DNA methylation biomarkers and their utility for solid cancer diagnostics

Abstract Cellular DNA undergoes profound changes in methylation during cancer development, with hypermethylation occurring in specific gene promoters, amidst a backdrop of generalized hypomethylation. DNA methylation in cancer often causes the silencing of tumor suppressors and other genes important for cellular growth, regulation and differentiation. Over the past two decades, there have been thousands of publications describing the methylation status of hundreds of genes in cancer, with numerous associations with clinical states, disease outcomes and therapeutic responses being reported. New methods for DNA methylation fingerprinting have emerged, allowing for the exponential growth of “epigenomic” information. Despite this wealth of data, only a handful of methylated genes are utilized as cancer biomarkers in the clinical laboratory. A literature review centered on DNA methylation in six solid cancers was performed, including colorectal, pancreatic, prostate, bladder, breast and ovarian. Commonly methylated genes in the six cancer types were identified and catalogued, and could serve in the future as tissue-based biomarkers or as part of cancer-specific panels. Perhaps more importantly, this endeavor has also focused on methylated genes that appear to be unique to particular cancers. These genes may be more versatile for clinical use, with blood or urine-based cancer screening becoming a reality.

[1]  Qilong Yi,et al.  DNA methylation patterns in blood of patients with colorectal cancer and adenomatous colorectal polyps , 2012, International journal of cancer.

[2]  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.

[3]  K. D. Sørensen,et al.  Downregulation of zinc finger protein 132 in prostate cancer is associated with aberrant promoter hypermethylation and poor prognosis , 2012, International journal of cancer.

[4]  Larissa V Furtado,et al.  Septin 9 methylated DNA is a sensitive and specific blood test for colorectal cancer , 2011, BMC medicine.

[5]  P. Laird,et al.  Genome-Scale Screen for DNA Methylation-Based Detection Markers for Ovarian Cancer , 2011, PloS one.

[6]  D. Dietrich,et al.  Performance evaluation of the DNA methylation biomarker SHOX2 for the aid in diagnosis of lung cancer based on the analysis of bronchial aspirates. , 2011, International journal of oncology.

[7]  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.

[8]  P. Kober,et al.  Methyl‐CpG binding column‐based identification of nine genes hypermethylated in colorectal cancer , 2011, Molecular carcinogenesis.

[9]  D. Dietrich,et al.  SHOX2 DNA Methylation Is a Biomarker for the Diagnosis of Lung Cancer in Plasma , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[10]  S. Clark,et al.  Epigenetics in prostate cancer: biologic and clinical relevance. , 2011, European urology.

[11]  Pieter Wesseling,et al.  A Hypermethylated Phenotype Is a Better Predictor of Survival than MGMT Methylation in Anaplastic Oligodendroglial Brain Tumors: A Report from EORTC Study 26951 , 2011, Clinical Cancer Research.

[12]  R. Lothe,et al.  TCF21 and PCDH17 methylation: An innovative panel of biomarkers for a simultaneous detection of urological cancers , 2011, Epigenetics.

[13]  Carsten Wiuf,et al.  Comprehensive Genome Methylation Analysis in Bladder Cancer: Identification and Validation of Novel Methylated Genes and Application of These as Urinary Tumor Markers , 2011, Clinical Cancer Research.

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

[15]  Thomas Lengauer,et al.  A DNA methylation fingerprint of 1628 human samples. , 2011, Genome research.

[16]  J. Eshleman,et al.  Genome-Wide Analysis of Promoter Methylation Associated with Gene Expression Profile in Pancreatic Adenocarcinoma , 2011, Clinical Cancer Research.

[17]  Yair Lotan,et al.  Detection of Bladder Cancer Using Novel DNA Methylation Biomarkers in Urine Sediments , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[18]  Martha L. Slattery,et al.  CpG Island Methylation in Colorectal Cancer: Past, Present and Future , 2011, Pathology research international.

[19]  A. Papavassiliou,et al.  Strategies for DNA methylation analysis in developmental studies , 2011, Development, growth & differentiation.

[20]  M. Esteller,et al.  Cancer epigenetics reaches mainstream oncology , 2011, Nature Medicine.

[21]  V. Levenson,et al.  Methylation patterns in cell‐free plasma DNA reflect removal of the primary tumor and drug treatment of breast cancer patients , 2011, International journal of cancer.

[22]  A. Kaneda,et al.  Two groups of DNA methylation markers to classify colorectal cancer into three epigenotypes , 2010, Cancer science.

[23]  Jun Yu,et al.  Epigenetic inactivation of T-box transcription factor 5, a novel tumor suppressor gene, is associated with colon cancer , 2010, Oncogene.

[24]  L. Altucci,et al.  Epigenetic Silencing of Peroxisome Proliferator-Activated Receptor γ Is a Biomarker for Colorectal Cancer Progression and Adverse Patients' Outcome , 2010, PloS one.

[25]  D. Dietrich,et al.  SHOX2 DNA Methylation is a Biomarker for the diagnosis of lung cancer based on bronchial aspirates , 2010, BMC Cancer.

[26]  R. Lothe,et al.  Three Epigenetic Biomarkers, GDF15, TMEFF2, and VIM, Accurately Predict Bladder Cancer from DNA-Based Analyses of Urine Samples , 2010, Clinical Cancer Research.

[27]  Pang-Kuo Lo,et al.  Epigenetic inactivation of the potential tumor suppressor gene FOXF1 in breast cancer. , 2010, Cancer research.

[28]  D. Ransohoff,et al.  Prospective Clinical Validation of an Assay for Methylated SEPT9 DNA in Human Plasma as a Colorectal Cancer Screening Tool in Average Risk Men and Women ≥50 Years , 2010 .

[29]  L. de Leval,et al.  Identification and validation of the methylated TWIST1 and NID2 genes through real-time methylation-specific polymerase chain reaction assays for the noninvasive detection of primary bladder cancer in urine samples. , 2010, European urology.

[30]  R. Abrams,et al.  Differential methylation of cell‐free circulating DNA among patients with pancreatic cancer versus chronic pancreatitis , 2010, Cancer.

[31]  T. Aas,et al.  DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response , 2010, Molecular Cancer.

[32]  P. Laird.  Principles and challenges of genome-wide DNA methylation analysis , 2010, Nature Reviews Genetics.

[33]  A. Jimeno,et al.  Characterizing DNA methylation patterns in pancreatic cancer genome , 2009, Molecular oncology.

[34]  B. Christensen,et al.  Aging and Environmental Exposures Alter Tissue-Specific DNA Methylation Dependent upon CpG Island Context , 2009, PLoS genetics.

[35]  K. Garg,et al.  Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma , 2009, Journal of Clinical Pathology.

[36]  Christian Pilarsky,et al.  Circulating methylated SEPT9 DNA in plasma is a biomarker for colorectal cancer. , 2009, Clinical chemistry.

[37]  M. Toyota,et al.  Cancer epigenomics: Implications of DNA methylation in personalized cancer therapy , 2009, Cancer science.

[38]  D. Scholtens,et al.  Methylation profile of circulating plasma DNA in patients with pancreatic cancer , 2009, Journal of surgical oncology.

[39]  C. Pilarsky,et al.  Sensitive Detection of Colorectal Cancer in Peripheral Blood by Septin 9 DNA Methylation Assay , 2008, PloS one.

[40]  W. Samowitz.  Genetic and epigenetic changes in colon cancer. , 2008, Experimental and molecular pathology.

[41]  Peter A. Jones,et al.  DNA methylation analysis by digital bisulfite genomic sequencing and digital MethyLight , 2008, Nucleic acids research.

[42]  A. Jimeno,et al.  Genome-wide profiling at methylated promoters in pancreatic adenocarcinoma , 2008, Cancer biology & therapy.

[43]  Leslie Cope,et al.  Convergence of Mutation and Epigenetic Alterations Identifies Common Genes in Cancer That Predict for Poor Prognosis , 2008, PLoS medicine.

[44]  Bela Molnar,et al.  DNA methylation biomarkers for blood-based colorectal cancer screening. , 2008, Clinical chemistry.

[45]  Jacqueline A. Hall,et al.  Identification of Novel High-Frequency DNA Methylation Changes in Breast Cancer , 2007, PloS one.

[46]  Qinghua Wu,et al.  DNA methylation profiling of ovarian carcinomas and their in vitro models identifies HOXA9, HOXB5, SCGB3A1, and CRABP1 as novel targets , 2007, Molecular Cancer.

[47]  Zsolt Tulassay,et al.  Identification and Validation of Colorectal Neoplasia–Specific Methylation Markers for Accurate Classification of Disease , 2007, Molecular Cancer Research.

[48]  R. Lothe,et al.  ADAMTS1, CRABP1, and NR3C1 Identified as Epigenetically Deregulated Genes in Colorectal Tumorigenesis , 2006, Cellular oncology : the official journal of the International Society for Cellular Oncology.

[49]  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.

[50]  S. Goodman,et al.  Quantitation of promoter methylation of multiple genes in urine DNA and bladder cancer detection. , 2006, Journal of the National Cancer Institute.

[51]  Wei Jiang,et al.  High-throughput DNA methylation profiling using universal bead arrays. , 2006, Genome research.

[52]  R. Wolff,et al.  Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. , 2005, Gastroenterology.

[53]  R. Gartenhaus,et al.  MSRE-PCR for analysis of gene-specific DNA methylation , 2005, Nucleic acids research.

[54]  E. Gelmann,et al.  Deletion, methylation, and expression of the NKX3.1 suppressor gene in primary human prostate cancer. , 2005, Cancer research.

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

[56]  M. Tsao,et al.  Identification of 27 5′ CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers , 2004, Oncogene.

[57]  E. Pilozzi,et al.  CDX1 expression is reduced in colorectal carcinoma and is associated with promoter hypermethylation , 2004, The Journal of pathology.

[58]  J. Epstein,et al.  Optimal Use of a Panel of Methylation Markers with GSTP1 Hypermethylation in the Diagnosis of Prostate Adenocarcinoma , 2004, Clinical Cancer Research.

[59]  S. Husain,et al.  The Contribution of Genetic and Epigenetic Changes in Granulosa Cell Tumors of Ovarian Origin , 2004, Clinical Cancer Research.

[60]  Luc Girard,et al.  Methylation profiles of sporadic ovarian tumors and nonmalignant ovaries from high-risk women. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[61]  John D Minna,et al.  Aberrant promoter methylation profile of prostate cancers and its relationship to clinicopathological features. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[62]  J. Minna,et al.  Aberrant promoter methylation profile of bladder cancer and its relationship to clinicopathological features. , 2001, Cancer research.

[63]  J Herman,et al.  Aberrant methylation of the adenomatous polyposis coli (APC) gene promoter 1A in breast and lung carcinomas. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[64]  T. Motoyama,et al.  Adenomatous polyposis coli (APC) gene promoter hypermethylation in primary breast cancers , 2001, British Journal of Cancer.

[65]  Scar,et al.  Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. , 2000, The New England journal of medicine.

[66]  A. de la Chapelle,et al.  Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers. , 2000, The American journal of pathology.

[67]  P. Laird,et al.  MethyLight: a high-throughput assay to measure DNA methylation. , 2000, Nucleic acids research.

[68]  J. Herman,et al.  CpG island methylator phenotype in colorectal cancer. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[69]  J. Herman,et al.  Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia. , 1998, Cancer research.

[70]  S N Thibodeau,et al.  Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. , 1998, Cancer research.

[71]  L. Kasturi,et al.  Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[72]  J. Herman,et al.  Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[73]  M. Loda,et al.  Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. , 1997, Cancer research.

[74]  J. Brooks,et al.  Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[75]  W. Gerald,et al.  Epigenetic lesions at the H19 locus in Wilms' tumour patients , 1994, Nature Genetics.

[76]  J. Costello,et al.  Graded methylation in the promoter and body of the O6-methylguanine DNA methyltransferase (MGMT) gene correlates with MGMT expression in human glioma cells. , 1994, The Journal of biological chemistry.

[77]  R. Fleischmann,et al.  Mutation of a mutL homolog in hereditary colon cancer. , 1994, Science.

[78]  D. Ward,et al.  Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer , 1994, Nature.

[79]  A. Bird,et al.  Purification, sequence, and cellular localization of a novel chromosomal protein that binds to Methylated DNA , 1992, Cell.

[80]  J. Costello,et al.  Direct correlation between methylation status and expression of the human O-6-methylguanine DNA methyltransferase gene. , 1991, Cancer communications.

[81]  Adrian Bird,et al.  DNA methylation inhibits transcription indirectly via a methyl-CpG binding protein , 1991, Cell.

[82]  B. Horsthemke,et al.  Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma , 1989, Human Genetics.

[83]  M. Lübbert,et al.  p53 in chronic myelogenous leukemia. Study of mechanisms of differential expression , 1988, The Journal of experimental medicine.

[84]  Howard Cedar,et al.  DNA methylation affects the formation of active chromatin , 1986, Cell.

[85]  H. Cedar,et al.  Effect of regional DNA methylation on gene expression. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[86]  G. Reifenberger,et al.  MGMT promoter methylation in malignant gliomas: ready for personalized medicine? , 2010, Nature Reviews Neurology.

[87]  D. Scholtens,et al.  Differential methylation profile of ovarian cancer in tissues and plasma. , 2009, The Journal of molecular diagnostics : JMD.

[88]  M. Srinivasulu,et al.  Role of BRCA1, HSD17B1 and HSD17B2 methylation in breast cancer tissue. , 2009, Cancer biomarkers : section A of Disease markers.

[89]  D. Scholtens,et al.  Array-based multiplex analysis of DNA methylation in breast cancer tissues. , 2008, The Journal of molecular diagnostics : JMD.