Prognostic DNA Methylation Markers for Prostate Cancer

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.

[1]  M. Srougi,et al.  Expression profile of standard and variants forms of CD44 related to prostate cancer behavior , 2015, The International journal of biological markers.

[2]  Amos Tanay,et al.  Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. , 2014, Cell reports.

[3]  G. Kristiansen,et al.  Nucleic acid-based biomarkers in body fluids of patients with urologic malignancies , 2014, Critical reviews in clinical laboratory sciences.

[4]  J. Boonstra,et al.  Causes and Consequences of Age-Related Changes in DNA Methylation: A Role for ROS? , 2014, Biology.

[5]  Alison S. Devonshire,et al.  Towards standardisation of cell-free DNA measurement in plasma: controls for extraction efficiency, fragment size bias and quantification , 2014, Analytical and Bioanalytical Chemistry.

[6]  C. Cordon-Cardo,et al.  Genomic analysis in active surveillance: predicting high-risk disease using tissue biomarkers , 2014, Current opinion in urology.

[7]  D. Chan,et al.  Biomarkers in prostate cancer: what's new? , 2014, Current opinion in oncology.

[8]  K. D. Sørensen,et al.  Hypermethylation of the GABRE∼miR-452∼miR-224 Promoter in Prostate Cancer Predicts Biochemical Recurrence after Radical Prostatectomy , 2014, Clinical Cancer Research.

[9]  Jian-Bing Fan,et al.  Validation Study of Genes with Hypermethylated Promoter Regions Associated with Prostate Cancer Recurrence , 2014, Cancer Epidemiology, Biomarkers & Prevention.

[10]  J. Tost,et al.  Synergistic chromatin repression of the tumor suppressor gene RARB in human prostate cancers , 2014, Epigenetics.

[11]  Dvir Aran,et al.  Unmasking risk loci: DNA methylation illuminates the biology of cancer predisposition , 2014, BioEssays : news and reviews in molecular, cellular and developmental biology.

[12]  K. Chiam,et al.  Epigenetic biomarkers in prostate cancer: Current and future uses. , 2014, Cancer letters.

[13]  Peter A. Jones.  At the tipping point for epigenetic therapies in cancer. , 2014, Journal of Clinical Investigation.

[14]  Wei Li,et al.  Large conserved domains of low DNA methylation maintained by Dnmt3a , 2013, Nature Genetics.

[15]  A. Haese*,et al.  DNA hypermethylation as a predictor of PSA recurrence in patients with low- and intermediate-grade prostate cancer. , 2013, Anticancer research.

[16]  Serena G. Liao,et al.  Whole-genome methylation sequencing reveals distinct impact of differential methylations on gene transcription in prostate cancer. , 2013, The American journal of pathology.

[17]  Peiyong Jiang,et al.  Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing , 2013, Proceedings of the National Academy of Sciences.

[18]  R. Young,et al.  Super-Enhancers in the Control of Cell Identity and Disease , 2013, Cell.

[19]  K. D. Sørensen,et al.  DNA methylation signatures for prediction of biochemical recurrence after radical prostatectomy of clinically localized prostate cancer. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  G. Hon,et al.  Adult tissue methylomes harbor epigenetic memory at embryonic enhancers , 2013, Nature Genetics.

[21]  A. Gnirke,et al.  Charting a dynamic DNA methylation landscape of the human genome , 2013, Nature.

[22]  V. Fiano,et al.  Methylation of APC and GSTP1 in Non-Neoplastic Tissue Adjacent to Prostate Tumour and Mortality from Prostate Cancer , 2013, PloS one.

[23]  D. García-Olmo,et al.  Circulating nucleic acids in plasma and serum (CNAPS): applications in oncology , 2013, OncoTargets and therapy.

[24]  C. Arsov,et al.  Association of PITX2 mRNA down-regulation in prostate cancer with promoter hypermethylation and poor prognosis. , 2013, Urologic oncology.

[25]  John T. Wei,et al.  Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer. , 2013, Urologic oncology.

[26]  Andrew P. Feinberg,et al.  Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host , 2013, Nature Reviews Cancer.

[27]  J. Kench,et al.  Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer , 2013, Oncogene.

[28]  R. Dhir,et al.  Using the epigenetic field defect to detect prostate cancer in biopsy negative patients. , 2013, The Journal of urology.

[29]  Michael Q. Zhang,et al.  Epigenomic Analysis of Multilineage Differentiation of Human Embryonic Stem Cells , 2013, Cell.

[30]  Kyung Park,et al.  Epigenomic alterations in localized and advanced prostate cancer. , 2013, Neoplasia.

[31]  David A. Orlando,et al.  Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers , 2013, Cell.

[32]  G. Kristiansen,et al.  Development and clinical validation of a real-time PCR assay for PITX2 DNA methylation to predict prostate-specific antigen recurrence in prostate cancer patients following radical prostatectomy. , 2013, The Journal of molecular diagnostics : JMD.

[33]  Wim Van Criekinge,et al.  Clinical utility of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study. , 2013, The Journal of urology.

[34]  J. Lindberg,et al.  Exome sequencing of prostate cancer supports the hypothesis of independent tumour origins. , 2013, European urology.

[35]  Martin J. Aryee,et al.  DNA Methylation Alterations Exhibit Intraindividual Stability and Interindividual Heterogeneity in Prostate Cancer Metastases , 2013, Science Translational Medicine.

[36]  Z. Mo,et al.  APC gene hypermethylation and prostate cancer: a systematic review and meta-analysis , 2013, European Journal of Human Genetics.

[37]  D M Berney,et al.  Association between DNA methylation of HSPB1 and death in low Gleason score prostate cancer , 2012, Prostate Cancer and Prostatic Diseases.

[38]  M. Cooperberg,et al.  Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  Sivan Sabato,et al.  DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes , 2013, Genome Biology.

[40]  M. Rubin,et al.  Genome-wide DNA methylation events in TMPRSS2-ERG fusion-negative prostate cancers implicate an EZH2-dependent mechanism with miR-26a hypermethylation. , 2012, Cancer discovery.

[41]  J. Lindberg,et al.  Identification of New Differentially Methylated Genes That Have Potential Functional Consequences in Prostate Cancer , 2012, PloS one.

[42]  T. H. van der Kwast,et al.  Quantitative DNA methylation analysis of genes coding for kallikrein-related peptidases 6 and 10 as biomarkers for prostate cancer , 2012, Epigenetics.

[43]  J. Herman,et al.  The Epigenetic promise for prostate cancer diagnosis , 2012, The Prostate.

[44]  B. Trock,et al.  Evaluation of GSTP1 and APC methylation as indicators for repeat biopsy in a high‐risk cohort of men with negative initial prostate biopsies , 2012, BJU international.

[45]  Peter A. Jones.  Functions of DNA methylation: islands, start sites, gene bodies and beyond , 2012, Nature Reviews Genetics.

[46]  K. V. Donkena,et al.  Global Methylation Profiling for Risk Prediction of Prostate Cancer , 2012, Clinical Cancer Research.

[47]  J. Issa.  DNA methylation as a clinical marker in oncology. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  H. Schayek,et al.  Global Methylation Analysis Identifies PITX2 as an Upstream Regulator of the Androgen Receptor and IGF-I Receptor Genes in Prostate Cancer , 2012, Hormone and Metabolic Research.

[49]  John T. Wei,et al.  Beyond PSA: The Next Generation of Prostate Cancer Biomarkers , 2012, Science Translational Medicine.

[50]  T. H. van der Kwast,et al.  Correlation of ERG Expression and DNA Methylation Biomarkers with Adverse Clinicopathologic Features of Prostate Cancer , 2012, Clinical Cancer Research.

[51]  W. Schulz,et al.  DNA methylation changes in prostate cancer. , 2012, Methods in molecular biology.

[52]  Vijay K. Tiwari,et al.  DNA-binding factors shape the mouse methylome at distal regulatory regions , 2011, Nature.

[53]  T. H. van der Kwast,et al.  Association of tissue promoter methylation levels of APC, TGFβ2, HOXD3 and RASSF1A with prostate cancer progression , 2011, International journal of cancer.

[54]  Peter A. Jones,et al.  A decade of exploring the cancer epigenome — biological and translational implications , 2011, Nature Reviews Cancer.

[55]  Theodorus H van der Kwast,et al.  The contemporary concept of significant versus insignificant prostate cancer. , 2011, European urology.

[56]  Gavin Sherlock,et al.  DNA methylation profiling reveals novel biomarkers and important roles for DNA methyltransferases in prostate cancer. , 2011, Genome research.

[57]  Lee T. Sam,et al.  Deep sequencing reveals distinct patterns of DNA methylation in prostate cancer. , 2011, Genome research.

[58]  J. Cuzick,et al.  Absolute Quantitation of DNA Methylation of 28 Candidate Genes in Prostate Cancer Using Pyrosequencing , 2011, Disease markers.

[59]  E. Giovannucci,et al.  Measurement of GSTP1 promoter methylation in body fluids may complement PSA screening: a meta-analysis , 2011, British Journal of Cancer.

[60]  M. Rizzo.  Cyclooxygenase-2 in oncogenesis. , 2011, Clinica chimica acta; international journal of clinical chemistry.

[61]  T. Cenci,et al.  Epigenetic silencing of SOCS3 identifies a subset of prostate cancer with an aggressive behavior , 2011, The Prostate.

[62]  K. D. Sørensen,et al.  Promoter hypomethylation and upregulation of trefoil factors in prostate cancer , 2010, International journal of cancer.

[63]  S. Freedland,et al.  Multicenter clinical validation of PITX2 methylation as a prostate specific antigen recurrence predictor in patients with post-radical prostatectomy prostate cancer. , 2010, The Journal of urology.

[64]  E. Higashihara,et al.  Association of circulating tumor cells with tumor‐related methylated DNA in patients with hormone‐refractory prostate cancer , 2010, International journal of urology : official journal of the Japanese Urological Association.

[65]  G. Kristiansen,et al.  Development of a diagnostic microarray assay to assess the risk of recurrence of prostate cancer based on PITX2 DNA methylation. , 2010, The Journal of molecular diagnostics : JMD.

[66]  J. Trachtenberg,et al.  DNA methylation of HOXD3 as a marker of prostate cancer progression , 2010, Laboratory Investigation.

[67]  O. Cussenot,et al.  Methylated genes as potential biomarkers in prostate cancer , 2010, BJU international.

[68]  B. G. Blijenberg,et al.  Screening and prostate-cancer mortality in a randomized European study. , 2009, The New England journal of medicine.

[69]  J. Serth,et al.  DNA methylation biomarkers of prostate cancer: Confirmation of candidates and evidence urine is the most sensitive body fluid for non‐invasive detection , 2009, The Prostate.

[70]  Olof Akre,et al.  Promoter methylation in APC, RUNX3, and GSTP1 and mortality in prostate cancer patients. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[71]  G. Kristiansen,et al.  DNA methylation of the PITX2 gene promoter region is a strong independent prognostic marker of biochemical recurrence in patients with prostate cancer after radical prostatectomy. , 2009, The Journal of urology.

[72]  T. H. van der Kwast,et al.  Discovery of Novel Hypermethylated Genes in Prostate Cancer Using Genomic CpG Island Microarrays , 2009, PloS one.

[73]  K. D. Sørensen,et al.  Genetic and Epigenetic SLC18A2 Silencing in Prostate Cancer Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy , 2009, Clinical Cancer Research.

[74]  J. Herman,et al.  Effect of DNA methylation on identification of aggressive prostate cancer. , 2008, Urology.

[75]  Pierre I Karakiewicz,et al.  An updated catalog of prostate cancer predictive tools , 2008, Cancer.

[76]  Mihaela Campan,et al.  Identification of a panel of sensitive and specific DNA methylation markers for squamous cell lung cancer , 2008, Molecular Cancer.

[77]  Guojun Wu,et al.  Hypermethylation of MCAM gene is associated with advanced tumor stage in prostate cancer , 2008, The Prostate.

[78]  F. Hamdy,et al.  Promoter hypermethylation in circulating blood cells identifies prostate cancer progression , 2008, International journal of cancer.

[79]  K. Biermann,et al.  CpG island hypermethylation at multiple gene sites in diagnosis and prognosis of prostate cancer. , 2008, Urology.

[80]  R. Büttner,et al.  CpG Island hypermethylation in cell‐free serum DNA identifies patients with localized prostate cancer , 2008, The Prostate.

[81]  A. Carvalho,et al.  High Promoter Methylation Levels of APC Predict Poor Prognosis in Sextant Biopsies from Prostate Cancer Patients , 2007, Clinical Cancer Research.

[82]  M. Taketo,et al.  Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene , 2007, Journal of Cell Science.

[83]  J. Foekens,et al.  DNA-methylation of the homeodomain transcription factor PITX2 reliably predicts risk of distant disease recurrence in tamoxifen-treated, node-negative breast cancer patients--Technical and clinical validation in a multi-centre setting in collaboration with the European Organisation for Research and , 2007, European journal of cancer.

[84]  J. Issa,et al.  Age-Related DNA Methylation Changes in Normal Human Prostate Tissues , 2007, Clinical Cancer Research.

[85]  Klaus Jung,et al.  Discovery and validation of 3 novel DNA methylation markers of prostate cancer prognosis. , 2007, The Journal of urology.

[86]  P. Vineis,et al.  Circulating free DNA in plasma or serum as biomarker of carcinogenesis: practical aspects and biological significance. , 2007, Mutation research.

[87]  A. D. De Marzo,et al.  Abnormal DNA methylation, epigenetics, and prostate cancer. , 2007, Frontiers in bioscience : a journal and virtual library.

[88]  J. Roberts,et al.  The expanding role of epigenetics in the development, diagnosis and treatment of prostate cancer and benign prostatic hyperplasia. , 2007, The Journal of urology.

[89]  J. Ellinger,et al.  Prognostic value of CpG island hypermethylation at PTGS2, RAR-beta, EDNRB, and other gene loci in patients undergoing radical prostatectomy. , 2007, European urology.

[90]  L. Hesson,et al.  The Role of RASSF1A Methylation in Cancer , 2007, Disease markers.

[91]  E W Steyerberg,et al.  Prediction of indolent prostate cancer: validation and updating of a prognostic nomogram. , 2006, The Journal of urology.

[92]  K. O’Reilly,et al.  CD44 and PTGS2 Methylation are Independent Prognostic Markers for Biochemical Recurrence Among Prostate Cancer Patients with Clinically Localized Disease , 2006, Epigenetics.

[93]  Douglas G Altman,et al.  Dichotomizing continuous predictors in multiple regression: a bad idea , 2006, Statistics in medicine.

[94]  A. Partin,et al.  Promoter Hypermethylation as an Independent Prognostic Factor for Relapse in Patients with Prostate Cancer Following Radical Prostatectomy , 2005, Clinical Cancer Research.

[95]  B. Trock,et al.  Preoperative Serum DNA GSTP1 CpG Island Hypermethylation and the Risk of Early Prostate-Specific Antigen Recurrence Following Radical Prostatectomy , 2005, Clinical Cancer Research.

[96]  James A Hanley,et al.  20-year outcomes following conservative management of clinically localized prostate cancer. , 2005, JAMA.

[97]  A. Wellmann,et al.  Diagnostic and prognostic information in prostate cancer with the help of a small set of hypermethylated gene loci. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[98]  Rajvir Dahiya,et al.  Epigenetic changes in prostate cancer: implication for diagnosis and treatment. , 2005, Journal of the National Cancer Institute.

[99]  William J Catalona,et al.  Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. , 2004, The Journal of urology.

[100]  Jeanne Kowalski,et al.  Hypermethylation of CpG Islands in Primary and Metastatic Human Prostate Cancer , 2004, Cancer Research.

[101]  A. D. De Marzo,et al.  GSTP1 CpG island hypermethylation as a molecular biomarker for prostate cancer , 2004, Journal of cellular biochemistry.

[102]  Hartwig Huland,et al.  Counseling men with prostate cancer: a nomogram for predicting the presence of small, moderately differentiated, confined tumors. , 2003, The Journal of urology.

[103]  L. Holmberg,et al.  Quality of life after radical prostatectomy or watchful waiting. , 2002, The New England journal of medicine.

[104]  M. Toyota,et al.  Methylation profiling in acute myeloid leukemia. , 2001, Blood.

[105]  J. Herman,et al.  Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. , 2001, Human molecular genetics.

[106]  K. Miller,et al.  Fluorescent methylation-specific polymerase chain reaction for DNA-based detection of prostate cancer in bodily fluids. , 2000, Cancer research.

[107]  A. Wolffe,et al.  Epigenetics: regulation through repression. , 1999, Science.

[108]  Y. Lo,et al.  Rapid clearance of fetal DNA from maternal plasma. , 1999, American journal of human genetics.

[109]  J. Herman,et al.  Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[110]  Rudolf Jaenisch,et al.  Targeted mutation of the DNA methyltransferase gene results in embryonic lethality , 1992, Cell.

[111]  S. Narayanan,et al.  Creatinine: a review. , 1980, Clinical chemistry.