DNA methylation array analysis identifies profiles of blood-derived DNA methylation associated with bladder cancer.

PURPOSE Epigenetic alterations in tissues targeted for cancer play a causal role in carcinogenesis. Changes in DNA methylation in nontarget tissues, specifically peripheral blood, can also affect risk of malignant disease. We sought to identify specific profiles of DNA methylation in peripheral blood that are associated with bladder cancer risk and therefore serve as an epigenetic marker of disease susceptibility. METHODS We performed genome-wide DNA methylation profiling on participants involved in a population-based incident case-control study of bladder cancer. RESULTS In a training set of 112 cases and 118 controls, we identified a panel of 9 CpG loci whose profile of DNA methylation was significantly associated with bladder cancer in a masked, independent testing series of 111 cases and 119 controls (P < .0001). Membership in three of the most methylated classes was associated with a 5.2-fold increased risk of bladder cancer (95% CI, 2.8 to 9.7), and a model that included the methylation classification, participant age, sex, smoking status, and family history of bladder cancer was a significant predictor of bladder cancer (area under the curve, 0.76; 95% CI, 0.70 to 0.82). CpG loci associated with bladder cancer and aging had neighboring sequences enriched for transcription-factor binding sites related to immune modulation and forkhead family members. CONCLUSION These results indicate that profiles of epigenetic states in blood are associated with risk of bladder cancer and signal the potential utility of epigenetic profiles in peripheral blood as novel markers of susceptibility to this and other malignancies.

[1]  R. DePinho,et al.  Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells , 2010, Nature Immunology.

[2]  Matthew J Hayat,et al.  Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. , 2007, The oncologist.

[3]  Trond Stokke,et al.  Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery , 2006, Molecular Cancer.

[4]  Margaret R. Karagas,et al.  Model-based clustering of DNA methylation array data: a recursive-partitioning algorithm for high-dimensional data arising as a mixture of beta distributions , 2008, BMC Bioinformatics.

[5]  T. Tosteson,et al.  Design of an epidemiologic study of drinking water arsenic exposure and skin and bladder cancer risk in a U.S. population. , 1998, Environmental health perspectives.

[6]  Henry J. Lin,et al.  Pooled analysis and meta-analysis of glutathione S-transferase M1 and bladder cancer: a HuGE review. , 2002, American journal of epidemiology.

[7]  A. Smith,et al.  Contamination of drinking-water by arsenic in Bangladesh: a public health emergency. , 2000, Bulletin of the World Health Organization.

[8]  Kathleen Shordt,et al.  Arsenic in drinking water. , 2001, Journal of environmental health.

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

[10]  L. Tanoue.  Cancer Statistics, 2009 , 2010 .

[11]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[12]  L. Kiemeney,et al.  Genome-wide association studies in bladder cancer: first results and potential relevance , 2009, Current opinion in urology.

[13]  D. Parkin,et al.  The global burden of urinary bladder cancer , 2008, Scandinavian journal of urology and nephrology. Supplementum.

[14]  A. Jemal,et al.  Cancer Statistics, 2009 , 2009, CA: a cancer journal for clinicians.

[15]  A. Teschendorff,et al.  An Epigenetic Signature in Peripheral Blood Predicts Active Ovarian Cancer , 2009, PloS one.

[16]  Peter A. Jones,et al.  Cancer-epigenetics comes of age , 1999, Nature Genetics.

[17]  Margaret R Karagas,et al.  Selenium and Risk of Bladder Cancer: A Population-Based Case-Control Study , 2009, Cancer Prevention Research.

[18]  J Vandekerckhove,et al.  Pathway leading to correctly folded beta-tubulin. , 1996, Cell.

[19]  H. Brenner,et al.  Epigenotyping in Peripheral Blood Cell DNA and Breast Cancer Risk: A Proof of Principle Study , 2008, PloS one.

[20]  L. Coussens,et al.  Lymphocytes in cancer development: polarization towards pro-tumor immunity. , 2010, Cytokine & growth factor reviews.

[21]  Xifeng Wu,et al.  Genome-wide association studies of bladder cancer risk: a field synopsis of progress and potential applications , 2009, Cancer and Metastasis Reviews.

[22]  A H Smith,et al.  Case-control study of bladder cancer and arsenic in drinking water. , 1995, American journal of epidemiology.

[23]  L. Wilkens,et al.  Risk factors for lower urinary tract cancer: the role of total fluid consumption, nitrites and nitrosamines, and selected foods. , 1996, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[24]  R. Tibshirani,et al.  Semi-Supervised Methods to Predict Patient Survival from Gene Expression Data , 2004, PLoS biology.

[25]  V. Pankratz,et al.  Methylation Markers for Small Cell Lung Cancer in Peripheral Blood Leukocyte DNA , 2010, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[26]  Margaret R. Karagas,et al.  Incidence of Transitional Cell Carcinoma of the Bladder and Arsenic Exposure in New Hampshire , 2004, Cancer Causes & Control.

[27]  Alberto Redaelli,et al.  The health economics of bladder cancer: a comprehensive review of the published literature. , 2003, PharmacoEconomics.

[28]  W. Sterry,et al.  Identification of dysregulated genes in cutaneous squamous cell carcinoma. , 2006, Oncology reports.

[29]  Jian Gu,et al.  Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer , 2009, Nature Genetics.

[30]  H. von der Maase,et al.  [Urinary bladder cancer]. , 2002, Ugeskrift for laeger.

[31]  T. Tötterman,et al.  Human bladder carcinoma is dominated by T-regulatory cells and Th1 inhibitory cytokines. , 2007, The Journal of urology.

[32]  K. Dietrich,et al.  Glucocorticoid therapy and risk of bladder cancer , 2009, British Journal of Cancer.

[33]  H. Ahsan,et al.  Cancer burden from arsenic in drinking water in Bangladesh. , 2004, American journal of public health.

[34]  K. Frazer,et al.  Common vs. rare allele hypotheses for complex diseases. , 2009, Current opinion in genetics & development.

[35]  D. Riesner,et al.  Induction of Tumors in Mice by Genomic Hypomethylation , 2003 .

[36]  Wolfgang Wagner,et al.  Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. , 2010, Genome research.

[37]  Devin C. Koestler,et al.  Semi-supervised recursively partitioned mixture models for identifying cancer subtypes , 2010, Bioinform..

[38]  Christophe Ampe,et al.  Pathway Leading to Correctly Folded β-Tubulin , 1996, Cell.

[39]  M. Greene,et al.  Familial and genetic risk of transitional cell carcinoma of the urinary tract. , 2008, Urologic oncology.

[40]  Helen Y Wang,et al.  Regulatory T cells and cancer. , 2007, Current opinion in immunology.

[41]  M. Spitz,et al.  Projecting individualized probabilities of developing bladder cancer in white individuals. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  W. King,et al.  Case-control study of bladder cancer and chlorination by-products in treated water (Ontario, Canada) , 1996, Cancer Causes & Control.

[43]  D. Silverman,et al.  Occupation and Bladder Cancer Risk in a Population-based Case-control Study in New Hampshire , 2004, Cancer Causes & Control.

[44]  C. Marsit,et al.  Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer. , 2005, Cancer research.

[45]  D. Miller,et al.  Urinary Bladder Cancer , 2002, Clinical obstetrics and gynecology.