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.

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.

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

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.

Epigenetics and Colorectal Cancer Pathogenesis

Energy Technology Data Exchange (ETDEWEB)

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.

THE EPIGENETICS OF RENAL CELL TUMORS: FROM BIOLOGY TO BIOMARKERS

Directory of Open Access Journals (Sweden)

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.

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

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.

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

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.

The Interactions of microRNA and Epigenetic Modifications in Prostate Cancer

Directory of Open Access Journals (Sweden)

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.

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)

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...

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

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.

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.

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.

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.

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.

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...

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.

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

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.

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.

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.

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

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...

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.

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.

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.

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.

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.

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.

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.

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

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

[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.

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.

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.

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.

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.

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

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

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.

DNA Methylation and Chromatin Remodeling: The Blueprint of Cancer Epigenetics

Directory of Open Access Journals (Sweden)

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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

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...

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.

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...

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...

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 ...

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

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.

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.

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

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

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.

Prostate Cancer: Epigenetic Alterations, Risk Factors, and Therapy

Directory of Open Access Journals (Sweden)

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.

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.

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.

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

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.

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.

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.

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...

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.

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.

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.

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.

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.

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.

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

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.

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.

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

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)

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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

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...

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.

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.

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.

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...

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.

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.

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.

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

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.

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.

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

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....

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.

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.

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.

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.

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

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...

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.

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

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.

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

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.

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

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.

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.

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.

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.

Epigenetic Markers of Renal Function in African Americans

Directory of Open Access Journals (Sweden)

Samantha M. Bomotti

2013-01-01

Full Text Available Chronic kidney disease (CKD is an increasing concern in the United States due to its rapidly rising prevalence, particularly among African Americans. Epigenetic DNA methylation markers are becoming important biomarkers of chronic diseases such as CKD. To better understand how these methylation markers play a role in kidney function, we measured 26,428 DNA methylation sites in 972 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA study. We then evaluated (1 whether epigenetic markers are associated with estimated glomerular filtration rate (eGFR, (2 whether the significantly associated markers are also associated with traditional risk factors and/or novel biomarkers for eGFR, and (3 how much additional variation in eGFR is explained by epigenetic markers beyond established risk factors and biomarkers. The majority of methylation markers most significantly associated with eGFR (24 out of the top 30 appeared to function, at least in part, through pathways related to aging, inflammation, or cholesterol. However, six epigenetic markers were still able to significantly predict eGFR after adjustment for other risk factors. This work shows that epigenetic markers may offer valuable new insight into the complex pathophysiology of CKD in African Americans.

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.

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

DNA methylation, microRNAs, and their crosstalk as potential biomarkers in hepatocellular carcinoma

Science.gov (United States)

Anwar, Sumadi Lukman; Lehmann, Ulrich

2014-01-01

Epigenetic alterations have been identified as a major characteristic in human cancers. Advances in the field of epigenetics have contributed significantly in refining our knowledge of molecular mechanisms underlying malignant transformation. DNA methylation and microRNA expression are epigenetic mechanisms that are widely altered in human cancers including hepatocellular carcinoma (HCC), the third leading cause of cancer related mortality worldwide. Both DNA methylation and microRNA expression patterns are regulated in developmental stage specific-, cell type specific- and tissue-specific manner. The aberrations are inferred in the maintenance of cancer stem cells and in clonal cell evolution during carcinogenesis. The availability of genome-wide technologies for DNA methylation and microRNA profiling has revolutionized the field of epigenetics and led to the discovery of a number of epigenetically silenced microRNAs in cancerous cells and primary tissues. Dysregulation of these microRNAs affects several key signalling pathways in hepatocarcinogenesis suggesting that modulation of DNA methylation and/or microRNA expression can serve as new therapeutic targets for HCC. Accumulative evidence shows that aberrant DNA methylation of certain microRNA genes is an event specifically found in HCC which correlates with unfavorable outcomes. Therefore, it can potentially serve as a biomarker for detection as well as for prognosis, monitoring and predicting therapeutic responses in HCC. PMID:24976726

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

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

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

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.

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

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.

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.

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

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

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.

Telomere Length – a New Biomarker in Medicine

Directory of Open Access Journals (Sweden)

Agnieszka Kozłowska

2015-12-01

Full Text Available A number of xenobiotics in the environment and workplace influences on our health and life. Biomarkers are tools for measuring such exposures and their effects in the organism. Nowadays, telomere length, epigenetic changes, mutations and changes in gene expression pattern have become new molecular biomarkers. Telomeres play the role of molecular clock, which influences on expectancy of cell life and thus aging, the formation of damages, development diseases and carcinogenesis. The telomere length depends on mechanisms of replication and the activity of telomerase. Telomere length is currently used as a biomarker of susceptibility and/or exposure. This paper describes the role of telomere length as a biomarker of aging cells, oxidative stress, a marker of many diseases including cancer, and as a marker of environmental and occupational exposure.

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

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.

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

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.

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

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

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.

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.

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....

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.

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

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....

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Oxidative Stress and DNA Methylation in Prostate Cancer

Directory of Open Access Journals (Sweden)

Krishna Vanaja Donkena

2010-01-01

Full Text Available The protective effects of fruits, vegetables, and other foods on prostate cancer may be due to their antioxidant properties. An imbalance in the oxidative stress/antioxidant status is observed in prostate cancer patients. Genome oxidative damage in prostate cancer patients is associated with higher lipid peroxidation and lower antioxidant levels. Oxygen radicals are associated with different steps of carcinogenesis, including structural DNA damage, epigenetic changes, and protein and lipid alterations. Epigenetics affects genetic regulation, cellular differentiation, embryology, aging, cancer, and other diseases. DNA methylation is perhaps the most extensively studied epigenetic modification, which plays an important role in the regulation of gene expression and chromatin architecture, in association with histone modification and other chromatin-associated proteins. This review will provide a broad overview of the interplay of oxidative stress and DNA methylation, DNA methylation changes in regulation of gene expression, lifestyle changes for prostate cancer prevention, DNA methylation as biomarkers for prostate cancer, methods for detection of methylation, and clinical application of DNA methylation inhibitors for epigenetic therapy.

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.

Epigenomics in cancer management

International Nuclear Information System (INIS)

Costa, Fabricio F

2010-01-01

The identification of all epigenetic modifications implicated in gene expression is the next step for a better understanding of human biology in both normal and pathological states. This field is referred to as epigenomics, and it is defined as epigenetic changes (ie, DNA methylation, histone modifications and regulation by noncoding RNAs such as microRNAs) on a genomic scale rather than a single gene. Epigenetics modulate the structure of the chromatin, thereby affecting the transcription of genes in the genome. Different studies have already identified changes in epigenetic modifications in a few genes in specific pathways in cancers. Based on these epigenetic changes, drugs against different types of tumors were developed, which mainly target epimutations in the genome. Examples include DNA methylation inhibitors, histone modification inhibitors, and small molecules that target chromatin-remodeling proteins. However, these drugs are not specific, and side effects are a major problem; therefore, new DNA sequencing technologies combined with epigenomic tools have the potential to identify novel biomarkers and better molecular targets to treat cancers. The purpose of this review is to discuss current and emerging epigenomic tools and to address how these new technologies may impact the future of cancer management

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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

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.

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 ...

Epigenetic Dysregulation in Laryngeal Squamous Cell Carcinoma

Directory of Open Access Journals (Sweden)

Thian-Sze Wong

2012-01-01

Full Text Available Laryngeal carcinoma is a common head and neck cancer with poor prognosis. Patients with laryngeal carcinoma usually present late leading to the reduced treatment efficacy and high rate of recurrence. Despite the advance in the use of molecular markers for monitoring human cancers in the past decades, there are still no reliable markers for use to screen laryngeal carcinoma and follow the patients after treatment. Epigenetics emerged as an important field in understanding the biology of the human malignancies. Epigenetic alterations refer to the dysregulation of gene, which do not involve the alterations of the DNA sequence. Major epigenetic changes including methylation imbalance, histone modification, and small RNA dysregulation could play a role in the development of human malignancies. Global epigenetic change is now regarded as a molecular signature of cancer. The characteristics and behavior of a cancer could be predicted based on the specific epigenetic pattern. We here provide a review on the understanding of epigenetic dysregulation in laryngeal carcinoma. Further knowledge on the initiation and progression of laryngeal carcinoma at epigenetic level could promote the translation of the knowledge to clinical use.

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....

Epigenetic changes in solid and hematopoietic tumors.

Science.gov (United States)

Toyota, Minoru; Issa, Jean-Pierre J

2005-10-01

There are three connected molecular mechanisms of epigenetic cellular memory in mammalian cells: DNA methylation, histone modifications, and RNA interference. The first two have now been firmly linked to neoplastic transformation. Hypermethylation of CpG-rich promoters triggers local histone code modifications resulting in a cellular camouflage mechanism that sequesters gene promoters away from transcription factors and results in stable silencing. This normally restricted mechanism is ubiquitously used in cancer to silence hundreds of genes, among which some critically contribute to the neoplastic phenotype. Virtually every pathway important to cancer formation is affected by this process. Methylation profiling of human cancers reveals tissue-specific epigenetic signatures, as well as tumor-specific signatures, reflecting in particular the presence of epigenetic instability in a subset of cancers affected by the CpG island methylator phenotype. Generally, methylation patterns can be traced to a tissue-specific, proliferation-dependent accumulation of aberrant promoter methylation in aging tissues, a process that can be accelerated by chronic inflammation and less well-defined mechanisms including, possibly, diet and genetic predisposition. The epigenetic machinery can also be altered in cancer by specific lesions in epigenetic effector genes, or by aberrant recruitment of these genes by mutant transcription factors and coactivators. Epigenetic patterns are proving clinically useful in human oncology via risk assessment, early detection, and prognostic classification. Pharmacologic manipulation of these patterns-epigenetic therapy-is also poised to change the way we treat cancer in the clinic.

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

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

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.

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.

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.

Using Epigenetic Therapy to Overcome Chemotherapy Resistance.

Science.gov (United States)

Strauss, Julius; Figg, William D

2016-01-01

It has been known for decades that as cancer progresses, tumors develop genetic alterations, making them highly prone to developing resistance to therapies. Classically, it has been thought that these acquired genetic changes are fixed. This has led to the paradigm of moving from one cancer therapy to the next while avoiding past therapies. However, emerging data on epigenetic changes during tumor progression and use of epigenetic therapies have shown that epigenetic modifications leading to chemotherapy resistance have the potential to be reversible with epigenetic therapy. In fact, promising clinical data exist that treatment with epigenetic agents can diminish chemotherapy resistance in a number of tumor types including chronic myelogenous leukemia, colorectal, ovarian, lung and breast cancer. The potential for epigenetic-modifying drugs to allow for treatment of resistant disease is exciting and clinical trials have just begun to evaluate this area. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

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.

The Epigenetic Cytocrin Pathway to the Nucleus. Epigenetic Factors, Epigenetic Mediators, and Epigenetic Traits. A Biochemist Perspective

Directory of Open Access Journals (Sweden)

Gemma Navarro

2017-11-01

Full Text Available A single word, Epigenetics, underlies one exciting subject in today's Science, with different sides and with interactions with philosophy. The apparent trivial description includes everything in between genotype and phenotype that occurs for a given unique DNA sequence/genome. This Perspective article first presents an historical overview and the reasons for the lack of consensus in the field, which derives from different interpretations of the diverse operative definitions of Epigenetics. In an attempt to reconcile the different views, we propose a novel concept, the “cytocrin system.” Secondly, the article questions the inheritability requirement and makes emphasis in the epigenetic mechanisms, known or to be discovered, that provide hope for combating human diseases. Hopes in cancer are at present in deep need of deciphering mechanisms to support ad hoc therapeutic approaches. Better perspectives are for diseases of the central nervous system, in particular to combat neurodegeneration and/or cognitive deficits in Alzheimer's disease. Neurons are post-mitotic cells and, therefore, epigenetic targets to prevent neurodegeneration should operate in non-dividing diseased cells. Accordingly, epigenetic-based human therapy may not need to count much on transmissible potential.

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

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.

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.

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...

Recent Findings in Alzheimer Disease and Nutrition Focusing on Epigenetics.

Science.gov (United States)

Athanasopoulos, Dimitrios; Karagiannis, George; Tsolaki, Magda

2016-09-01

Alzheimer disease (AD) is a chronic neurodegenerative disease with no effective cure so far. The current review focuses on the epigenetic mechanisms of AD and how nutrition can influence the course of this disease through regulation of gene expression, according to the latest scientific findings. The search strategy was the use of scientific databases such as PubMed and Scopus in order to find relative research or review articles published in the years 2012-2015. By showing the latest data of various nutritional compounds, this study aims to stimulate the scientific community to recognize the value of nutrition in this subject. Epigenetics is becoming a very attractive subject for researchers because it can shed light on unknown aspects of complex diseases like AD. DNA methylation, histone modifications, and microRNAs are the principal epigenetic mechanisms involved in AD pathophysiology. Nutrition is an environmental factor that is related to AD through epigenetic pathways. Vitamin B-12, for instance, can alter the one-carbon metabolism and thus interfere in the DNA methylation process. The research results might seem ambiguous about the clinical role of nutrition, but there is strengthening evidence that proper nutrition can not only change epigenetic biomarker levels but also prevent the development of late-onset AD and attenuate cognition deficit. Nutrition might grow to become a preventive and even therapeutic alternative against AD, especially if combined with other antidementia interventions, brain exercise, physical training, etc. Epigenetic biomarkers can be a very helpful tool to help researchers find the exact nutrients needed to create specific remedies, and perhaps the same biomarkers can be used even in patient screening in the future. © 2016 American Society for Nutrition.

Epigenetic Impact on EBV Associated B-Cell Lymphomagenesis

Directory of Open Access Journals (Sweden)

Shatadru Ghosh Roy

2016-11-01

Full Text Available Epigenetic modifications leading to either transcriptional repression or activation, play an indispensable role in the development of human cancers. Epidemiological study revealed that approximately 20% of all human cancers are associated with tumor viruses. Epstein-Barr virus (EBV, the first human tumor virus, demonstrates frequent epigenetic alterations on both viral and host genomes in associated cancers—both of epithelial and lymphoid origin. The cell type-dependent different EBV latent gene expression patterns appear to be determined by the cellular epigenetic machinery and similarly viral oncoproteins recruit epigenetic regulators in order to deregulate the cellular gene expression profile resulting in several human cancers. This review elucidates the epigenetic consequences of EBV–host interactions during development of multiple EBV-induced B-cell lymphomas, which may lead to the discovery of novel therapeutic interventions against EBV-associated B-cell lymphomas by alteration of reversible patho-epigenetic markings.

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

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

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.

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

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

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...

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.

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

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.

Biomarkers and Mechanisms of FANCD2 Function

Directory of Open Access Journals (Sweden)

Henning Willers

2008-01-01

Full Text Available Genetic or epigenetic inactivation of the pathway formed by the Fanconi anemia (FA and BRCA1 proteins occurs in several cancer types, making the affected tumors potentially hypersensitive to DNA cross-linkers and other chemotherapeutic agents. It has been proposed that the inability of FA/BRCA-defective cells to form subnuclear foci of effector proteins, such as FANCD2, can be used as a biomarker to aid individualization of chemotherapy. We show that FANCD2 inactivation not only renders cells sensitive to cross-links, but also oxidative stress, a common effect of cancer therapeutics. Oxidative stress sensitivity does not correlate with FANCD2 or RAD51 foci formation, but associates with increased γH2AX foci levels and apoptosis. Therefore, FANCD2 may protect cells against cross-links and oxidative stress through distinct mechanisms, consistent with the growing notion that the pathway is not linear. Our data emphasize the need for multiple biomarkers, such as γH2AX, FANCD2, and RAD51, to capture all pathway activities.

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 ...

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

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)

Recent Findings in Alzheimer Disease and Nutrition Focusing on Epigenetics12

Science.gov (United States)

2016-01-01

Alzheimer disease (AD) is a chronic neurodegenerative disease with no effective cure so far. The current review focuses on the epigenetic mechanisms of AD and how nutrition can influence the course of this disease through regulation of gene expression, according to the latest scientific findings. The search strategy was the use of scientific databases such as PubMed and Scopus in order to find relative research or review articles published in the years 2012–2015. By showing the latest data of various nutritional compounds, this study aims to stimulate the scientific community to recognize the value of nutrition in this subject. Epigenetics is becoming a very attractive subject for researchers because it can shed light on unknown aspects of complex diseases like AD. DNA methylation, histone modifications, and microRNAs are the principal epigenetic mechanisms involved in AD pathophysiology. Nutrition is an environmental factor that is related to AD through epigenetic pathways. Vitamin B-12, for instance, can alter the one-carbon metabolism and thus interfere in the DNA methylation process. The research results might seem ambiguous about the clinical role of nutrition, but there is strengthening evidence that proper nutrition can not only change epigenetic biomarker levels but also prevent the development of late-onset AD and attenuate cognition deficit. Nutrition might grow to become a preventive and even therapeutic alternative against AD, especially if combined with other antidementia interventions, brain exercise, physical training, etc. Epigenetic biomarkers can be a very helpful tool to help researchers find the exact nutrients needed to create specific remedies, and perhaps the same biomarkers can be used even in patient screening in the future. PMID:27633107

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, ...

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.

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

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.

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

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.

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

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.

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

Epigenetics of obesity: beyond the genome sequence.

Science.gov (United States)

Cordero, Paul; Li, Jiawei; Oben, Jude A

2015-07-01

After the study of the gene code as a trigger for obesity, epigenetic code has appeared as a novel tool in the diagnosis, prognosis and treatment of obesity, and its related comorbidities. This review summarizes the status of the epigenetic field associated with obesity, and the current epigenetic-based approaches for obesity treatment. Thanks to technical advances, novel and key obesity-associated polymorphisms have been described by genome-wide association studies, but there are limitations with their predictive power. Epigenetics is also studied for disease association, which involves decoding of the genome information, transcriptional status and later phenotypes. Obesity could be induced during adult life by feeding and other environmental factors, and there is a strong association between obesity features and specific epigenetic patterns. These patterns could be established during early life stages, and programme the risk of obesity and its comorbidities during adult life. Furthermore, recent studies have shown that DNA methylation profile could be applied as biomarkers of diet-induced weight loss treatment. High-throughput technologies, recently implemented for commercial genetic test panels, could soon lead to the creation of epigenetic test panels for obesity. Nonetheless, epigenetics is a modifiable risk factor, and different dietary patterns or environmental insights during distinct stages of life could lead to rewriting of the epigenetic profile.

Prognostic DNA Methylation Markers for Prostate Cancer

Directory of Open Access Journals (Sweden)

Siri H. Strand

2014-09-01

Full Text Available Prostate cancer (PC is the most commonly diagnosed neoplasm and the third most common cause of cancer-related death amongst men in the Western world. PC is a clinically highly heterogeneous disease, and distinction between aggressive and indolent disease is a major challenge for the management of PC. Currently, no biomarkers or prognostic tools are able to accurately predict tumor progression at the time of diagnosis. Thus, improved biomarkers for PC prognosis are urgently needed. This review focuses on the prognostic potential of DNA methylation biomarkers for PC. Epigenetic changes are hallmarks of PC and associated with malignant initiation as well as tumor progression. Moreover, DNA methylation is the most frequently studied epigenetic alteration in PC, and the prognostic potential of DNA methylation markers for PC has been demonstrated in multiple studies. The most promising methylation marker candidates identified so far include PITX2, C1orf114 (CCDC181 and the GABRE~miR-452~miR-224 locus, in addition to the three-gene signature AOX1/C1orf114/HAPLN3. Several other biomarker candidates have also been investigated, but with less stringent clinical validation and/or conflicting evidence regarding their possible prognostic value available at this time. Here, we review the current evidence for the prognostic potential of DNA methylation markers in PC.

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.

Epigenetic Pathways of Oncogenic Viruses: Therapeutic Promises.

Science.gov (United States)

El-Araby, Amr M; Fouad, Abdelrahman A; Hanbal, Amr M; Abdelwahab, Sara M; Qassem, Omar M; El-Araby, Moustafa E

2016-02-01

Cancerous transformation comprises different events that are both genetic and epigenetic. The ultimate goal for such events is to maintain cell survival and proliferation. This transformation occurs as a consequence of different features such as environmental and genetic factors, as well as some types of infection. Many viral infections are considered to be causative agents of a number of different malignancies. To convert normal cells into cancerous cells, oncogenic viruses must function at the epigenetic level to communicate with their host cells. Oncogenic viruses encode certain epigenetic factors that lead to the immortality and proliferation of infected cells. The epigenetic effectors produced by oncogenic viruses constitute appealing targets to prevent and treat malignant diseases caused by these viruses. In this review, we highlight the importance of epigenetic reprogramming for virus-induced oncogenesis, with special emphasis on viral epigenetic oncoproteins as therapeutic targets. The discovery of molecular components that target epigenetic pathways, especially viral factors, is also discussed. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

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

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...

Conference scene: Select Biosciences Epigenetics Europe 2010.

Science.gov (United States)

Razvi, Enal S

2011-02-01

The field of epigenetics is now on a geometric rise, driven in a large part by the realization that modifiers of chromatin are key regulators of biological processes in vivo. The three major classes of epigenetic effectors are DNA methylation, histone post-translational modifications (such as acetylation, methylation or phosphorylation) and small noncoding RNAs (most notably microRNAs). In this article, I report from Select Biosciences Epigenetics Europe 2010 industry conference held on 14-15 September 2010 at The Burlington Hotel, Dublin, Ireland. This industry conference was extremely well attended with a global pool of delegates representing the academic research community, biotechnology companies and pharmaceutical companies, as well as the technology/tool developers. This conference represented the current state of the epigenetics community with cancer/oncology as a key driver. In fact, it has been estimated that approximately 45% of epigenetic researchers today identify cancer/oncology as their main area of focus vis-à-vis their epigenetic research efforts.

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.

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.

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.

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.

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.

PET Metabolic Biomarkers for Cancer

Directory of Open Access Journals (Sweden)

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.

Long Non-Coding RNA in Cancer

Directory of Open Access Journals (Sweden)

Damjan Glavač

2013-02-01

Full Text Available Long non-coding RNAs (lncRNAs are pervasively transcribed in the genome and are emerging as new players in tumorigenesis due to their various functions in transcriptional, posttranscriptional and epigenetic mechanisms of gene regulation. LncRNAs are deregulated in a number of cancers, demonstrating both oncogenic and tumor suppressive roles, thus suggesting their aberrant expression may be a substantial contributor in cancer development. In this review, we will summarize their emerging role in human cancer and discuss their perspectives in diagnostics as potential biomarkers.

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.

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

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.

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.

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

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.

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.

Nutrients and the Pancreas: An Epigenetic Perspective

Directory of Open Access Journals (Sweden)

Andee Weisbeck

2017-03-01

Full Text Available Pancreatic cancer is the fourth most common cause of cancer-related deaths with a dismal average five-year survival rate of six percent. Substitutional progress has been made in understanding how pancreatic cancer develops and progresses. Evidence is mounting which demonstrates that diet and nutrition are key factors in carcinogenesis. In particular, diets low in folate and high in fruits, vegetables, red/processed meat, and saturated fat have been identified as pancreatic cancer risk factors with a proposed mechanism involving epigenetic modifications or gene regulation. We review the current literature assessing the correlation between diet, epigenetics, and pancreatic cancer.

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.

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

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

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

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.

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...

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

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.

Epigenetics of oropharyngeal squamous cell carcinoma: opportunities for novel chemotherapeutic targets.

Science.gov (United States)

Lindsay, Cameron; Seikaly, Hadi; Biron, Vincent L

2017-01-31

Epigenetic modifications are heritable changes in gene expression that do not directly alter DNA sequence. These modifications include DNA methylation, histone post-translational modifications, small and non-coding RNAs. Alterations in epigenetic profiles cause deregulation of fundamental gene expression pathways associated with carcinogenesis. The role of epigenetics in oropharyngeal squamous cell carcinoma (OPSCC) has recently been recognized, with implications for novel biomarkers, molecular diagnostics and chemotherapeutics. In this review, important epigenetic pathways in human papillomavirus (HPV) positive and negative OPSCC are summarized, as well as the potential clinical utility of this knowledge.This material has never been published and is not currently under evaluation in any other peer-reviewed publication.

Epigenetic architecture and miRNA: reciprocal regulators

DEFF Research Database (Denmark)

Wiklund, Erik D; Kjems, Jørgen; Clark, Susan J

2010-01-01

Deregulation of epigenetic and microRNA (miRNA) pathways are emerging as key events in carcinogenesis. miRNA genes can be epigenetically regulated and miRNAs can themselves repress key enzymes that drive epigenetic remodeling. Epigenetic and miRNA functions are thus tightly interconnected......RNAs) are considered especially promising in clinical applications, and their biogenesis and function is a subject of active research. In this review, the current status of epigenetic miRNA regulation is summarized and future therapeutic prospects in the field are discussed with a focus on cancer....

Comparing the DNA hypermethylome with gene mutations in human colorectal cancer.

Directory of Open Access Journals (Sweden)

Kornel E Schuebel

2007-09-01

Full Text Available We have developed a transcriptome-wide approach to identify genes affected by promoter CpG island DNA hypermethylation and transcriptional silencing in colorectal cancer. By screening cell lines and validating tumor-specific hypermethylation in a panel of primary human colorectal cancer samples, we estimate that nearly 5% or more of all known genes may be promoter methylated in an individual tumor. When directly compared to gene mutations, we find larger numbers of genes hypermethylated in individual tumors, and a higher frequency of hypermethylation within individual genes harboring either genetic or epigenetic changes. Thus, to enumerate the full spectrum of alterations in the human cancer genome, and to facilitate the most efficacious grouping of tumors to identify cancer biomarkers and tailor therapeutic approaches, both genetic and epigenetic screens should be undertaken.

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.

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.

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...

Epigenetic regulation of ageing: linking environmental inputs to genomic stability

Science.gov (United States)

Benayoun, Bérénice A.; Pollina, Elizabeth A.; Brunet, Anne

2016-01-01

Preface Ageing is affected by both genetic and non-genetic factors. Here, we review the chromatin-based epigenetic changes that occur during ageing, the role of chromatin modifiers in modulating lifespan and the importance of epigenetic signatures as biomarkers of ageing. We also discuss how epigenome remodeling by environmental stimuli impacts several aspects of transcription and genomic stability, with important consequences on longevity, and outline epigenetic differences between the ‘mortal soma’ and the ‘immortal germline’. Finally, we discuss the inheritance of ageing characteristics and potential chromatin-based strategies to delay or reverse hallmarks of ageing or age-related diseases. PMID:26373265

Environmental chemical exposures and human epigenetics

Science.gov (United States)

Hou, Lifang; Zhang, Xiao; Wang, Dong; Baccarelli, Andrea

2012-01-01

Every year more than 13 million deaths worldwide are due to environmental pollutants, and approximately 24% of diseases are caused by environmental exposures that might be averted through preventive measures. Rapidly growing evidence has linked environmental pollutants with epigenetic variations, including changes in DNA methylation, histone modifications and microRNAs. Environ mental chemicals and epigenetic changes All of these mechanisms are likely to play important roles in disease aetiology, and their modifications due to environmental pollutants might provide further understanding of disease aetiology, as well as biomarkers reflecting exposures to environmental pollutants and/or predicting the risk of future disease. We summarize the findings on epigenetic alterations related to environmental chemical exposures, and propose mechanisms of action by means of which the exposures may cause such epigenetic changes. We discuss opportunities, challenges and future directions for future epidemiology research in environmental epigenomics. Future investigations are needed to solve methodological and practical challenges, including uncertainties about stability over time of epigenomic changes induced by the environment, tissue specificity of epigenetic alterations, validation of laboratory methods, and adaptation of bioinformatic and biostatistical methods to high-throughput epigenomics. In addition, there are numerous reports of epigenetic modifications arising following exposure to environmental toxicants, but most have not been directly linked to disease endpoints. To complete our discussion, we also briefly summarize the diseases that have been linked to environmental chemicals-related epigenetic changes. PMID:22253299

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.

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.

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.

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

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...

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.

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.

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.

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

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/.

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.

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.

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

Epigenetic impact of curcumin on stroke prevention

OpenAIRE

Kalani, Anuradha; Kamat, Pradip K; Kalani, Komal; Tyagi, Neetu

2014-01-01

The epigenetic impact of curcumin in stroke and neurodegenerative disorders is curiosity-arousing. It is derived from Curcuma longa (spice), possesses anti-oxidative, anti-inflammatory, anti-lipidemic, neuro-protective and recently shown to exhibit epigenetic modulatory properties. Epigenetic studies include DNA methylation, histone modifications and RNA-based mechanisms which regulate gene expression without altering nucleotide sequences. Curcumin has been shown to affect cancer by altering ...

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

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.

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...

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.

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...

Multi-platform whole-genome microarray analyses refine the epigenetic signature of breast cancer metastasis with gene expression and copy number.

Directory of Open Access Journals (Sweden)

Joseph Andrews

2010-01-01

Full Text Available We have previously identified genome-wide DNA methylation changes in a cell line model of breast cancer metastasis. These complex epigenetic changes that we observed, along with concurrent karyotype analyses, have led us to hypothesize that complex genomic alterations in cancer cells (deletions, translocations and ploidy are superimposed over promoter-specific methylation events that are responsible for gene-specific expression changes observed in breast cancer metastasis.We undertook simultaneous high-resolution, whole-genome analyses of MDA-MB-468GFP and MDA-MB-468GFP-LN human breast cancer cell lines (an isogenic, paired lymphatic metastasis cell line model using Affymetrix gene expression (U133, promoter (1.0R, and SNP/CNV (SNP 6.0 microarray platforms to correlate data from gene expression, epigenetic (DNA methylation, and combination copy number variant/single nucleotide polymorphism microarrays. Using Partek Software and Ingenuity Pathway Analysis we integrated datasets from these three platforms and detected multiple hypomethylation and hypermethylation events. Many of these epigenetic alterations correlated with gene expression changes. In addition, gene dosage events correlated with the karyotypic differences observed between the cell lines and were reflected in specific promoter methylation patterns. Gene subsets were identified that correlated hyper (and hypo methylation with the loss (or gain of gene expression and in parallel, with gene dosage losses and gains, respectively. Individual gene targets from these subsets were also validated for their methylation, expression and copy number status, and susceptible gene pathways were identified that may indicate how selective advantage drives the processes of tumourigenesis and metastasis.Our approach allows more precisely profiling of functionally relevant epigenetic signatures that are associated with cancer progression and metastasis.

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

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.

Prenatal and early life influences on epigenetic age in children

DEFF Research Database (Denmark)

Simpkin, Andrew J; Hemani, Gibran; Suderman, Matthew

2016-01-01

age for these samples. AA was defined as the residuals from regressing epigenetic age on actual age. AA was tested for associations with cross-sectional clinical variables in children. We identified associations between AA and sex, birth weight, birth by caesarean section and several maternal......). In children, epigenetic AA measures are associated with several clinically relevant variables, and early life exposures appear to be associated with changes in AA during adolescence. Further research into epigenetic aging, including the use of causal inference methods, is required to better our understanding......DNA methylation-based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration (AA) in adults. Very little is known about genetic or environmental...

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...

Individuality and epigenetics in obesity.

Science.gov (United States)

Campión, J; Milagro, F I; Martínez, J A

2009-07-01

Excessive weight gain arises from the interactions among environmental factors, genetic predisposition and the individual behavior. However, it is becoming evident that interindividual differences in obesity susceptibility depend also on epigenetic factors. Epigenetics studies the heritable changes in gene expression that do not involve changes to the underlying DNA sequence. These processes include DNA methylation, covalent histone modifications, chromatin folding and, more recently described, the regulatory action of miRNAs and polycomb group complexes. In this review, we focus on experimental evidences concerning dietary factors influencing obesity development by epigenetic mechanisms, reporting treatment doses and durations. Moreover, we present a bioinformatic analysis of promoter regions for the search of future epigenetic biomarkers of obesity, including methylation pattern analyses of several obesity-related genes (epiobesigenes), such as FGF2, PTEN, CDKN1A and ESR1, implicated in adipogenesis, SOCS1/SOCS3, in inflammation, and COX7A1 LPL, CAV1, and IGFBP3, in intermediate metabolism and insulin signalling. The identification of those individuals that at an early age could present changes in the methylation profiles of specific genes could help to predict their susceptibility to later develop obesity, which may allow to prevent and follow-up its progress, as well as to research and develop newer therapeutic approaches.

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.

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

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.

Current and future molecular diagnostics in non-small-cell lung cancer.

Science.gov (United States)

Li, Chun Man; Chu, Wing Ying; Wong, Di Lun; Tsang, Hin Fung; Tsui, Nancy Bo Yin; Chan, Charles Ming Lok; Xue, Vivian Wei Wen; Siu, Parco Ming Fai; Yung, Benjamin Yat Ming; Chan, Lawrence Wing Chi; Wong, Sze Chuen Cesar

2015-01-01

The molecular investigation of lung cancer has opened up an advanced area for the diagnosis and therapeutic management of lung cancer patients. Gene alterations in cancer initiation and progression provide not only information on molecular changes in lung cancer but also opportunities in advanced therapeutic regime by personalized targeted therapy. EGFR mutations and ALK rearrangement are important predictive biomarkers for the efficiency of tyrosine kinase inhibitor treatment in lung cancer patients. Moreover, epigenetic aberration and microRNA dysregulation are recent advances in the early detection and monitoring of lung cancer. Although a wide range of molecular tests are available, standardization and validation of assay protocols are essential for the quality of the test outcome. In this review, current and new advancements of molecular biomarkers for non-small-cell lung cancer will be discussed. Recommendations on future development of molecular diagnostic services will also be explored.

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 ...

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

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.

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.

A new device for liver cancer biomarker detection with high accuracy

Directory of Open Access Journals (Sweden)

Shuaipeng Wang

2015-06-01

Full Text Available A novel cantilever array-based bio-sensor was batch-fabricated with IC compatible MEMS technology for precise liver cancer bio-marker detection. A micro-cavity was designed in the free end of the cantilever for local antibody-immobilization, thus adsorption of the cancer biomarker is localized in the micro-cavity, and the adsorption-induced k variation can be dramatically reduced with comparison to that caused by adsorption of the whole lever. The cantilever is pizeoelectrically driven into vibration which is pizeoresistively sensed by Wheatstone bridge. These structural features offer several advantages: high sensitivity, high throughput, high mass detection accuracy, and small volume. In addition, an analytical model has been established to eliminate the effect of adsorption-induced lever stiffness change and has been applied to precise mass detection of cancer biomarker AFP, the detected AFP antigen mass (7.6 pg/ml is quite close to the calculated one (5.5 pg/ml, two orders of magnitude better than the value by the fully antibody-immobilized cantilever sensor. These approaches will promote real application of the cantilever sensors in early diagnosis of cancer.

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.

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.

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

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.

Prognostic significance of aberrantly silenced ANPEP expression in prostate cancer

DEFF Research Database (Denmark)

Sørensen, Karina Dalsgaard; Abildgaard, Mette Opstrup; Haldrup, Christa

2013-01-01

Background:Novel biomarkers for prostate cancer (PC) are urgently needed. This study investigates the expression, epigenetic regulation, and prognostic potential of ANPEP in PC.Methods:Aminopeptidase N (APN; encoded by ANPEP) expression was analysed by immunohistochemistry using tissue microarrays...... in three hypermethylated prostate cell lines, suggesting epigenetic silencing. Negative APN immunoreactivity was significantly associated with short RFS and short CSS in the RP and CT cohort, respectively, independently of routine clinicopathological predictors. Combining APN with a known angiogenesis...... representing 267 radical prostatectomy (RP) and 111 conservatively treated (CT) PC patients. Clinical end points were recurrence-free survival (RFS) and cancer-specific survival (CSS), respectively. The ANPEP promoter methylation levels were determined by bisulphite sequencing or MethyLight analysis in 278...

Epigenetics in Alzheimer's Disease: Perspective of DNA Methylation.

Science.gov (United States)

Qazi, Talal Jamil; Quan, Zhenzhen; Mir, Asif; Qing, Hong

2018-02-01

Research over the years has shown that causes of Alzheimer's disease are not well understood, but over the past years, the involvement of epigenetic mechanisms in the developing memory formation either under pathological or physiological conditions has become clear. The term epigenetics represents the heredity of changes in phenotype that are independent of altered DNA sequences. Different studies validated that cytosine methylation of genomic DNA decreases with age in different tissues of mammals, and therefore, the role of epigenetic factors in developing neurological disorders in aging has been under focus. In this review, we summarized and reviewed the involvement of different epigenetic mechanisms especially the DNA methylation in Alzheimer's disease (AD), late-onset Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and autosomal dominant Alzheimer's disease (ADAD). Down to the minutest of details, we tried to discuss the methylation patterns like mitochondrial DNA methylation and ribosomal DNA (rDNA) methylation. Additionally, we mentioned some therapeutic approaches related to epigenetics, which could provide a potential cure for AD. Moreover, we reviewed some recent studies that validate DNA methylation as a potential biomarker and its role in AD. We hope that this review will provide new insights into the understanding of AD pathogenesis from the epigenetic perspective especially from the perspective of DNA methylation.

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.

Epigenetic features of testicular germ cell tumours in relation to epigenetic characteristics of foetal germ cells

DEFF Research Database (Denmark)

Kristensen, Dina Graae; Skakkebæk, Niels E; Rajpert-De Meyts, Ewa

2013-01-01

in humans. However, the common precursor of testicular cancers- the carcinoma in situ (CIS) cell- is thought to be an arrested foetal germ cell. Therefore studies of CIS cells may leverage information on human foetal germ cell development and, in particular, when neoplastic transformation is initiated....... In this review, we will focus on current knowledge of the epigenetics of CIS cells and relate it to the epigenetic changes occurring in early developing germ cells of mice during specification, migration and colonization. We will focus on DNA methylation and some of the best studied histone modifications like H3...... event in the initiation of testicular germ cell cancer. Even though only sparse information is available on epigenetic cues in human foetal germ cells, these indicate that the developmental patterns differ from the findings in mice and emphasize the need for further studies of foetal germ cell...

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.

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.

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.

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

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

MicroRNAs, epigenetics and disease

DEFF Research Database (Denmark)

Silahtaroglu, Asli; Stenvang, Jan

2010-01-01

Epigenetics is defined as the heritable chances that affect gene expression without changing the DNA sequence. Epigenetic regulation of gene expression can be through different mechanisms such as DNA methylation, histone modifications and nucleosome positioning. MicroRNAs are short RNA molecules...... which do not code for a protein but have a role in post-transcriptional silencing of multiple target genes by binding to their 3' UTRs (untranslated regions). Both epigenetic mechanisms, such as DNA methylation and histone modifications, and the microRNAs are crucial for normal differentiation...... diseases. In the present chapter we will mainly focus on microRNAs and methylation and their implications in human disease, mainly in cancer....

Epigenetic Modifications of Major Depressive Disorder

Directory of Open Access Journals (Sweden)

Kathleen Saavedra

2016-08-01

Full Text Available Major depressive disorder (MDD is a chronic disease whose neurological basis and pathophysiology remain poorly understood. Initially, it was proposed that genetic variations were responsible for the development of this disease. Nevertheless, several studies within the last decade have provided evidence suggesting that environmental factors play an important role in MDD pathophysiology. Alterations in epigenetics mechanism, such as DNA methylation, histone modification and microRNA expression could favor MDD advance in response to stressful experiences and environmental factors. The aim of this review is to describe genetic alterations, and particularly altered epigenetic mechanisms, that could be determinants for MDD progress, and how these alterations may arise as useful screening, diagnosis and treatment monitoring biomarkers of depressive disorders.

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...

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.

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

Aberrantly methylated genes in human papillary thyroid cancer and their association with BRAF/RAS mutation.

Directory of Open Access Journals (Sweden)

Yasuko eKikuchi

2013-12-01

Full Text Available Cancer arises through accumulation of epigenetic and genetic alteration. Aberrant promoter methylation is a common epigenetic mechanism of gene silencing in cancer cells. We here performed genome-wide analysis of DNA methylation of promoter regions by Infinium HumanMethylation27 BeadChip, using 14 clinical papillary thyroid cancer samples and 10 normal thyroid samples. Among the 14 papillary cancer cases, 11 showed frequent aberrant methylation, but the other three cases showed no aberrant methylation at all. Distribution of the hypermethylation among cancer samples was non-random, which implied existence of a subset of preferentially methylated papillary thyroid cancer. Among 25 frequently methylated genes, methylation status of six genes (HIST1H3J, POU4F2, SHOX2, PHKG2, TLX3, HOXA7 was validated quantitatively by pyrosequencing. Epigenetic silencing of these genes in methylated papillary thyroid cancer cell lines was confirmed by gene re-expression following treatment with 5-aza-2'-deoxycytidine and trichostatin A, and detected by real-time RT-PCR. Methylation of these six genes was validated by analysis of additional 20 papillary thyroid cancer and 10 normal samples. Among the 34 cancer samples in total, 26 cancer samples with preferential methylation were significantly associated with mutation of BRAF/RAS oncogene (P=0.04, Fisher’s exact test. Thus we identified new genes with frequent epigenetic hypermethylation in papillary thyroid cancer, two subsets of either preferentially methylated or hardly methylated papillary thyroid cancer, with a concomitant occurrence of oncogene mutation and gene methylation. These hypermethylated genes may constitute potential biomarkers for papillary thyroid cancer.

Aberrant Transforming Growth Factor β1 Signaling and SMAD4 Nuclear Translocation Confer Epigenetic Repression of ADAM19 in Ovarian Cancer

Directory of Open Access Journals (Sweden)

Michael W.Y. Chan

2008-09-01

Full Text Available Transforming growth factor-beta (TGF-β/SMAD signaling is a key growth regulatory pathway often dysregulated in ovarian cancer and other malignancies. Although loss of TGF-β–mediated growth inhibition has been shown to contribute to aberrant cell behavior, the epigenetic consequence(s of impaired TGF-β/SMAD signaling on target genes is not well established. In this study, we show that TGF-β1 causes growth inhibition of normal ovarian surface epithelial cells, induction of nuclear translocation SMAD4, and up-regulation of ADAM19 (a disintegrin and metalloprotease domain 19, a newly identified TGF-β1 target gene. Conversely, induction and nuclear translocation of SMAD4 were negligible in ovarian cancer cells refractory to TGF-β1 stimulation, and ADAM19 expression was greatly reduced. Furthermore, in the TGF-β1 refractory cells, an inactive chromatin environment, marked by repressive histone modifications (trimethyl-H3K27 and dimethyl-H3K9 and histone deacetylase, was associated with the ADAM19 promoter region. However, the CpG island found within the promoter and first exon of ADAM19 remained generally unmethylated. Although disrupted growth factor signaling has been linked to epigenetic gene silencing in cancer, this is the first evidence demonstrating that impaired TGF-β1 signaling can result in the formation of a repressive chromatin state and epigenetic suppression of ADAM19. Given the emerging role of ADAMs family proteins in growth factor regulation in normal cells, we suggest that epigenetic dysregulation of ADAM19 may contribute to the neoplastic process in ovarian cancer.

Epigenetics in women's health care.

Science.gov (United States)

Pozharny, Yevgeniya; Lambertini, Luca; Clunie, Garfield; Ferrara, Lauren; Lee, Men-Jean

2010-01-01

Epigenetics refers to structural modifications to genes that do not change the nucleotide sequence itself but instead control and regulate gene expression. DNA methylation, histone modification, and RNA regulation are some of the mechanisms involved in epigenetic modification. Epigenetic changes are believed to be a result of changes in an organism's environment that result in fixed and permanent changes in most differentiated cells. Some environmental changes that have been linked to epigenetic changes include starvation, folic acid, and various chemical exposures. There are periods in an organism's life cycle in which the organism is particularly susceptible to epigenetic influences; these include fertilization, gametogenesis, and early embryo development. These are also windows of opportunity for interventions during the reproductive life cycle of women to improve maternal-child health. New data suggest that epigenetic influences might be involved in the regulation of fetal development and the pathophysiology of adult diseases such as cancer, diabetes, obesity, and neurodevelopmental disorders. Various epigenetic mechanisms may also be involved in the pathogenesis of preeclampsia and intrauterine growth restriction. Additionally, environmental exposures are being held responsible for causing epigenetic changes that lead to a disease process. Exposure to heavy metals, bioflavonoids, and endocrine disruptors, such as bisphenol A and phthalates, has been shown to affect the epigenetic memory of an organism. Their long-term effects are unclear at this point, but many ongoing studies are attempting to elucidate the pathophysiological effects of such gene-environment interactions. (c) 2010 Mount Sinai School of Medicine.

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.

Epigenetic modifications and diabetic nephropathy

Directory of Open Access Journals (Sweden)

Marpadga A. Reddy

2012-09-01

Full Text Available Diabetic nephropathy (DN is a major complication associated with both type 1 and type 2 diabetes, and a leading cause of end-stage renal disease. Conventional therapeutic strategies are not fully efficacious in the treatment of DN, suggesting an incomplete understanding of the gene regulation mechanisms involved in its pathogenesis. Furthermore, evidence from clinical trials has demonstrated a “metabolic memory” of prior exposure to hyperglycemia that continues to persist despite subsequent glycemic control. This remains a major challenge in the treatment of DN and other vascular complications. Epigenetic mechanisms such as DNA methylation, nucleosomal histone modifications, and noncoding RNAs control gene expression through regulation of chromatin structure and function and post-transcriptional mechanisms without altering the underlying DNA sequence. Emerging evidence indicates that multiple factors involved in the etiology of diabetes can alter epigenetic mechanisms and regulate the susceptibility to diabetes complications. Recent studies have demonstrated the involvement of histone lysine methylation in the regulation of key fibrotic and inflammatory genes related to diabetes complications including DN. Interestingly, histone lysine methylation persisted in vascular cells even after withdrawal from the diabetic milieu, demonstrating a potential role of epigenetic modifications in metabolic memory. Rapid advances in high-throughput technologies in the fields of genomics and epigenomics can lead to the identification of genome-wide alterations in key epigenetic modifications in vascular and renal cells in diabetes. Altogether, these findings can lead to the identification of potential predictive biomarkers and development of novel epigenetic therapies for diabetes and its associated complications.

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.

The role of epigenetics in genetic and environmental epidemiology.

Science.gov (United States)

Ladd-Acosta, Christine; Fallin, M Daniele

2016-02-01

Epidemiology is the branch of science that investigates the causes and distribution of disease in populations in order to provide preventative measures and promote human health. The fields of genetic and environmental epidemiology primarily seek to identify genetic and environmental risk factors for disease, respectively. Epigenetics is emerging as an important piece of molecular data to include in these studies because it can provide mechanistic insights into genetic and environmental risk factors for disease, identify potential intervention targets, provide biomarkers of exposure, illuminate gene-environment interactions and help localize disease-relevant genomic regions. Here, we describe the importance of including epigenetics in genetic and environmental epidemiology studies, provide a conceptual framework when considering epigenetic data in population-based studies and touch upon the many challenges that lie ahead.

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.

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...

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.

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.

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.

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.

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.

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

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.

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...

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.

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.

Comparative Tissue Proteomics of Microdissected Specimens Reveals Novel Candidate Biomarkers of Bladder Cancer*

Science.gov (United States)

Chen, Chien-Lun; Chung, Ting; Wu, Chih-Ching; Ng, Kwai-Fong; Yu, Jau-Song; Tsai, Cheng-Han; Chang, Yu-Sun; Liang, Ying; Tsui, Ke-Hung; Chen, Yi-Ting

2015-01-01

More than 380,000 new cases of bladder cancer are diagnosed worldwide, accounting for ∼150,200 deaths each year. To discover potential biomarkers of bladder cancer, we employed a strategy combining laser microdissection, isobaric tags for relative and absolute quantitation labeling, and liquid chromatography-tandem MS (LC-MS/MS) analysis to profile proteomic changes in fresh-frozen bladder tumor specimens. Cellular proteins from four pairs of surgically resected primary bladder cancer tumor and adjacent nontumorous tissue were extracted for use in two batches of isobaric tags for relative and absolute quantitation experiments, which identified a total of 3220 proteins. A DAVID (database for annotation, visualization and integrated discovery) analysis of dysregulated proteins revealed that the three top-ranking biological processes were extracellular matrix organization, extracellular structure organization, and oxidation-reduction. Biological processes including response to organic substances, response to metal ions, and response to inorganic substances were highlighted by up-expressed proteins in bladder cancer. Seven differentially expressed proteins were selected as potential bladder cancer biomarkers for further verification. Immunohistochemical analyses showed significantly elevated levels of three proteins—SLC3A2, STMN1, and TAGLN2—in tumor cells compared with noncancerous bladder epithelial cells, and suggested that TAGLN2 could be a useful tumor tissue marker for diagnosis (AUC = 0.999) and evaluating lymph node metastasis in bladder cancer patients. ELISA results revealed significantly increased urinary levels of both STMN1 and TAGLN2 in bladder cancer subgroups compared with control groups. In comparisons with age-matched hernia urine specimens, urinary TAGLN2 in bladder cancer samples showed the largest fold change (7.13-fold), with an area-under-the-curve value of 0.70 (p < 0.001, n = 205). Overall, TAGLN2 showed the most significant

EPA Workshop on Epigenetics and Cumulative Risk ...

Science.gov (United States)

Agenda Download the Workshop Agenda (PDF) The workshop included presentations and discussions by scientific experts pertaining to three topics (i.e., epigenetic changes associated with diverse stressors, key science considerations in understanding epigenetic changes, and practical application of epigenetic tools to address cumulative risks from environmental stressors), to address several questions under each topic, and included an opportunity for attendees to participate in break-out groups, provide comments and ask questions. Workshop Goals The workshop seeks to examine the opportunity for use of aggregate epigenetic change as an indicator in cumulative risk assessment for populations exposed to multiple stressors that affect epigenetic status. Epigenetic changes are specific molecular changes around DNA that alter expression of genes. Epigenetic changes include DNA methylation, formation of histone adducts, and changes in micro RNAs. Research today indicates that epigenetic changes are involved in many chronic diseases (cancer, cardiovascular disease, obesity, diabetes, mental health disorders, and asthma). Research has also linked a wide range of stressors including pollution and social factors with occurrence of epigenetic alterations. Epigenetic changes have the potential to reflect impacts of risk factors across multiple stages of life. Only recently receiving attention is the nexus between the factors of cumulative exposure to environmental

Is epigenetics an important link between early life events and adult disease?

Science.gov (United States)

Epigenetic mechanisms provide one potential explanation for how environmental influences in early life cause long-term changes in chronic disease susceptibility. Whereas epigenetic dysregulation is increasingly implicated in various rare developmental syndromes and cancer, the role of epigenetics in...

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.

Biomarker discovery for colon cancer using a 761 gene RT-PCR assay

Directory of Open Access Journals (Sweden)

Hackett James R

2007-08-01

Full Text Available Abstract Background Reverse transcription PCR (RT-PCR is widely recognized to be the gold standard method for quantifying gene expression. Studies using RT-PCR technology as a discovery tool have historically been limited to relatively small gene sets compared to other gene expression platforms such as microarrays. We have recently shown that TaqMan® RT-PCR can be scaled up to profile expression for 192 genes in fixed paraffin-embedded (FPE clinical study tumor specimens. This technology has also been used to develop and commercialize a widely used clinical test for breast cancer prognosis and prediction, the Onco typeDX™ assay. A similar need exists in colon cancer for a test that provides information on the likelihood of disease recurrence in colon cancer (prognosis and the likelihood of tumor response to standard chemotherapy regimens (prediction. We have now scaled our RT-PCR assay to efficiently screen 761 biomarkers across hundreds of patient samples and applied this process to biomarker discovery in colon cancer. This screening strategy remains attractive due to the inherent advantages of maintaining platform consistency from discovery through clinical application. Results RNA was extracted from formalin fixed paraffin embedded (FPE tissue, as old as 28 years, from 354 patients enrolled in NSABP C-01 and C-02 colon cancer studies. Multiplexed reverse transcription reactions were performed using a gene specific primer pool containing 761 unique primers. PCR was performed as independent TaqMan® reactions for each candidate gene. Hierarchal clustering demonstrates that genes expected to co-express form obvious, distinct and in certain cases very tightly correlated clusters, validating the reliability of this technical approach to biomarker discovery. Conclusion We have developed a high throughput, quantitatively precise multi-analyte gene expression platform for biomarker discovery that approaches low density DNA arrays in numbers of

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

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.

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...

Epigenetics and Vasculitis: a Comprehensive Review.

Science.gov (United States)

Renauer, Paul; Coit, Patrick; Sawalha, Amr H

2016-06-01

Vasculitides represent a group of relatively rare systemic inflammatory diseases of the blood vessels. Despite recent progress in understanding the genetic basis and the underlying pathogenic mechanisms in vasculitis, the etiology and pathogenesis of vasculitis remain incompletely understood. Epigenetic dysregulation plays an important role in immune-mediated diseases, and the contribution of epigenetic aberrancies in vasculitis is increasingly being recognized. Histone modifications in the PR3 and MPO gene loci might be mechanistically involved in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Similarly, other studies revealed important epigenetic contribution to other vasculitides, including Kawasaki disease and IgA vasculitis. More recently, genome-wide epigenomic studies have been performed in several vasculitides. A recent genome-wide DNA methylation study uncovered an important role for epigenetic remodeling of cytoskeleton-related genes in the pathogenesis of Behçet's disease and suggested that reversal of some of these DNA methylation changes associates with disease remission. Genome-wide DNA methylation profiling characterized the inflammatory response in temporal artery tissue from patients with giant cell arteritis and showed increased activation of calcineurin/nuclear factor of activated T cells (NFAT) signaling, prompting the suggestion that a specific calcineurin/NFAT inhibitor that is well tolerated and with the added beneficial anti-platelet activity, such as dipyridamole, might be of therapeutic potential in giant cell arteritis. While epigenetic studies in systemic vasculitis are still in their infancy, currently available data clearly indicate that investigating the epigenetic mechanisms underlying these diseases will help to better understand the pathogenesis of vasculitis and provide novel targets for the development of disease biomarkers and new therapies.

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....

An emerging role for epigenetic factors in relation to executive function.

Science.gov (United States)

Ibrahim, Omar; Sutherland, Heidi G; Haupt, Larisa M; Griffiths, Lyn R

2017-11-20

Executive function (EF) includes a range of decision-making and higher-order thinking processes. Although the genetic basis of EF has been studied and reviewed, epigenetic factors that influence EF are an emerging field of interest; here, we summarize the current research. Work relating to different word combinations of 'Executive Function' and 'Epigenetic' was identified through three academic search directories. Inclusion criteria were human populations, EF testing, epigenetic testing or genotyping related to epigenetic regulation. To date, 14 studies have been reported, which examined epigenetic variation, in particular DNA methylation, in relation to EF assessments conducted in human subjects, with some positive associations found. Study populations included healthy cohorts, as well as psychiatric and neurological patient cohorts. Epigenetics in relation to EF is an emerging area of investigation with relatively few studies to date. Most assay DNA methylation, with some studies suggesting that epigenetic factors can be associated with EF. EF constitutes complex phenotypic and genotypic correlates that differ because of cohort attributes as well as the targeted task examined. Larger studies are required to further elucidate the contribution of epigenetic factors to EF with the identification of epigenetic modifications influencing EF having potential to provide new biomarkers for neuropsychiatric disorders. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

Human adipose-derived mesenchymal stromal cell pigment epithelium-derived factor cytotherapy modifies genetic and epigenetic profiles of prostate cancer cells.

Science.gov (United States)

Zolochevska, Olga; Shearer, Joseph; Ellis, Jayne; Fokina, Valentina; Shah, Forum; Gimble, Jeffrey M; Figueiredo, Marxa L

2014-03-01

Adipose-derived mesenchymal stromal cells (ASCs) are promising tools for delivery of cytotherapy against cancer. However, ASCs can exert profound effects on biological behavior of tumor cells. Our study aimed to examine the influence of ASCs on gene expression and epigenetic methylation profiles of prostate cancer cells as well as the impact of expressing a therapeutic gene on modifying the interaction between ASCs and prostate cancer cells. ASCs were modified by lentiviral transduction to express either green fluorescent protein as a control or pigment epithelium-derived factor (PEDF) as a therapeutic molecule. PC3 prostate cancer cells were cultured in the presence of ASC culture-conditioned media (CCM), and effects on PC3 or DU145. Ras cells were examined by means of real-time quantitative polymerase chain reaction, EpiTect methyl prostate cancer-focused real-time quantitative polymerase chain reaction arrays, and luciferase reporter assays. ASCs transduced with lentiviral vectors were able to mediate expression of several tumor-inhibitory genes, some of which correlated with epigenetic methylation changes on cocultured PC3 prostate cancer cells. When PC3 cells were cultured with ASC-PEDF CCM, we observed a shift in the balance of gene expression toward tumor inhibition, which suggests that PEDF reduces the potential tumor-promoting activity of unmodified ASCs. These results suggest that ASC-PEDF CCM can promote reprogramming of tumor cells in a paracrine manner. An improved understanding of genetic and epigenetic events in prostate cancer growth in response to PEDF paracrine therapy would enable a more effective use of ASC-PEDF, with the goal of achieving safer yet more potent anti-tumor effects. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Identification of DNA methylation biomarkers from Infinium arrays

Directory of Open Access Journals (Sweden)

Richard D Emes

2012-08-01

Full Text Available Epigenetic modifications of DNA, such as cytosine methylation are differentially abundant in diseases such as cancer. A goal for clinical research is finding sites that are differentially methylated between groups of samples to act as potential biomarkers for disease outcome. However, clinical samples are often limited in availability, represent a heterogeneous collection of cells or are of uncertain clinical class. Array based methods for identification of methylation provide a cost effective method to survey a proportion of the methylome at single base resolution. The Illumina Infinium array has become a popular and reliable high throughput method in this field and are proving useful in the identification of biomarkers for disease. Here, we compare a commonly used statistical test with a new intuitive and flexible computational approach to quickly detect differentially methylated sites. The method rapidly identifies and ranks candidate lists with greatest inter-group variability whilst controlling for intra-group variability. Intuitive and biologically relevant filters can be imposed to quickly identify sites and genes of interest.

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

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

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.

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

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

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.

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...

Epigenetic Modifications and Diabetic Retinopathy

Directory of Open Access Journals (Sweden)

Renu A. Kowluru

2013-01-01

Full Text Available Diabetic retinopathy remains one of the most debilitating chronic complications, but despite extensive research in the field, the exact mechanism(s responsible for how retina is damaged in diabetes remains ambiguous. Many metabolic pathways have been implicated in its development, and genes associated with these pathways are altered. Diabetic environment also facilitates epigenetics modifications, which can alter the gene expression without permanent changes in DNA sequence. The role of epigenetics in diabetic retinopathy is now an emerging area, and recent work has shown that genes encoding mitochondrial superoxide dismutase (Sod2 and matrix metalloproteinase-9 (MMP-9 are epigenetically modified, activates of epigenetic modification enzymes, histone lysine demethylase 1 (LSD1, and DNA methyltransferase are increased, and the micro RNAs responsible for regulating nuclear transcriptional factor and VEGF are upregulated. With the growing evidence of epigenetic modifications in diabetic retinopathy, better understanding of these modifications has potential to identify novel targets to inhibit this devastating disease. Fortunately, the inhibitors and mimics targeted towards histone modification, DNA methylation, and miRNAs are now being tried for cancer and other chronic diseases, and better understanding of the role of epigenetics in diabetic retinopathy will open the door for their possible use in combating this blinding disease.

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