design clinical studies to identify predictive biomarkers in cancer research.

    Science.gov (United States)

    Perez-Gracia, Jose Luis; Sanmamed, Miguel F; Bosch, Ana; Patiño-Garcia, Ana; Schalper, Kurt A; Segura, Victor; Bellmunt, Joaquim; Tabernero, Josep; Sweeney, Christopher J; Choueiri, Toni K; Martín, Miguel; Fusco, Juan Pablo; Rodriguez-Ruiz, Maria Esperanza; Calvo, Alfonso; Prior, Celia; Paz-Ares, Luis; Pio, Ruben; Gonzalez-Billalabeitia, Enrique; Gonzalez Hernandez, Alvaro; Páez, David; Piulats, Jose María; Gurpide, Alfonso; Andueza, Mapi; de Velasco, Guillermo; Pazo, Roberto; Grande, Enrique; Nicolas, Pilar; Abad-Santos, Francisco; Garcia-Donas, Jesus; Castellano, Daniel; Pajares, María J; Suarez, Cristina; Colomer, Ramon; Montuenga, Luis M; Melero, Ignacio

    2017-02-01

    The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework-the DESIGN guidelines-to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. Circulating exosomes and exosomal microRNAs as biomarkers in gastrointestinal cancer.

    Science.gov (United States)

    Nedaeinia, R; Manian, M; Jazayeri, M H; Ranjbar, M; Salehi, R; Sharifi, M; Mohaghegh, F; Goli, M; Jahednia, S H; Avan, A; Ghayour-Mobarhan, M

    2017-02-01

    The most important biological function of exosomes is their possible use as biomarkers in clinical diagnosis. Compared with biomarkers identified in conventional specimens such as serum or urine, exosomal biomarkers provide the highest amount of sensitivity and specificity, which can be attributed to their excellent stability. Exosomes, which harbor different types of proteins, nucleic acids and lipids, are present in almost all bodily fluids. The molecular constituents of exosomes, especially exosomal proteins and microRNAs (miRNAs), are promising as biomarkers in clinical diagnosis. This discovery that exosomes also contain messenger RNAs and miRNAs shows that they could be carriers of genetic information. Although the majority of RNAs found in exosomes are degraded RNA fragments with a length of exosomal miRNAs have been found to be associated with certain diseases. Several studies have pointed out miRNA contents of circulating exosomes that are similar to those of originating cancer cells. In this review, the recent advances in circulating exosomal miRNAs as biomarkers in gastrointestinal cancers are discussed. These studies indicated that miRNAs can be detected in exosomes isolated from body fluids such as saliva, which suggests potential advantages of using exosomal miRNAs as noninvasive novel biomarkers.

  8. The endothelial lipase protein is promising urinary biomarker for diagnosis of gastric cancer.

    Science.gov (United States)

    Dong, Xueyan; Wang, Guoqing; Zhang, Guoqing; Ni, Zhaohui; Suo, Jian; Cui, Juan; Cui, Ai; Yang, Qing; Xu, Ying; Li, Fan

    2013-03-19

    Gastric cancer is one of the most common malignant tumors in the world. Finding effective diagnostic biomarkers in urine or serum would represent the most ideal solution to detecting gastric cancer during annual physical examination. This study was to evaluate the potential of endothelial lipase (EL) as a urinary biomarker for diagnosis of gastric cancer. The expression levels of EL was measured using Western blotting and immunohistochemical staining experiments on (tissue, serum, and urine) samples of gastric cancer patients versus healthy people. We also checked the EL levels in the urine samples of other cancer types (lung, colon and rectum cancers) and benign lesions (gastritis and gastric leiomyoma) to check if EL was specific to gastric cancer. We observed a clear separation between the EL expression levels in the urine samples of 90 gastric cancer patients and of 57 healthy volunteers. It was approximately 9.9 fold average decrease of the EL expression levels in the urine samples of gastric cancer compared to the healthy controls (P cancer. Interestingly, the expression levels of EL in tissue and serum samples were not nearly as discriminative as in urine samples (P = 0.90 and P = 0.79). In immunohistochemical experiments, positive expression of the EL protein was found in 67% (8/12) of gastric adjacent noncancerous and in 58% (7/12) of gastric cancer samples. There was no significant statistical in the expression levels of this protein between the gastric cancer and the matching noncancerous tissues (P =0.67). The urinary EL as a highly accurate gastric cancer biomarker that is potentially applicable to the general screening with high sensitivity and specificity. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4527331618757552.

  9. Up-regulation of HOXB cluster genes are epigenetically regulated in tamoxifen-resistant MCF7 breast cancer cells.

    Science.gov (United States)

    Yang, Seoyeon; Lee, Ji-Yeon; Hur, Ho; Oh, Ji Hoon; Kim, Myoung Hee

    2018-05-28

    Tamoxifen (TAM) is commonly used to treat estrogen receptor (ER)-positive breast cancer. Despite the remarkable benefits, resistance to TAM presents a serious therapeutic challenge. Since several HOX transcription factors have been proposed as strong candidates in the development of resistance to TAM therapy in breast cancer, we generated an in vitro model of acquired TAM resistance using ER-positive MCF7 breast cancer cells (MCF7-TAMR), and analyzed the expression pattern and epigenetic states of HOX genes. HOXB cluster genes were uniquely up-regulated in MCF7-TAMR cells. Survival analysis of in slico data showed the correlation of high expression of HOXB genes with poor response to TAM in ER-positive breast cancer patients treated with TAM. Gain- and loss-of-function experiments showed that the overexpression of multi HOXB genes in MCF7 renders cancer cells more resistant to TAM, whereas the knockdown restores TAM sensitivity. Furthermore, activation of HOXB genes in MCF7-TAMR was associated with histone modifications, particularly the gain of H3K9ac. These findings imply that the activation of HOXB genes mediate the development of TAM resistance, and represent a target for development of new strategies to prevent or reverse TAM resistance.

  10. Quantitative proteomic analysis of microdissected oral epithelium for cancer biomarker discovery.

    Science.gov (United States)

    Xiao, Hua; Langerman, Alexander; Zhang, Yan; Khalid, Omar; Hu, Shen; Cao, Cheng-Xi; Lingen, Mark W; Wong, David T W

    2015-11-01

    Specific biomarkers are urgently needed for the detection and progression of oral cancer. The objective of this study was to discover cancer biomarkers from oral epithelium through utilizing high throughput quantitative proteomics approaches. Morphologically malignant, epithelial dysplasia, and adjacent normal epithelial tissues were laser capture microdissected (LCM) from 19 patients and used for proteomics analysis. Total proteins from each group were extracted, digested and then labelled with corresponding isobaric tags for relative and absolute quantitation (iTRAQ). Labelled peptides from each sample were combined and analyzed by liquid chromatography-mass spectrometry (LC-MS/MS) for protein identification and quantification. In total, 500 proteins were identified and 425 of them were quantified. When compared with adjacent normal oral epithelium, 17 and 15 proteins were consistently up-regulated or down-regulated in malignant and epithelial dysplasia, respectively. Half of these candidate biomarkers were discovered for oral cancer for the first time. Cornulin was initially confirmed in tissue protein extracts and was further validated in tissue microarray. Its presence in the saliva of oral cancer patients was also explored. Myoglobin and S100A8 were pre-validated by tissue microarray. These data demonstrated that the proteomic biomarkers discovered through this strategy are potential targets for oral cancer detection and salivary diagnostics. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Long non-coding RNA PVT1: Emerging biomarker in digestive system cancer.

    Science.gov (United States)

    Zhou, Dan-Dan; Liu, Xiu-Fen; Lu, Cheng-Wei; Pant, Om Prakash; Liu, Xiao-Dong

    2017-12-01

    The digestive system cancers are leading cause of cancer-related death worldwide, and have high risks of morbidity and mortality. More and more long non-coding RNAs (lncRNAs) have been studied to be abnormally expressed in cancers and play a key role in the process of digestive system tumour progression. Plasmacytoma variant translocation 1 (PVT1) seems fairly novel. Since 1984, PVT1 was identified to be an activator of MYC in mice. Its role in human tumour initiation and progression has long been a subject of interest. The expression of PVT1 is elevated in digestive system cancers and correlates with poor prognosis. In this review, we illustrate the various functions of PVT1 during the different stages in the complex process of digestive system tumours (including oesophageal cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma and pancreatic cancer). The growing evidence shows the involvement of PVT1 in both proliferation and differentiation process in addition to its involvement in epithelial to mesenchymal transition (EMT). These findings lead us to conclude that PVT1 promotes proliferation, survival, invasion, metastasis and drug resistance in digestive system cancer cells. We will also discuss PVT1's potential in diagnosis and treatment target of digestive system cancer. There was a great probability PVT1 could be a novel biomarker in screening tumours, prognosis biomarkers and future targeted therapy to improve the survival rate in cancer patients. © 2017 John Wiley & Sons Ltd.

  12. Lung Cancer Signature Biomarkers: tissue specific semantic similarity based clustering of Digital Differential Display (DDD data

    Directory of Open Access Journals (Sweden)

    Srivastava Mousami

    2012-11-01

    Full Text Available Abstract Background The tissue-specific Unigene Sets derived from more than one million expressed sequence tags (ESTs in the NCBI, GenBank database offers a platform for identifying significantly and differentially expressed tissue-specific genes by in-silico methods. Digital differential display (DDD rapidly creates transcription profiles based on EST comparisons and numerically calculates, as a fraction of the pool of ESTs, the relative sequence abundance of known and novel genes. However, the process of identifying the most likely tissue for a specific disease in which to search for candidate genes from the pool of differentially expressed genes remains difficult. Therefore, we have used ‘Gene Ontology semantic similarity score’ to measure the GO similarity between gene products of lung tissue-specific candidate genes from control (normal and disease (cancer sets. This semantic similarity score matrix based on hierarchical clustering represents in the form of a dendrogram. The dendrogram cluster stability was assessed by multiple bootstrapping. Multiple bootstrapping also computes a p-value for each cluster and corrects the bias of the bootstrap probability. Results Subsequent hierarchical clustering by the multiple bootstrapping method (α = 0.95 identified seven clusters. The comparative, as well as subtractive, approach revealed a set of 38 biomarkers comprising four distinct lung cancer signature biomarker clusters (panel 1–4. Further gene enrichment analysis of the four panels revealed that each panel represents a set of lung cancer linked metastasis diagnostic biomarkers (panel 1, chemotherapy/drug resistance biomarkers (panel 2, hypoxia regulated biomarkers (panel 3 and lung extra cellular matrix biomarkers (panel 4. Conclusions Expression analysis reveals that hypoxia induced lung cancer related biomarkers (panel 3, HIF and its modulating proteins (TGM2, CSNK1A1, CTNNA1, NAMPT/Visfatin, TNFRSF1A, ETS1, SRC-1, FN1, APLP2, DMBT1

  13. Searching for new biomarkers in ovarian cancer patients

    DEFF Research Database (Denmark)

    Hentze, Julie L.; Høgdall, Claus; Kjær, Susanne K.

    2017-01-01

    , by predicting which patients will benefit from specific treatment strategies. The Mermaid III project is consisting of 3 parts including “Early detection, screening and long-term survival,” “Biomarkers and/or prognostic markers” and “The infection theory.” The present paper gives an overview of the part...

  14. Can Biomarker Assessment on Circulating Tumor Cells Help Direct Therapy in Metastatic Breast Cancer?

    Directory of Open Access Journals (Sweden)

    Natalie Turner

    2014-03-01

    Full Text Available Circulating tumor cell (CTC count has prognostic significance in metastatic breast cancer, but the predictive utility of CTCs is uncertain. Molecular studies on CTCs have often been limited by a low number of CTCs isolated from a high background of leukocytes. Improved enrichment techniques are now allowing molecular characterisation of single CTCs, whereby molecular markers on single CTCs may provide a real-time assessment of tumor biomarker status from a blood test or “liquid biopsy”, potentially negating the need for a more invasive tissue biopsy. The predictive ability of CTC biomarker analysis has predominantly been assessed in relation to HER2, with variable and inconclusive results. Limited data exist for other biomarkers, such as the estrogen receptor. In addition to the need to define and validate the most accurate and reproducible method for CTC molecular analysis, the clinical relevance of biomarkers, including gain of HER2 on CTC after HER2 negative primary breast cancer, remains uncertain. This review summarises the currently available data relating to biomarker evaluation on CTCs and its role in directing management in metastatic breast cancer, discusses limitations, and outlines measures that may enable future development of this approach.

  15. Fusion peptides from oncogenic chimeric proteins as putative specific biomarkers of cancer.

    Science.gov (United States)

    Conlon, Kevin P; Basrur, Venkatesha; Rolland, Delphine; Wolfe, Thomas; Nesvizhskii, Alexey I; MacCoss, Michael J; Lim, Megan S; Elenitoba-Johnson, Kojo S J

    2013-10-01

    Chromosomal translocations encoding chimeric fusion proteins constitute one of the most common mechanisms underlying oncogenic transformation in human cancer. Fusion peptides resulting from such oncogenic chimeric fusions, though unique to specific cancer subtypes, are unexplored as cancer biomarkers. Here we show, using an approach termed fusion peptide multiple reaction monitoring mass spectrometry, the direct identification of different cancer-specific fusion peptides arising from protein chimeras that are generated from the juxtaposition of heterologous genes fused by recurrent chromosomal translocations. Using fusion peptide multiple reaction monitoring mass spectrometry in a clinically relevant scenario, we demonstrate the specific, sensitive, and unambiguous detection of a specific diagnostic fusion peptide in clinical samples of anaplastic large cell lymphoma, but not in a diverse array of benign lymph nodes or other forms of primary malignant lymphomas and cancer-derived cell lines. Our studies highlight the utility of fusion peptides as cancer biomarkers and carry broad implications for the use of protein biomarkers in cancer detection and monitoring.

  16. Effects of epigenetic-based anti-cancer drugs in leukaemia and multiple myeloma cells

    Czech Academy of Sciences Publication Activity Database

    Jugová, Alžbeta; Galiová-Šustáčková, Gabriela; Legartová, Soňa; Stixová, Lenka; Kozubek, Stanislav; Bártová, Eva

    2011-01-01

    Roč. 35, č. 12 (2011), 1195-1203 ISSN 1065-6995 R&D Projects: GA MŠk(CZ) LC06027; GA MŠk(CZ) ME 919; GA ČR(CZ) GAP302/10/1022; GA MŠk(CZ) LD11020 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : epigenetics * histone code * leukaemia cells Subject RIV: BO - Biophysics Impact factor: 1.482, year: 2011

  17. Potential Biomarker of L type Amino Acid Transporter 1 in Breast Cancer Progression

    International Nuclear Information System (INIS)

    Liang, Zhongxing; Cho, Heidi T.; Williams, Larry; Zhu, Aizhi; Liang, Ke; Huang, Ke; Wu, Hui; Jiang, Chunsu; Hong, Samuel; Crowe, Ronald; Goodman, Mark M.; Shim, Hyunsuk

    2011-01-01

    L type amino acid transporter 1 (LAT1) is essential for the transport of large neutral amino acids. However, its role in breast cancer growth remains largely unknown. The purpose of the study is to investigate whether LAT1 is a potential biomarker for the diagnosis and treatment of breast cancer. LAT1 mRNA and protein levels in breast cancer cell lines and tissues were analyzed. In addition, the effects of targeting LAT1 for the inhibition of breast cancer cell tumorigenesis were assessed with soft agar assay. The imaging of xenograft with 1 amino 3 [ 18F ]fluorocyclo butane 1 carboxylic acid ([ 18F ]FACBC) PET was assessed for its diagnostic biomarker potential. Normal breast tissue or low malignant cell lines expressed low levels of LAT1 mRNA and protein, while highly malignant cancer cell lines and high grade breast cancer tissue expressed high levels of LAT1. In addition, higher expression levels of LAT1 in breast cancer tissues were consistent with advanced stage breast cancer. Furtermore, the blockade of LAT1 with its inhibitor, 2 amino bicyclo[2.2.1]heptane 2 carboxylic acid (BCH), or the knockdown of LAT1 with siRNA, inhibited proliferation and tumorigenesis of breast cancer cells. A leucine analog, [ 18F ]FACBC, has been demonstrated to be an excellent PET tracer for the non invasive imaging og malignant breast cancer using an orthotopic animal model. The overexpression of LAT1 is required for the progression of breast cancer. LAT1 represents a potential biomarker for therapy and diagnosis of breast cancer. [ 18F ]FACBC that correlates with LAT1 function is a potential PET tracer for malignant breast tumor imaging

  18. The clinical impact of recent advances in LC-MS for cancer biomarker discovery and verification

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Hui; Shi, Tujin; Qian, Wei-Jun; Liu, Tao; Kagan, Jacob; Srivastava, Sudhir; Smith, Richard D.; Rodland, Karin D.; Camp, David G.

    2015-12-04

    Mass spectrometry-based proteomics has become an indispensable tool in biomedical research with broad applications ranging from fundamental biology, systems biology, and biomarker discovery. Recent advances in LC-MS have made it become a major technology in clinical applications, especially in cancer biomarker discovery and verification. To overcome the challenges associated with the analysis of clinical samples, such as extremely wide dynamic range of protein concentrations in biofluids and the need to perform high throughput and accurate quantification, significant efforts have been devoted to improve the overall performance of LC-MS bases clinical proteomics. In this review, we summarize the recent advances in LC-MS in the aspect of cancer biomarker discovery and quantification, and discuss its potentials, limitations, and future perspectives.

  19. Environmental toxicants, incidence of degenerative diseases, and therapies from the epigenetic point of view.

    Science.gov (United States)

    Hodjat, Mahshid; Rahmani, Soheila; Khan, Fazlullah; Niaz, Kamal; Navaei-Nigjeh, Mona; Mohammadi Nejad, Solmaz; Abdollahi, Mohammad

    2017-07-01

    Epigenotoxicology is an emerging field of study that investigates the non-genotoxic epigenetic effects of environmental toxicants resulting in alteration of normal gene expression and disruption of cell function. Recent findings on the role of toxicant-induced epigenetic modifications in the development of degenerative diseases have opened up a promising research direction to explore epigenetic therapy approaches and related prognostic biomarkers. In this review, we presented comprehensive data on epigenetic alterations identified in various diseases, including cancer, autoimmune disorders, pulmonary conditions as well as cardiovascular, gastrointestinal and bone disease. Although data on abnormalities of DNA methylation and their role in the development of diseases are abundant, less is known about the impact of histone modifications and microRNA expressions. Further, we discussed the effects of selected common environmental toxicants on epigenetic modifications and their association with particular abnormalities. A number of different environmental toxicants have been identified for their role in aberrant DNA methylation, histone modifications, and microRNA expression. Such epigenetic effects were shown to be tissue-type specific and highly associated with the level and duration of exposure. Finally, we described present and future therapeutic strategies, including medicines and dietary compounds for combating the toxicant-induced epigenetic alterations. There are currently seven histone deacetylase inhibitors and two DNA methyltransferase inhibitors approved for clinical use and many other promising candidates are in preclinical and clinical testing. Dietary compounds are thought to be the effective and safe strategies for treating and prevention of epigenetic pathophysiological conditions. Still more concentrated epigenetic researches are required for evaluation of chemical toxicity and identifying the causal association between key epigenetic alteration and

  20. Defining glycoprotein cancer biomarkers by MS in conjunction with glycoprotein enrichment.

    Science.gov (United States)

    Song, Ehwang; Mechref, Yehia

    2015-01-01

    Protein glycosylation is an important and common post-translational modification. More than 50% of human proteins are believed to be glycosylated to modulate the functionality of proteins. Aberrant glycosylation has been correlated to several diseases, such as inflammatory skin diseases, diabetes mellitus, cardiovascular disorders, rheumatoid arthritis, Alzheimer's and prion diseases, and cancer. Many approved cancer biomarkers are glycoproteins which are not highly abundant proteins. Therefore, effective qualitative and quantitative assessment of glycoproteins entails enrichment methods. This chapter summarizes glycoprotein enrichment methods, including lectin affinity, immunoaffinity, hydrazide chemistry, hydrophilic interaction liquid chromatography, and click chemistry. The use of these enrichment approaches in assessing the qualitative and quantitative changes of glycoproteins in different types of cancers are presented and discussed. This chapter highlights the importance of glycoprotein enrichment techniques for the identification and characterization of new reliable cancer biomarkers.

  1. Molecular biomarker set for early detection of ovarian cancer

    KAUST Repository

    Bajic, Vladimir B.

    2015-06-16

    Embodiments of the present invention concern methods and compositions related to detection of ovarian cancer, including detection of the stage of ovarian cancer, in some cases. In particular, the invention encompasses use of expression of TFAP2A and in some embodiments CA125 and/or E2F5 to identify ovarian cancer, including detecting mRNA and/or protein levels of the respective gene products. Kits for detection of ovarian cancer are also described.

  2. Molecular biomarker set for early detection of ovarian cancer

    KAUST Repository

    Bajic, Vladimir B.; Kaur, Mandeep

    2015-01-01

    Embodiments of the present invention concern methods and compositions related to detection of ovarian cancer, including detection of the stage of ovarian cancer, in some cases. In particular, the invention encompasses use of expression of TFAP2A and in some embodiments CA125 and/or E2F5 to identify ovarian cancer, including detecting mRNA and/or protein levels of the respective gene products. Kits for detection of ovarian cancer are also described.

  3. Exercise, weight loss and biomarkers for breast cancer risk

    NARCIS (Netherlands)

    Gemert, W.A.M. van

    2015-01-01

    Background: Postmenopausal breast cancer is the most prevalent cancer in Western women. There are several known risk factors for postmenopausal breast cancer of which few are lifestyle-related and, thereby, modifiable. These risk factors provide an opportunity for primary prevention. In this thesis,

  4. Sequencing-based breast cancer diagnostics as an alternative to routine biomarkers.

    Science.gov (United States)

    Rantalainen, Mattias; Klevebring, Daniel; Lindberg, Johan; Ivansson, Emma; Rosin, Gustaf; Kis, Lorand; Celebioglu, Fuat; Fredriksson, Irma; Czene, Kamila; Frisell, Jan; Hartman, Johan; Bergh, Jonas; Grönberg, Henrik

    2016-11-30

    Sequencing-based breast cancer diagnostics have the potential to replace routine biomarkers and provide molecular characterization that enable personalized precision medicine. Here we investigate the concordance between sequencing-based and routine diagnostic biomarkers and to what extent tumor sequencing contributes clinically actionable information. We applied DNA- and RNA-sequencing to characterize tumors from 307 breast cancer patients with replication in up to 739 patients. We developed models to predict status of routine biomarkers (ER, HER2,Ki-67, histological grade) from sequencing data. Non-routine biomarkers, including mutations in BRCA1, BRCA2 and ERBB2(HER2), and additional clinically actionable somatic alterations were also investigated. Concordance with routine diagnostic biomarkers was high for ER status (AUC = 0.95;AUC(replication) = 0.97) and HER2 status (AUC = 0.97;AUC(replication) = 0.92). The transcriptomic grade model enabled classification of histological grade 1 and histological grade 3 tumors with high accuracy (AUC = 0.98;AUC(replication) = 0.94). Clinically actionable mutations in BRCA1, BRCA2 and ERBB2(HER2) were detected in 5.5% of patients, while 53% had genomic alterations matching ongoing or concluded breast cancer studies. Sequencing-based molecular profiling can be applied as an alternative to histopathology to determine ER and HER2 status, in addition to providing improved tumor grading and clinically actionable mutations and molecular subtypes. Our results suggest that sequencing-based breast cancer diagnostics in a near future can replace routine biomarkers.

  5. Epigenetic control of the basal-like gene expression profile via Interleukin-6 in breast cancer cells

    Directory of Open Access Journals (Sweden)

    Mitrugno Valentina

    2010-11-01

    Full Text Available Abstract Background Basal-like carcinoma are aggressive breast cancers that frequently carry p53 inactivating mutations, lack estrogen receptor-α (ERα and express the cancer stem cell markers CD133 and CD44. These tumors also over-express Interleukin 6 (IL-6, a pro-inflammatory cytokine that stimulates the growth of breast cancer stem/progenitor cells. Results Here we show that p53 deficiency in breast cancer cells induces a loss of methylation at IL-6 proximal promoter region, which is maintained by an IL-6 autocrine loop. IL-6 also elicits the loss of methylation at the CD133 promoter region 1 and of CD44 proximal promoter, enhancing CD133 and CD44 gene transcription. In parallel, IL-6 induces the methylation of estrogen receptor (ERα promoter and the loss of ERα mRNA expression. Finally, IL-6 induces the methylation of IL-6 distal promoter and of CD133 promoter region 2, which harbour putative repressor regions. Conclusion We conclude that IL-6, whose methylation-dependent autocrine loop is triggered by the inactivation of p53, induces an epigenetic reprogramming that drives breast carcinoma cells towards a basal-like/stem cell-like gene expression profile.

  6. LncRNA-SNHG16 predicts poor prognosis and promotes tumor proliferation through epigenetically silencing p21 in bladder cancer.

    Science.gov (United States)

    Cao, Xianxiang; Xu, Jing; Yue, Dong

    2018-02-01

    More and more evidences have ensured the crucial functions of long non-coding RNAs (lncRNAs) in multiple tumors. It has been discovered that lncRNA-SNHG16 is involved in many tumors. Even so, it is still necessary to study SNHG16 comprehensively in bladder cancer. In terms of our study, the level of SNHG16 both in the tumor tissues and cell lines was measured and the relationship among SNHG16, clinicopathological traits and prognosis was explored. Interference assays were applied to determine the biological functions of SNHG16. It was discovered that the level of SNHG16 was evidently enhanced both in tissues and cell lines of bladder cancer. Patients with highly expressed SNHG16 suffered from poor overall survival. Multivariable Cox proportional hazards regression analysis implied that highly expressed SNHG16 could be used as an independent prognostic marker. It could be known from functional assays that silenced SNHG16 impaired cell proliferation, owing to the effects of SNHG16 on cell cycle and apoptosis. Finally, mechanism experiments revealed that SNHG16 could epigenetically silence the expression of p21. The facts above pointed out that lncRNA-SNHG16 might be quite vital for the diagnosis and development of bladder cancer, and could even become an important therapeutic target for bladder cancer.

  7. Urinary high molecular weight matrix metalloproteinases as non-invasive biomarker for detection of bladder cancer

    OpenAIRE

    Mohammed, Mohammed A; Seleim, Manar F; Abdalla, Mohga S; Sharada, Hayat M; Abdel Wahab, Abdel Hady A

    2013-01-01

    Background Matrix Metalloproteinases (MMPs) are key molecules for tumor growth, invasion and metastasis. Over-expression of different MMPs in tumor tissues can disturb the homeostasis and increase the level of various body fluids. Many MMPs including high molecular weights (HMWs) were detected in the urine of prostate and bladder cancer patients. Our aim here is to assess the usefulness of HMW MMPs as non invasive biomarkers in bilharzial bladder cancer in Egyptian patients. Methods The activ...

  8. Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error

    OpenAIRE

    Shipitsin, M; Small, C; Choudhury, S; Giladi, E; Friedlander, S; Nardone, J; Hussain, S; Hurley, A D; Ernst, C; Huang, Y E; Chang, H; Nifong, T P; Rimm, D L; Dunyak, J; Loda, M

    2014-01-01

    Background: Key challenges of biopsy-based determination of prostate cancer aggressiveness include tumour heterogeneity, biopsy-sampling error, and variations in biopsy interpretation. The resulting uncertainty in risk assessment leads to significant overtreatment, with associated costs and morbidity. We developed a performance-based strategy to identify protein biomarkers predictive of prostate cancer aggressiveness and lethality regardless of biopsy-sampling variation. Methods: Prostatectom...

  9. Biomarkers for Early Detection of Clinically Relevant Prostate Cancer. A Multi-Institutional Validation Trial

    Science.gov (United States)

    2016-10-01

    aim 2: Evaluate a panel of four-kallikrein plasma-based markers to determine the presence of or progression to clinically relevant prostate cancer...and sent to Genomic Health, Inc. for processing. Task 3: Analysis of scientific Aim 2: Evaluate a panel of four-kallikrein plasma-based markers to...site: FHCRC) PCA3 and the TMPRSS2:ERG fusion are prostate cancer-specific biomarkers that hold promise for stratifying risk in the setting of AS

  10. From the endometrium physiology to a comprehensive strategy for the discovery of ovarian cancer biomarkers

    OpenAIRE

    Janos L. Tanyi; Nathalie Scholler

    2011-01-01

    The development of comprehensive strategies for biomarker discovery of gynecological cancers is needed. The unique physiology of the female genital track revolves around ovulatory cycles ending by the proteolysis of the endometrium triggered by progesterone decline during the last part of the luteal phase. Building on the known link between incessant ovulation and ovarian cancer, we hypothesize that life-long menstruations could damage neighboring organs such as fallopian tubes, ovaries and p...

  11. A Novel Electrochemical Microfluidic Chip Combined with Multiple Biomarkers for Early Diagnosis of Gastric Cancer

    Science.gov (United States)

    Xie, Yao; Zhi, Xiao; Su, Haichuan; Wang, Kan; Yan, Zhen; He, Nongyue; Zhang, Jingpu; Chen, Di; Cui, Daxiang

    2015-12-01

    Early diagnosis is very important to improve the survival rate of patients with gastric cancer and to understand the biology of cancer. In order to meet the clinical demands for early diagnosis of gastric cancer, we developed a disposable easy-to-use electrochemical microfluidic chip combined with multiple antibodies against six kinds of biomarkers (carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), Helicobacter pylori CagA protein (H.P.), P53oncoprotein (P53), pepsinogen I (PG I), and PG-II). The six kinds of biomarkers related to gastric cancer can be detected sensitively and synchronously in a short time. The specially designed three electrodes system enables cross-contamination to be avoided effectively. The linear ranges of detection of the electrochemical microfluidic chip were as follows: 0.37-90 ng mL-1 for CEA, 10.75-172 U mL-1 for CA19-9, 10-160 U L-1 for H.P., 35-560 ng mL-1 for P53, 37.5-600 ng mL-1 for PG I, and 2.5-80 ng mL-1for PG II. This method owns better sensitivity compared with enzyme-linked immunosorbent assay (ELISA) results of 394 specimens of gastric cancer sera. Furthermore, we established a multi-index prediction model based on the six kinds of biomarkers for predicting risk of gastric cancer. In conclusion, the electrochemical microfluidic chip for detecting multiple biomarkers has great potential in applications such as early screening of gastric cancer patients, and therapeutic evaluation, and real-time dynamic monitoring the progress of gastric cancer in near future.

  12. Association between changes in fat distribution and biomarkers for breast cancer

    NARCIS (Netherlands)

    van Gemert, Willemijn A.M.; Monninkhof, Evelyn M.; May, Anne M.; Elias, Sjoerd G.; Van Der Palen, Job; Veldhuis, Wouter B.; Stapper, Maaike; Stellato, Rebecca K.; Schuit, Jantine A.; Peeters, Petra H.

    2017-01-01

    We assessed the associations between changes in total and abdominal fat and changes in biomarkers for breast cancer risk using data of the SHAPE-2 trial. In the SHAPE-2 trial, 243 postmenopausal overweight women were included. The intervention in this trial consisted of 5-6 kg weight loss either by

  13. Nanobody medicated immunoassay for ultrasensitive detection of cancer biomarker alpha-fetoprotein.

    Science.gov (United States)

    Chen, Jing; He, Qing-hua; Xu, Yang; Fu, Jin-heng; Li, Yan-ping; Tu, Zhui; Wang, Dan; Shu, Mei; Qiu, Yu-lou; Yang, Hong-wei; Liu, Yuan-yuan

    2016-01-15

    Immunoassay for cancer biomarkers plays an important role in cancer prevention and early diagnosis. To the development of immunoassay, the quality and stability of applied antibody is one of the key points to obtain reliability and high sensitivity for immunoassay. The main purpose of this study was to develop a novel immunoassay for ultrasensitive detection of cancer biomarker alpha-fetoprotein (AFP) based on nanobody against AFP. Two nanobodies which bind to AFP were selected from a phage display nanobody library by biopanning strategy. The prepared nanobodies are clonable, thermally stable and applied in both sandwich enzyme linked immunoassay (ELISA) and immuno-PCR assay for ultrasensitive detection of AFP. The limit detection of sandwich ELISA setup with optimized nanobodies was 0.48ng mL(-1), and the half of saturation concentration (SC50) value was 6.68±0.56ng mL(-1). These nanobodies were also used to develop an immuno-PCR assay for ultrasensitive detection of AFP, its limit detection values was 0.005ng mL(-1), and the linear range was 0.01-10,000ng mL(-1). These established immunoassays based on nanobodies were highly specific to AFP and with negligible cross reactivity with other tested caner biomarkers. Furthermore, this novel concept of nanobodies mediated immunoassay may provide potential applications in a general method for the ultrasensitive detection of various cancer biomarkers. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Association between changes in fat distribution and biomarkers for breast cancer.

    NARCIS (Netherlands)

    van Gemert, Willemijn A; Monninkhof, Evelyn M; May, Anne M; Elias, Sjoerd G; van der Palen, Job; Veldhuis, Wouter; Stapper, Maaike; Stellato, Rebecca K; Schuit, Jantine A; Peeters, Petra H

    We assessed the associations between changes in total and abdominal fat and changes in biomarkers for breast cancer risk using data of the SHAPE-2 trial. In the SHAPE-2 trial, 243 postmenopausal overweight women were included. The intervention in this trial consisted of 5-6 kg weight loss either by

  15. Plasma alkylresorcinols, biomarkers of whole-grain wheat and rye intake, and incidence of colorectal cancer

    NARCIS (Netherlands)

    Kyrø, Cecilie; Olsen, Anja; Landberg, Rikard; Skeie, Guri; Loft, Steffen; Åman, Per; Leenders, Max; Dik, Vincent K.; Siersema, Peter D.; Pischon, Tobias; Christensen, Jane; Overvad, Kim; Boutron-Ruault, Marie Christine; Fagherazzi, Guy; Cottet, Vanessa; Kühn, Tilman; Chang-Claude, Jenny; Boeing, Heiner; Trichopoulou, Antonia; Bamia, Christina; Trichopoulos, Dimitrios; Palli, Domenico; Krogh, Vittorio; Tumino, Rosario; Vineis, Paolo; Panico, Salvatore; Peeters, Petra H.; Weiderpass, Elisabete; Bakken, Toril; Åsli, Lene Angell; Argüelles, Marcial; Jakszyn, Paula; Sánchez, María José; Amiano, Pilar; Huerta, José María; Barricarte, Aurelio; Ljuslinder, Ingrid; Palmqvist, Richard; Khaw, Kay Tee; Wareham, Nick; Key, Timothy J.; Travis, Ruth C.; Ferrari, Pietro; Freisling, Heinz; Jenab, Mazda; Gunter, Marc J.; Murphy, Neil; Riboli, Eilo; Tjønneland, Anne; Bueno-De-Mesquita, H. B.

    2014-01-01

    BackgroundFew studies have investigated the association between whole-grain intake and colorectal cancer. Because whole-grain intake estimation might be prone to measurement errors, more objective measures (eg, biomarkers) could assist in investigating such associations.MethodsThe association

  16. Proteomics pipeline for biomarker discovery of laser capture microdissected breast cancer tissue

    NARCIS (Netherlands)

    N.Q. Liu (Ning Qing); R.B.H. Braakman (René); C. Stingl (Christoph); T.M. Luider (Theo); J.W.M. Martens (John); J.A. Foekens (John); A. Umar (Arzu)

    2012-01-01

    textabstractMass spectrometry (MS)-based label-free proteomics offers an unbiased approach to screen biomarkers related to disease progression and therapy-resistance of breast cancer on the global scale. However, multi-step sample preparation can introduce large variation in generated data, while

  17. The Role of Biomarkers in Decreasing Risk of Cardiac Toxicity after Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Christine Henri

    2016-01-01

    Full Text Available With the improvement of cancer therapy, survival related to malignancy has improved, but the prevalence of long-term cardiotoxicity has also increased. Cancer therapies with known cardiac toxicity include anthracyclines, biologic agents (trastuzumab, and multikinase inhibitors (sunitinib. The most frequent presentation of cardiac toxicity is dilated cardiomyopathy associated with poorest prognosis. Monitoring of cardiac toxicity is commonly performed by assessment of left ventricular (LV ejection fraction, which requires a significant amount of myocardial damage to allow detection of cardiac toxicity. Accordingly, this creates the impetus to search for more sensitive and reproducible biomarkers of cardiac toxicity after cancer therapy. Different biomarkers have been proposed to that end, the most studied ones included troponin release resulting from cardiomyocyte damage and natriuretic peptides reflecting elevation in LV filling pressure and wall stress. Increase in the levels of troponin and natriuretic peptides have been correlated with cumulative dose of anthracycline and the degree of LV dysfunction. Troponin is recognized as a highly efficient predictor of early and chronic cardiac toxicity, but there remains some debate regarding the clinical usefulness of the measurement of natriuretic peptides because of divergent results. Preliminary data are available for other biomarkers targeting inflammation, endothelial dysfunction, myocardial ischemia, and neuregulin-1. The purpose of this article is to review the available data to determine the role of biomarkers in decreasing the risk of cardiac toxicity after cancer therapy.

  18. Antioxidant vitamins and cancer risk: is oxidative damage to DNA a relevant biomarker?

    DEFF Research Database (Denmark)

    Loft, Steffen; Møller, Peter; Cooke, Marcus S

    2008-01-01

    -dihydroguanine (8-oxodG) are increasingly being regarded as reliable biomarkers of oxidative stress and they may have a predictive value of cancer risk, although this needs to be established independently in several cohort studies. A survey of intervention studies of the ingestion of antioxidant-containing foods...

  19. Can Prostate Specific Antigen Be Used as New Biomarker for Early Diagnosis of Breast Cancer?

    Directory of Open Access Journals (Sweden)

    Seyed Mostafa Shiryazdi

    2015-09-01

    Conclusion: Plasma PSA level is not a reliable biomarker to diagnose breast cancer, though regarding existing scientific evidence, more comprehensive studies are required to consider other features of malignant samples so as to evaluate the role of PSA in differentiating breast neoplastic lesions in a more meticulous way based on the degree of tumor differentiation.

  20. Tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker in gastric cancer

    DEFF Research Database (Denmark)

    Grunnet, Mie; Mau-Sørensen, Morten; Brünner, Nils

    2013-01-01

    The value of Tissue Inhibitor of MetalloProteinase-1 (TIMP-1) as a biomarker in patients with gastric cancer (GC) is widely debated. The aim of this review is to evaluate available literature describing the association between levels of TIMP-1 in tumor tissue and/or blood and the prognosis...

  1. Early diagnostic protein biomarkers for breast cancer: how far have we come?

    NARCIS (Netherlands)

    Opstal - van Winden, A.W.J.; Vermeulen, R.C.H.; Peeters, P.H.M.; Beijnen, J.H.; van Gils, C.H.

    2012-01-01

    Many studies have used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to search for blood-based proteins that are related to the presence of breast cancer. We review the biomarkers

  2. Epigenetic silencing of serine protease HTRA1 drives polyploidy

    International Nuclear Information System (INIS)

    Schmidt, Nina; Irle, Inga; Ripkens, Kamilla; Lux, Vanda; Nelles, Jasmin; Johannes, Christian; Parry, Lee; Greenow, Kirsty; Amir, Sarah; Campioni, Mara; Baldi, Alfonso; Oka, Chio; Kawaichi, Masashi; Clarke, Alan R.; Ehrmann, Michael

    2016-01-01

    Increased numbers and improperly positioned centrosomes, aneuploidy or polyploidy, and chromosomal instability are frequently observed characteristics of cancer cells. While some aspects of these events and the checkpoint mechanisms are well studied, not all players have yet been identified. As the role of proteases other than the proteasome in tumorigenesis is an insufficiently addressed question, we investigated the epigenetic control of the widely conserved protease HTRA1 and the phenotypes of deregulation. Mouse embryonal fibroblasts and HCT116 and SW480 cells were used to study the mechanism of epigenetic silencing of HTRA1. In addition, using cell biological and genetic methods, the phenotypes of downregulation of HTRA1 expression were investigated. HTRA1 is epigenetically silenced in HCT116 colon carcinoma cells via the epigenetic adaptor protein MBD2. On the cellular level, HTRA1 depletion causes multiple phenotypes including acceleration of cell growth, centrosome amplification and polyploidy in SW480 colon adenocarcinoma cells as well as in primary mouse embryonic fibroblasts (MEFs). Downregulation of HTRA1 causes a number of phenotypes that are hallmarks of cancer cells suggesting that the methylation state of the HtrA1 promoter may be used as a biomarker for tumour cells or cells at risk of transformation. The online version of this article (doi:10.1186/s12885-016-2425-8) contains supplementary material, which is available to authorized users

  3. Serum biomarkers reflecting specific tumor tissue remodeling processes are valuable diagnostic tools for lung cancer

    International Nuclear Information System (INIS)

    Willumsen, Nicholas; Bager, Cecilie L; Leeming, Diana J; Smith, Victoria; Christiansen, Claus; Karsdal, Morten A; Dornan, David; Bay-Jensen, Anne-Christine

    2014-01-01

    Extracellular matrix (ECM) proteins, such as collagen type I and elastin, and intermediate filament (IMF) proteins, such as vimentin are modified and dysregulated as part of the malignant changes leading to disruption of tissue homeostasis. Noninvasive biomarkers that reflect such changes may have a great potential for cancer. Levels of matrix metalloproteinase (MMP) generated fragments of type I collagen (C1M), of elastin (ELM), and of citrullinated vimentin (VICM) were measured in serum from patients with lung cancer (n = 40), gastrointestinal cancer (n = 25), prostate cancer (n = 14), malignant melanoma (n = 7), chronic obstructive pulmonary disease (COPD) (n = 13), and idiopathic pulmonary fibrosis (IPF) (n = 10), as well as in age-matched controls (n = 33). The area under the receiver operating characteristics (AUROC) was calculated and a diagnostic decision tree generated from specific cutoff values. C1M and VICM were significantly elevated in lung cancer patients as compared with healthy controls (AUROC = 0.98, P < 0.0001) and other cancers (AUROC = 0.83 P < 0.0001). A trend was detected when comparing lung cancer with COPD+IPF. No difference could be seen for ELM. Interestingly, C1M and VICM were able to identify patients with lung cancer with a positive predictive value of 0.9 and an odds ratio of 40 (95% CI = 8.7–186, P < 0.0001). Biomarkers specifically reflecting degradation of collagen type I and citrullinated vimentin are applicable for lung cancer patients. Our data indicate that biomarkers reflecting ECM and IMF protein dysregulation are highly applicable in the lung cancer setting. We speculate that these markers may aid in diagnosing and characterizing patients with lung cancer

  4. Biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy: a novel strategy in drug development

    Directory of Open Access Journals (Sweden)

    Jan eStenvang

    2013-12-01

    Full Text Available Cancer is a leading cause of mortality worldwide and matters are only set to worsen as its incidence continues to rise. Traditional approaches to combat cancer include improved prevention, early diagnosis, optimized surgery, development of novel drugs and honing regimens of existing anti-cancer drugs. Although discovery and development of novel and effective anti-cancer drugs is a major research area, it is well known that oncology drug development is a lengthy process, extremely costly and with high attrition rates. Furthermore, those drugs that do make it through the drug development mill are often quite expensive, laden with severe side-effects and, unfortunately, to date, have only demonstrated minimal increases in overall survival. Therefore, a strong interest has emerged to identify approved non-cancer drugs that possess anti-cancer activity, thus shortcutting the development process. This research strategy is commonly known as drug repurposing or drug repositioning and provides a faster path to the clinics. We have developed and implemented a modification of the standard drug repurposing strategy that we review here; rather than investigating target-promiscuous non-cancer drugs for possible anti-cancer activity, we focus on the discovery of novel cancer indications for already approved chemotherapeutic anti-cancer drugs. Clinical implementation of this strategy is normally commenced at clinical phase II trials and includes pre-treated patients. As the response rates to any non-standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I inhibitors and topoisomerase I as a potential predictive biomarker as case in point.

  5. Circulating microRNAs as specific biomarkers for breast cancer detection.

    Directory of Open Access Journals (Sweden)

    Enders K O Ng

    Full Text Available We previously showed microRNAs (miRNAs in plasma are potential biomarkers for colorectal cancer detection. Here, we aimed to develop specific blood-based miRNA assay for breast cancer detection.TaqMan-based miRNA profiling was performed in tumor, adjacent non-tumor, corresponding plasma from breast cancer patients, and plasma from matched healthy controls. All putative markers identified were verified in a training set of breast cancer patients. Selected markers were validated in a case-control cohort of 170 breast cancer patients, 100 controls, and 95 other types of cancers and then blindly validated in an independent set of 70 breast cancer patients and 50 healthy controls. Profiling results showed 8 miRNAs were concordantly up-regulated and 1 miRNA was concordantly down-regulated in both plasma and tumor tissue of breast cancer patients. Of the 8 up-regulated miRNAs, only 3 were significantly elevated (p<0.0001 before surgery and reduced after surgery in the training set. Results from the validation cohort showed that a combination of miR-145 and miR-451 was the best biomarker (p<0.0001 in discriminating breast cancer from healthy controls and all other types of cancers. In the blind validation, these plasma markers yielded Receiver Operating Characteristic (ROC curve area of 0.931. The positive predictive value was 88% and the negative predictive value was 92%. Altered levels of these miRNAs in plasma have been detected not only in advanced stages but also early stages of tumors. The positive predictive value for ductal carcinoma in situ (DCIS cases was 96%.These results suggested that these circulating miRNAs could be a potential specific biomarker for breast cancer screening.

  6. Computational and Experimental Approaches to Cancer Biomarker Discovery

    DEFF Research Database (Denmark)

    Krzystanek, Marcin

    of a patient’s response to a particular treatment, thus helping to avoid unnecessary treatment and unwanted side effects in non-responding individuals.Currently biomarker discovery is facilitated by recent advances in high-throughput technologies when association between a given biological phenotype...... and the state or level of a large number of molecular entities is investigated. Such associative analysis could be confounded by several factors, leading to false discoveries. For example, it is assumed that with the exception of the true biomarkers most molecular entities such as gene expression levels show...... random distribution in a given cohort. However, gene expression levels may also be affected by technical bias when the actual measurement technology or sample handling may introduce a systematic error. If the distribution of systematic errors correlates with the biological phenotype then the risk...

  7. PET imaging biomarkers in head and neck cancer

    Energy Technology Data Exchange (ETDEWEB)

    Differding, Sarah; Gregoire, Vincent [Universite Catholique de Louvain, St-Luc University Hospital, Department of Radiation Oncology, and Center for Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Experimentale et Clinique (IREC), Brussels (Belgium); Hanin, Francois-Xavier [Universite Catholique de Louvain, St-Luc University Hospital, Department of Nuclear Medicine, and Center for Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Experimentale et Clinique (IREC), Brussels (Belgium)

    2015-04-01

    In locally advanced head and neck squamous cell carcinoma (HNSCC), the role of imaging becomes more and more critical in the management process. In this framework, molecular imaging techniques such as PET allow noninvasive assessment of a range of tumour biomarkers such as metabolism, hypoxia and proliferation, which can serve different purposes. First, in a pretreatment setting they can influence therapy selection strategies and target delineation for radiation therapy. Second, their predictive and/or prognostic value could help enhance the therapeutic ratio in the management of HNSCC. Third, treatment modification can be performed through the generation of a molecular-based heterogeneous dose distribution with dose escalation to the most resistant parts of the tumour, a concept known as dose painting. Fourth, they are increasingly becoming a tool for monitoring response to therapy. In this review, PET imaging biomarkers used in the routine management of HNSCC or under investigation are discussed. (orig.)

  8. Epigenetics and depression: return of the repressed.

    Science.gov (United States)

    Dalton, Victoria S; Kolshus, Erik; McLoughlin, Declan M

    2014-02-01

    Epigenetics has recently emerged as a potential mechanism by which adverse environmental stimuli can result in persistent changes in gene expression. Epigenetic mechanisms function alongside the DNA sequence to modulate gene expression and ultimately influence protein production. The current review provides an introduction and overview of epigenetics with a particular focus on preclinical and clinical studies relevant to major depressive disorder (MDD). PubMed and Web of Science databases were interrogated from January 1995 up to December 2012 using combinations of search terms, including "epigenetic", "microRNA" and "DNA methylation" cross referenced with "depression", "early life stress" and "antidepressant". There is an association between adverse environmental stimuli, such as early life stress, and epigenetic modification of gene expression. Epigenetic changes have been reported in humans with MDD and may serve as biomarkers to improve diagnosis. Antidepressant treatments appear to reverse or initiate compensatory epigenetic alterations that may be relevant to their mechanism of action. As a narrative review, the current report was interpretive and qualitative in nature. Epigenetic modification of gene expression provides a mechanism for understanding the link between long-term effects of adverse life events and the changes in gene expression that are associated with depression. Although still a developing field, in the future, epigenetic modifications of gene expression may provide novel biomarkers to predict future susceptibility and/or onset of MDD, improve diagnosis, and aid in the development of epigenetics-based therapies for depression. © 2013 Published by Elsevier B.V.

  9. Lung cancer screening beyond low-dose computed tomography: the role of novel biomarkers.

    Science.gov (United States)

    Hasan, Naveed; Kumar, Rohit; Kavuru, Mani S

    2014-10-01

    Lung cancer is the most common and lethal malignancy in the world. The landmark National lung screening trial (NLST) showed a 20% relative reduction in mortality in high-risk individuals with screening low-dose computed tomography. However, the poor specificity and low prevalence of lung cancer in the NLST provide major limitations to its widespread use. Furthermore, a lung nodule on CT scan requires a nuanced and individualized approach towards management. In this regard, advances in high through-put technology (molecular diagnostics, multi-gene chips, proteomics, and bronchoscopic techniques) have led to discovery of lung cancer biomarkers that have shown potential to complement the current screening standards. Early detection of lung cancer can be achieved by analysis of biomarkers from tissue samples within the respiratory tract such as sputum, saliva, nasal/bronchial airway epithelial cells and exhaled breath condensate or through peripheral biofluids such as blood, serum and urine. Autofluorescence bronchoscopy has been employed in research setting to identify pre-invasive lesions not identified on CT scan. Although these modalities are not yet commercially available in clinic setting, they will be available in the near future and clinicians who care for patients with lung cancer should be aware. In this review, we present up-to-date state of biomarker development, discuss their clinical relevance and predict their future role in lung cancer management.

  10. Nutritional epigenetics

    Science.gov (United States)

    This chapter is intended to provide a timely overview of the current state of research at the intersection of nutrition and epigenetics. I begin by describing epigenetics and molecular mechanisms of eigenetic regulation, then highlight four classes of nutritional exposures currently being investiga...

  11. Genetic and Epigenetic Tumor Suppressor Gene Silencing are Distinct Molecular Phenotypes Driven by Growth Promoting Mutations in Non small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Marsit, C. J.; Kelsey, K. T.; Houseman, E. A.; Kelsey, K. T.; Houseman, E. A.; Nelson, H. H.

    2008-01-01

    Both genetic and epigenetic alterations characterize human non small cell lung cancer (NSCLC), but the biological processes that create or select these alterations remain incompletely investigated. Our hypothesis posits that a roughly reciprocal relationship between the propensity for promoter hyper methylation and a propensity for genetic deletion leads to distinct molecular phenotypes of lung cancer. To test this hypothesis, we examined promoter hyper methylation of 17 tumor suppressor genes, as a marker of epigenetic alteration propensity, and deletion events at the 3p21 region, as a marker of genetic alteration. To model the complex biology between these somatic alterations, we utilized an item response theory model. We demonstrated that tumors exhibiting LOH at greater than 30% of informative alleles in the 3p21 region have a significantly reduced propensity for hyper methylation. At the same time, tumors with activating KRAS mutations showed a significantly increased propensity for hyper methylation of the loci examined, a result similar to what has been observed in colon cancer. These data suggest that NSCLCs have distinct epigenetic or genetic alteration phenotypes acting upon tumor suppressor genes and that mutation of oncogenic growth promoting genes, such as KRAS, is associated with the epigenetic phenotype.

  12. Genetic and Epigenetic Tumor Suppressor Gene Silencing Are Distinct Molecular Phenotypes Driven by Growth Promoting Mutations in Nonsmall Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Carmen J. Marsit

    2008-01-01

    Full Text Available Both genetic and epigenetic alterations characterize human nonsmall cell lung cancer (NSCLC, but the biological processes that create or select these alterations remain incompletely investigated. Our hypothesis posits that a roughly reciprocal relationship between the propensity for promoter hypermethylation and a propensity for genetic deletion leads to distinct molecular phenotypes of lung cancer. To test this hypothesis, we examined promoter hypermethylation of 17 tumor suppressor genes, as a marker of epigenetic alteration propensity, and deletion events at the 3p21 region, as a marker of genetic alteration. To model the complex biology between these somatic alterations, we utilized an item response theory model. We demonstrated that tumors exhibiting LOH at greater than 30% of informative alleles in the 3p21 region have a significantly reduced propensity for hypermethylation. At the same time, tumors with activating KRAS mutations showed a significantly increased propensity for hypermethylation of the loci examined, a result similar to what has been observed in colon cancer. These data suggest that NSCLCs have distinct epigenetic or genetic alteration phenotypes acting upon tumor suppressor genes and that mutation of oncogenic growth promoting genes, such as KRAS, is associated with the epigenetic phenotype.

  13. Podoplanin emerges as a functionally relevant oral cancer biomarker and therapeutic target.

    Science.gov (United States)

    Retzbach, Edward P; Sheehan, Stephanie A; Nevel, Evan M; Batra, Amber; Phi, Tran; Nguyen, Angels T P; Kato, Yukinari; Baredes, Soly; Fatahzadeh, Mahnaz; Shienbaum, Alan J; Goldberg, Gary S

    2018-03-01

    Oral cancer has become one of the most aggressive types of cancer, killing 140,000 people worldwide every year. Current treatments for oral cancer include surgery and radiation therapies. These procedures can be very effective; however, they can also drastically decrease the quality of life for survivors. New chemotherapeutic treatments are needed to more effectively combat oral cancer. The transmembrane receptor podoplanin (PDPN) has emerged as a functionally relevant oral cancer biomarker and chemotherapeutic target. PDPN expression promotes tumor cell migration leading to oral cancer invasion and metastasis. Here, we describe the role of PDPN in oral squamous cell carcinoma progression, and how it may be exploited to prevent and treat oral cancer. Copyright © 2018 Elsevier Ltd. All rights reserved.

  14. Searching for new biomarkers in ovarian cancer patients: Rationale and design of a retrospective study under the Mermaid III project

    Directory of Open Access Journals (Sweden)

    Julie L. Hentze

    2017-12-01

    A thorough investigation of biomarkers in ovarian cancer, including large numbers of different markers, has never been done before. Besides from improving diagnosis and treatment, other outcomes could be markers for screening, knowledge of the molecular aspects of cancer and the discovery of new drugs. Moreover, biomarkers are a prerequisite for the development of precision medicine. This study will attack the ovarian cancer problem from several angles, thereby increasing the chance of successfully contributing to saving lives.

  15. The extracellular domain of Her2 in serum as a biomarker of breast cancer.

    Science.gov (United States)

    Perrier, Alexandre; Gligorov, Joseph; Lefèvre, Guillaume; Boissan, Mathieu

    2018-02-28

    Breast cancer is a major health problem worldwide. In ~15% of breast cancers, the epidermal growth factor receptor HER2, a transmembrane protein, is overexpressed. This HER2 overexpression is associated with an aggressive form of the disease and a poor clinical prognosis. The extracellular domain (ECD) of HER2 is released into the blood by a proteolytic mechanism known as "ECD shedding". This proteolytic shedding leaves a constitutively active truncated receptor in the membrane that is 10-100-fold more oncogenic than the full-length receptor and promotes the growth and survival of cancer cells. Shedding of the HER2 ECD is increased during metastasis: whereas 15% of primary breast cancer patients have elevated levels of serum HER2 ECD (sHER2 ECD), the levels reach 45% in patients with metastatic disease. Thus, sHER2 ECD has been proposed as a promising biomarker for cancer recurrence and for monitoring the disease status of patients overexpressing HER2. Nevertheless, in 2016, the American Society of Clinical Oncology advises clinicians not to use soluble HER2 levels to guide their choice of adjuvant therapy for patients with HER2-positive breast cancer, because the evidence was considered not strong enough. Currently, biomarkers such as carcinoembryonic antigen and cancer antigen 15-3 are widely used to monitor metastatic breast cancer disease even if the level of evidence of clinical impact of this monitoring is poor. In this article, we review the evidence that sHER2 ECD might be used in some situations as a biomarker for breast cancer. Although this serum biomarker will not replace the direct measurement of tumor HER2 status for diagnosis of early-stage tumors; it might be especially useful in metastatic disease for prognosis, as an indicator of cancer progression and of therapy response, particularly to anti-HER2 therapies. Owing to these data, sHER2 ECD should be considered as a promising biomarker to detect cancer recurrence and metastasis.

  16. Epigenetic silencing of ADAMTS5 is associated with increased invasiveness and poor survival in patients with colorectal cancer.

    Science.gov (United States)

    Li, Jizhen; Liao, Yi; Huang, Jintuan; Sun, Yi; Chen, Hao; Chen, Chunyu; Li, Senmao; Yang, Zuli

    2018-02-01

    A disintegrin and metalloprotease with motif 5(ADAMTS5) has been involved in colorectal cancer (CRC) with hypermethylation in the promoter. However, its role in CRC remains unclear. The aim of this study was to explore the clinical significance and biological effect of ADAMTS5 on colorectal carcinogenesis. Through MSP, qRT-PCR, WB and IHC analysis, followed by a variety of in vitro assays, we report the function of ADAMTS5 in CRC. ADAMTS5 was markedly hypermethylaed and downregulated in tumor tissues compared with non-tumor tissues (p colorectal cancer, and correlates with OS and DFS, indicating that ADAMTS5 might be a useful biomarker in colorectal cancer therapy.

  17. Connective tissue-activating peptide III: a novel blood biomarker for early lung cancer detection.

    Science.gov (United States)

    Yee, John; Sadar, Marianne D; Sin, Don D; Kuzyk, Michael; Xing, Li; Kondra, Jennifer; McWilliams, Annette; Man, S F Paul; Lam, Stephen

    2009-06-10

    There are no reliable blood biomarkers to detect early lung cancer. We used a novel strategy that allows discovery of differentially present proteins against a complex and variable background. Mass spectrometry analyses of paired pulmonary venous-radial arterial blood from 16 lung cancer patients were applied to identify plasma proteins potentially derived from the tumor microenvironment. Two differentially expressed proteins were confirmed in 64 paired venous-arterial blood samples using an immunoassay. Twenty-eight pre- and postsurgical resection peripheral blood samples and two independent, blinded sets of plasma from 149 participants in a lung cancer screening study (49 lung cancers and 100 controls) and 266 participants from the National Heart Lung and Blood Institute Lung Health Study (45 lung cancer and 221 matched controls) determined the accuracy of the two protein markers to detect subclinical lung cancer. Connective tissue-activating peptide III (CTAP III)/ neutrophil activating protein-2 (NAP-2) and haptoglobin were identified to be significantly higher in venous than in arterial blood. CTAP III/NAP-2 levels decreased after tumor resection (P = .01). In two independent population cohorts, CTAP III/NAP-2 was significantly associated with lung cancer and improved the accuracy of a lung cancer risk prediction model that included age, smoking, lung function (FEV(1)), and an interaction term between FEV(1) and CTAP III/NAP-2 (area under the curve, 0.84; 95% CI, 0.77 to 0.91) compared to CAPIII/NAP-2 alone. We identified CTAP III/NAP-2 as a novel biomarker to detect preclinical lung cancer. The study underscores the importance of applying blood biomarkers as part of a multimodal lung cancer risk prediction model instead of as stand-alone tests.

  18. Molecular lipid species in urinary exosomes as potential prostate cancer biomarkers.

    Science.gov (United States)

    Skotland, Tore; Ekroos, Kim; Kauhanen, Dimple; Simolin, Helena; Seierstad, Therese; Berge, Viktor; Sandvig, Kirsten; Llorente, Alicia

    2017-01-01

    Exosomes have recently appeared as a novel source of noninvasive cancer biomarkers, since these nanovesicles contain molecules from cancer cells and can be detected in biofluids. We have here investigated the potential use of lipids in urinary exosomes as prostate cancer biomarkers. A high-throughput mass spectrometry quantitative lipidomic analysis was performed to reveal the lipid composition of urinary exosomes in prostate cancer patients and healthy controls. Control samples were first analysed to characterise the lipidome of urinary exosomes and test the reproducibility of the method. In total, 107 lipid species were quantified in urinary exosomes. Several differences, for example, in cholesterol and phosphatidylcholine, were found between urinary exosomes and exosomes derived from cell lines, thus showing the importance of in vivo studies for biomarker analysis. The 36 most abundant lipid species in urinary exosomes were then quantified in 15 prostate cancer patients and 13 healthy controls. Interestingly, the levels of nine lipids species were found to be significantly different when the two groups were compared. The highest significance was shown for phosphatidylserine (PS) 18:1/18:1 and lactosylceramide (d18:1/16:0), the latter also showed the highest patient-to-control ratio. Furthermore, combinations of these lipid species and PS 18:0-18:2 distinguished the two groups with 93% sensitivity and 100% specificity. Finally, in agreement with the reported dysregulation of sphingolipid metabolism in cancer cells, alteration in specific sphingolipid lipid classes were observed. This study shows for the first time the potential use of exosomal lipid species in urine as prostate cancer biomarkers. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate

    Energy Technology Data Exchange (ETDEWEB)

    Saldanha, Sabita N., E-mail: sabivan@uab.edu [Department of Biology, University of Alabama at Birmingham, 175 Campbell Hall, 1300 University Boulevard, Birmingham, AL 35294 (United States); Department of Biological Sciences, Alabama State University, Montgomery, AL 36104 (United States); Kala, Rishabh [Department of Biology, University of Alabama at Birmingham, 175 Campbell Hall, 1300 University Boulevard, Birmingham, AL 35294 (United States); Tollefsbol, Trygve O., E-mail: trygve@uab.edu [Department of Biology, University of Alabama at Birmingham, 175 Campbell Hall, 1300 University Boulevard, Birmingham, AL 35294 (United States); Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Comprehensive Center for Healthy Aging, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Comprehensive Diabetes Research Center, University of Alabama at Birmingham, Birmingham, AL 35294 (United States)

    2014-05-15

    Bioactive compounds are considered safe and have been shown to alter genetic and epigenetic profiles of tumor cells. However, many of these changes have been reported at molecular concentrations higher than physiologically achievable levels. We investigated the role of the combinatorial effects of epigallocatechin gallate (EGCG), a predominant polyphenol in green tea, and sodium butyrate (NaB), a dietary microbial fermentation product of fiber, in the regulation of survivin, which is an overexpressed anti-apoptotic protein in colon cancer cells. For the first time, our study showed that the combination treatment induced apoptosis and cell cycle arrest in RKO, HCT-116 and HT-29 colorectal cancer cells. This was found to be regulated by the decrease in HDAC1, DNMT1, survivin and HDAC activity in all three cell lines. A G2/M arrest was observed for RKO and HCT-116 cells, and G1 arrest for HT-29 colorectal cancer cells for combinatorial treatment. Further experimentation of the molecular mechanisms in RKO colorectal cancer (CRC) cells revealed a p53-dependent induction of p21 and an increase in nuclear factor kappa B (NF-κB)-p65. An increase in double strand breaks as determined by gamma-H2A histone family member X (γ-H2AX) protein levels and induction of histone H3 hyperacetylation was also observed with the combination treatment. Further, we observed a decrease in global CpG methylation. Taken together, these findings suggest that at low and physiologically achievable concentrations, combinatorial EGCG and NaB are effective in promoting apoptosis, inducing cell cycle arrest and DNA-damage in CRC cells. - Highlights: • EGCG and NaB as a combination inhibits colorectal cancer cell proliferation. • The combination treatment induces DNA damage, G2/M and G1 arrest and apoptosis. • Survivin is effectively down-regulated by the combination treatment. • p21 and p53 expressions are induced by the combination treatment. • Epigenetic proteins DNMT1 and HDAC1 are

  20. Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate

    International Nuclear Information System (INIS)

    Saldanha, Sabita N.; Kala, Rishabh; Tollefsbol, Trygve O.

    2014-01-01

    Bioactive compounds are considered safe and have been shown to alter genetic and epigenetic profiles of tumor cells. However, many of these changes have been reported at molecular concentrations higher than physiologically achievable levels. We investigated the role of the combinatorial effects of epigallocatechin gallate (EGCG), a predominant polyphenol in green tea, and sodium butyrate (NaB), a dietary microbial fermentation product of fiber, in the regulation of survivin, which is an overexpressed anti-apoptotic protein in colon cancer cells. For the first time, our study showed that the combination treatment induced apoptosis and cell cycle arrest in RKO, HCT-116 and HT-29 colorectal cancer cells. This was found to be regulated by the decrease in HDAC1, DNMT1, survivin and HDAC activity in all three cell lines. A G2/M arrest was observed for RKO and HCT-116 cells, and G1 arrest for HT-29 colorectal cancer cells for combinatorial treatment. Further experimentation of the molecular mechanisms in RKO colorectal cancer (CRC) cells revealed a p53-dependent induction of p21 and an increase in nuclear factor kappa B (NF-κB)-p65. An increase in double strand breaks as determined by gamma-H2A histone family member X (γ-H2AX) protein levels and induction of histone H3 hyperacetylation was also observed with the combination treatment. Further, we observed a decrease in global CpG methylation. Taken together, these findings suggest that at low and physiologically achievable concentrations, combinatorial EGCG and NaB are effective in promoting apoptosis, inducing cell cycle arrest and DNA-damage in CRC cells. - Highlights: • EGCG and NaB as a combination inhibits colorectal cancer cell proliferation. • The combination treatment induces DNA damage, G2/M and G1 arrest and apoptosis. • Survivin is effectively down-regulated by the combination treatment. • p21 and p53 expressions are induced by the combination treatment. • Epigenetic proteins DNMT1 and HDAC1 are

  1. Epigenetic modulation of AR gene expression in prostate cancer DU145 cells with the combination of sodium butyrate and 5'-Aza-2'-deoxycytidine.

    Science.gov (United States)

    Fialova, Barbora; Luzna, Petra; Gursky, Jan; Langova, Katerina; Kolar, Zdenek; Trtkova, Katerina Smesny

    2016-10-01

    The androgen receptor (AR) plays an essential role in the development and progression of prostate cancer. Castration-resistant prostate cancer (CRPC) is a consequence of androgen deprivation therapy. Unchecked CRPC followed by metastasis is lethal. Some CRPCs show decreased AR gene expression due to epigenetic mechanisms such as DNA methylation and histone deacetylation. The aim of this study was to epigenetically modulate the methylated state of the AR gene leading to targeted demethylation and AR gene expression in androgen-independent human prostate cancer DU145 cell line, representing the CRPC model with very low or undetectable AR levels. The cell treatment was based on single and combined applications of two epigenetic inhibitors, sodium butyrate (NaB) as histone deacetylases inhibitor and 5'-Aza-2'-deoxycytidine (Aza-dC) as DNA methyltransferases inhibitor. We found that the Aza-dC in combination with NaB may help reduce the toxicity of higher NaB concentrations in cancer cells. In normal RWPE-1 cells and even stronger in cancer DU145 cells, the combined treatment induced both AR gene expression on the mRNA level and increased histone H4 acetylation in AR gene promoter. Also activation and maintenance of G2/M cell cycle arrest and better survival in normal RWPE-1 cells compared to cancer DU145 cells were observed after the treatments. These results imply the selective toxicity effect of both inhibitors used and their potentially more effective combined use in the epigenetic therapy of prostate cancer patients.

  2. In Silico discovery of transcription factors as potential diagnostic biomarkers of ovarian cancer

    KAUST Repository

    Kaur, Mandeep

    2011-09-19

    Background: Our study focuses on identifying potential biomarkers for diagnosis and early detection of ovarian cancer (OC) through the study of transcription regulation of genes affected by estrogen hormone.Results: The results are based on a set of 323 experimentally validated OC-associated genes compiled from several databases, and their subset controlled by estrogen. For these two gene sets we computationally determined transcription factors (TFs) that putatively regulate transcription initiation. We ranked these TFs based on the number of genes they are likely to control. In this way, we selected 17 top-ranked TFs as potential key regulators and thus possible biomarkers for a set of 323 OC-associated genes. For 77 estrogen controlled genes from this set we identified three unique TFs as potential biomarkers.Conclusions: We introduced a new methodology to identify potential diagnostic biomarkers for OC. This report is the first bioinformatics study that explores multiple transcriptional regulators of OC-associated genes as potential diagnostic biomarkers in connection with estrogen responsiveness. We show that 64% of TF biomarkers identified in our study are validated based on real-time data from microarray expression studies. As an illustration, our method could identify CP2 that in combination with CA125 has been reported to be sensitive in diagnosing ovarian tumors. 2011 Kaur et al; licensee BioMed Central Ltd.

  3. In Silico discovery of transcription factors as potential diagnostic biomarkers of ovarian cancer

    KAUST Repository

    Kaur, Mandeep; MacPherson, Cameron R; Schmeier, Sebastian; Narasimhan, Kothandaraman; Choolani, Mahesh; Bajic, Vladimir B.

    2011-01-01

    Background: Our study focuses on identifying potential biomarkers for diagnosis and early detection of ovarian cancer (OC) through the study of transcription regulation of genes affected by estrogen hormone.Results: The results are based on a set of 323 experimentally validated OC-associated genes compiled from several databases, and their subset controlled by estrogen. For these two gene sets we computationally determined transcription factors (TFs) that putatively regulate transcription initiation. We ranked these TFs based on the number of genes they are likely to control. In this way, we selected 17 top-ranked TFs as potential key regulators and thus possible biomarkers for a set of 323 OC-associated genes. For 77 estrogen controlled genes from this set we identified three unique TFs as potential biomarkers.Conclusions: We introduced a new methodology to identify potential diagnostic biomarkers for OC. This report is the first bioinformatics study that explores multiple transcriptional regulators of OC-associated genes as potential diagnostic biomarkers in connection with estrogen responsiveness. We show that 64% of TF biomarkers identified in our study are validated based on real-time data from microarray expression studies. As an illustration, our method could identify CP2 that in combination with CA125 has been reported to be sensitive in diagnosing ovarian tumors. 2011 Kaur et al; licensee BioMed Central Ltd.

  4. BRCA1 Expression Is Epigenetically Repressed in Sporadic Ovarian Cancer Cells by Overexpression of C-Terminal Binding Protein 2

    Directory of Open Access Journals (Sweden)

    Taymaa May

    2013-06-01

    Full Text Available INTRODUCTION: Ovarian cancer is the leading cause of mortality from gynecological malignancy despite advancements in novel therapeutics. We have recently demonstrated that the transcriptional co-repressor C-terminal binding protein 2 (CtBP2 is overexpressed in epithelial ovarian carcinoma. MATERIALS AND METHODS: Reverse-transcribed cDNA from CtBP2 wild-type and knockdown ovarian cancer cell lines was hybridized to Affymetrix Gene 1.0 ST microarrays, and differentially expressed genes were studied. Immunohistochemical analysis of CtBP2 and BRCA1 staining of ovarian tissues was performed. Chromatin immunoprecipitation (ChIP and luciferase assays were carried out. The effect of the drugs 4-methylthio-2-oxobutyric acid (MTOB and poly(ADP-ribose polymerase (PARP inhibitor Olaparib on CtBP2 wild-type and knockdown cell lines was examined using methylthiazol tetrazolium assays and an xCELLigence System. RESULTS: Eighty-five genes involved in DNA repair, mitotic checkpoint, nucleosome assembly, and the BRCA1 network were differentially regulated by CtBP2 expression. ChIP and luciferase reporter assays using a BRCA1 promoter-regulated luciferase construct indicated that the CtBP2 complex binds the BRCA1 promoter and represses BRCA1 transcription. Immunohistochemistry illustrated a significant inverse CtBP2 and BRCA1 expression in a panel of malignant ovarian tumor tissues. The CtBP2 inhibitor MTOB suppressed ovarian cancer cell survival in a CtBP2-dependent manner. Ovarian cancer cells with CtBP2 knockdown did not display increased sensitivity to the PARP inhibitor Olaparib. CONCLUSION: CtBP2 is an ovarian cancer oncogene that may play a significant role in epigenetically silencing BRCA1 function in sporadic epithelial ovarian cancer. CtBP2-specific inhibitors, such as MTOB, may be effective adjunct therapies in the management of patients with CtBP2-positive ovarian carcinoma.

  5. The up-stream regulation of polymerase-1 and transcript release factor(PTRF/Cavin-1 in prostate cancer: an epigenetic analysis

    Directory of Open Access Journals (Sweden)

    Helen D. Nicholson

    2016-09-01

    Full Text Available The expression of PTRF is down-regulated in prostate cell lines and tissues. Restorationof PTRF expression leads to a reduction in aggressive phenotypes of prostate cancer cells both in vitro and in vivo. Epigenetics examines the changes in gene expression that occur without changing DNA sequences. Two main epigenetic mechanisms include hypermethylation of the gene’s promoter region and changes to the chromatin structure through histone modification. We investigated the involvement of possible epigenetic up-stream regulatory mechanisms that may down-regulate PTRF in prostate cancer cells. Normal (RWPE-1 and prostate cancer (LNCaP and PC3 cell lines were treated with DNA methylation inhibitor, 5-aza-2Ꞌ-deoxycytidine (5AZA and histone deacetylase inhibitor, Trichostatin-A (TSA either independently or in combination. A bioinformatics approach was also used to investigate the changes of epigenetic driver genes in silico. In normal prostate cells(RWPE-1, and androgen independent prostate cancer cells (PC3, treatment with 5AZA and/or TSA did not affect PTRF expression. However, TSA and TSA + 5AZA treatments, but not 5AZA alone,up-regulated the expression of PTRF in LNCaP cells. Bioinformatic analysis of the potential histone deacetylase (HDAC genes involved showed that HDAC2, HDAC6 and HDAC10 may be potential candidate genes for the regulation of PTRF. This corroborative study describes the possible role of an epigenetic mechanism onPTRF, further studies are required to allow a better understanding of theup-stream mechanisms that regulate PTRF expression.

  6. Genetic and Epigenetic Determinants of Lung Cancer Subtype: Adenocarcinoma to Small Cell Conversion

    Science.gov (United States)

    2016-10-01

    reported in other contexts including breast cancer and bladder cancer . While beyond the scope of this grant, and not funded by this mechanism, we...have participated in a recent collaborative analysis of common genomic alterations in small cell bladder cancer vs. small cell lung cancer . A paper...of the project is to study drug resistance mechanisms in vitro and using tumors from lung cancer patients with epidermal growth factor receptor

  7. Alterations in inflammatory biomarkers and energy intake in cancer cachexia: a prospective study in patients with inoperable pancreatic cancer.

    Science.gov (United States)

    Bye, Asta; Wesseltoft-Rao, Nima; Iversen, Per Ole; Skjegstad, Grete; Holven, Kirsten B; Ulven, Stine; Hjermstad, Marianne J

    2016-06-01

    Chronic systemic inflammatory response is proposed as an underlying mechanism for development of cancer cachexia. We conducted a prospective study to examine changes in inflammatory biomarkers during the disease course and the relationship between inflammatory biomarkers and cachexia in patients with inoperable pancreatic cancer. Twenty patients, median (range) age 67.5 (35-79) years, 5 females, were followed for median 5.5 (1-12) months. Cachexia was diagnosed according to the 2011 consensus-based classification system (weight loss >5 % past six months, BMI 2 %, or sarcopenia) and the modified Glasgow Prognostic score (mGPS) that combines CRP and albumin levels. Inflammatory biomarkers were measured by enzyme immunoassays. The patients had increased levels of most inflammatory biomarkers, albeit not all statistically significant, both at study entry and close to death, indicating ongoing inflammation. According to the consensus-based classification system, eleven (55 %) patients were classified as cachectic upon inclusion. They did not differ from non-cachectic patients with regard to inflammatory biomarkers or energy intake. According to the mGPS, seven (35 %) were defined as cachectic and had a higher IL-6 (p cachexia.

  8. Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error.

    Science.gov (United States)

    Shipitsin, M; Small, C; Choudhury, S; Giladi, E; Friedlander, S; Nardone, J; Hussain, S; Hurley, A D; Ernst, C; Huang, Y E; Chang, H; Nifong, T P; Rimm, D L; Dunyak, J; Loda, M; Berman, D M; Blume-Jensen, P

    2014-09-09

    Key challenges of biopsy-based determination of prostate cancer aggressiveness include tumour heterogeneity, biopsy-sampling error, and variations in biopsy interpretation. The resulting uncertainty in risk assessment leads to significant overtreatment, with associated costs and morbidity. We developed a performance-based strategy to identify protein biomarkers predictive of prostate cancer aggressiveness and lethality regardless of biopsy-sampling variation. Prostatectomy samples from a large patient cohort with long follow-up were blindly assessed by expert pathologists who identified the tissue regions with the highest and lowest Gleason grade from each patient. To simulate biopsy-sampling error, a core from a high- and a low-Gleason area from each patient sample was used to generate a 'high' and a 'low' tumour microarray, respectively. Using a quantitative proteomics approach, we identified from 160 candidates 12 biomarkers that predicted prostate cancer aggressiveness (surgical Gleason and TNM stage) and lethal outcome robustly in both high- and low-Gleason areas. Conversely, a previously reported lethal outcome-predictive marker signature for prostatectomy tissue was unable to perform under circumstances of maximal sampling error. Our results have important implications for cancer biomarker discovery in general and development of a sampling error-resistant clinical biopsy test for prediction of prostate cancer aggressiveness.

  9. Robust prediction of anti-cancer drug sensitivity and sensitivity-specific biomarker.

    Directory of Open Access Journals (Sweden)

    Heewon Park

    Full Text Available The personal genomics era has attracted a large amount of attention for anti-cancer therapy by patient-specific analysis. Patient-specific analysis enables discovery of individual genomic characteristics for each patient, and thus we can effectively predict individual genetic risk of disease and perform personalized anti-cancer therapy. Although the existing methods for patient-specific analysis have successfully uncovered crucial biomarkers, their performance takes a sudden turn for the worst in the presence of outliers, since the methods are based on non-robust manners. In practice, clinical and genomic alterations datasets usually contain outliers from various sources (e.g., experiment error, coding error, etc. and the outliers may significantly affect the result of patient-specific analysis. We propose a robust methodology for patient-specific analysis in line with the NetwrokProfiler. In the proposed method, outliers in high dimensional gene expression levels and drug response datasets are simultaneously controlled by robust Mahalanobis distance in robust principal component space. Thus, we can effectively perform for predicting anti-cancer drug sensitivity and identifying sensitivity-specific biomarkers for individual patients. We observe through Monte Carlo simulations that the proposed robust method produces outstanding performances for predicting response variable in the presence of outliers. We also apply the proposed methodology to the Sanger dataset in order to uncover cancer biomarkers and predict anti-cancer drug sensitivity, and show the effectiveness of our method.

  10. Prostate-specific antigen (PSA) as a possible biomarker in non-prostatic cancer: A review.

    Science.gov (United States)

    Pérez-Ibave, Diana Cristina; Burciaga-Flores, Carlos Horacio; Elizondo-Riojas, Miguel-Ángel

    2018-06-01

    Prostate-specific antigen (PSA) is a serine protease produced by epithelial prostatic cells and its main function is to liquefy seminal coagulum. Currently, PSA is a biomarker for the diagnosis and screening of prostate cancer and it was the first cancer biomarker approved by the FDA. The quantity and serum isoforms of male PSA, allows distinguishing between carcinoma and benign inflammatory disease of the prostate. Initially, it was thought that PSA was produced only by the prostate, and thus, a protein that was expressed exclusively in men. However, several authors report that PSA is a protein that is expressed by multiple non-prostatic tissues not only in men but also in women. Some authors also report that in women, the expression of this protein is highly related to breast and colon cancer and therefore can act as a possible biomarker for early detection, diagnosis and prognosis of these cancers in women. In this review, we will focus on the characteristics of the PSA at a molecular level, its current clinical implications, the expression of this protein in non-prostatic tissues, and its relationship with cancer, especially in women. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. Characterization of KIF11 as a novel prognostic biomarker and therapeutic target for oral cancer.

    Science.gov (United States)

    Daigo, Kayo; Takano, Atsushi; Thang, Phung Manh; Yoshitake, Yoshihiro; Shinohara, Masanori; Tohnai, Iwau; Murakami, Yoshinori; Maegawa, Jiro; Daigo, Yataro

    2018-01-01

    Oral cancer has a high mortality rate, and its incidence is increasing gradually worldwide. As the effectiveness of standard treatments is still limited, the development of new therapeutic strategies is eagerly awaited. Kinesin family member 11 (KIF11) is a motor protein required for establishing a bipolar spindle in cell division. The role of KIF11 in oral cancer is unclear. Therefore, the present study aimed to assess the role of KIF11 in oral cancer and evaluate its role as a prognostic biomarker and therapeutic target for treating oral cancer. Immunohistochemical analysis demonstrated that KIF11 was expressed in 64 of 99 (64.6%) oral cancer tissues but not in healthy oral epithelia. Strong KIF11 expression was significantly associated with poor prognosis among oral cancer patients (P=0.034), and multivariate analysis confirmed its independent prognostic value. In addition, inhibition of KIF11 expression by transfection of siRNAs into oral cancer cells or treatment of cells with a KIF11 inhibitor significantly suppressed cell proliferation, probably through G2/M arrest and subsequent induction of apoptosis. These results suggest that KIF11 could be a potential prognostic biomarker and therapeutic target for oral cancer.

  12. Isolation and enrichment of circulating biomarkers for cancer screening, detection, and diagnostics.

    Science.gov (United States)

    Hyun, Kyung-A; Kim, Junmoo; Gwak, Hogyeong; Jung, Hyo-Il

    2016-01-21

    Much research has been performed over the past several decades in an attempt to conquer cancer. Tissue biopsy is the conventional method for gathering biological materials to analyze cancer and has contributed greatly to the understanding of cancer. However, this method is limited because it is time-consuming (requires tissue sectioning, staining, and pathological analysis), costly, provides scarce starting materials for multiple tests, and is painful. A liquid biopsy, which analyzes cancer-derived materials from various body fluids using a minimally invasive procedure, is more practical for real-time monitoring of disease progression than tissue biopsy. Biomarkers analyzable through liquid biopsy include circulating tumor cells (CTCs), exosomes, circulating cell-free DNA (cfDNA), miRNA, and proteins. Research on CTCs has been actively conducted because CTCs provide information on the whole cell, unlike the other biomarkers mentioned above. However, owing to the rarity and heterogeneity of CTCs, CTC research faces many critical concerns. Although exosomes and cfDNA have some technical challenges, they are being highlighted as new target materials. That is because they also have genetic information on cancers. Even though the number of exosomes and cfDNA from early stage cancer patients are similar to healthy individuals, they are present in high concentrations after metastasis. In this article, we review several technologies for material analyses of cancer, discuss the critical concerns based on hands-on experience, and describe future directions for cancer screening, detection, and diagnostics.

  13. Searching for New Biomarkers and the Use of Multivariate Analysis in Gastric Cancer Diagnostics.

    Science.gov (United States)

    Kucera, Radek; Smid, David; Topolcan, Ondrej; Karlikova, Marie; Fiala, Ondrej; Slouka, David; Skalicky, Tomas; Treska, Vladislav; Kulda, Vlastimil; Sima