Association of the Colorectal CpG Island Methylator Phenotype with Molecular Features, Risk Factors, and Family History

Background: The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread aberrant DNA hypermethylation at select CpG islands. The risk factors and environmental exposures contributing to etiologic heterogeneity between CIMP and non-CIMP tumors are not known. Methods: We measured the CIMP status of 3,119 primary population-based colorectal cancer tumors from the multinational Colon Cancer Family Registry. Etiologic heterogeneity was assessed by a case–case study comparing risk factor frequency of colorectal cancer cases with CIMP and non-CIMP tumors using logistic regression to estimate the case–case odds ratio (ccOR). Results: We found associations between tumor CIMP status and MSI-H (ccOR = 7.6), BRAF V600E mutation (ccOR = 59.8), proximal tumor site (ccOR = 9; all P < 0.0001), female sex [ccOR = 1.8; 95% confidence interval (CI), 1.5–2.1], older age (ccOR = 4.0 comparing over 70 years vs. under 50; 95% CI, 3.0–5.5), and family history of CRC (ccOR = 0.6; 95% CI, 0.5–0.7). While use of NSAIDs varied by tumor CIMP status for both males and females (P = 0.0001 and P = 0.02, respectively), use of multivitamin or calcium supplements did not. Only for female colorectal cancer was CIMP status associated with increased pack-years of smoking (Ptrend < 0.001) and body mass index (BMI; Ptrend = 0.03). Conclusions: The frequency of several colorectal cancer risk factors varied by CIMP status, and the associations of smoking and obesity with tumor subtype were evident only for females. Impact: Differences in the associations of a unique DNA methylation–based subgroup of colorectal cancer with important lifestyle and environmental exposures increase understanding of the molecular pathologic epidemiology of this heavily methylated subset of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 512–9. ©2015 AACR.

[1]  Peter W. Laird,et al.  Interplay between the Cancer Genome and Epigenome , 2013, Cell.

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

[3]  N. Cho,et al.  Subsets of microsatellite-unstable colorectal cancers exhibit discordance between the CpG island methylator phenotype and MLH1 methylation status , 2013, Modern Pathology.

[4]  J. Potter,et al.  Vegetables, fruit, and cancer prevention: a review. , 1996, Journal of the American Dietetic Association.

[5]  K. Kinzler,et al.  Cancer genes and the pathways they control , 2004, Nature Medicine.

[6]  Aung Ko Win,et al.  PIK3CA Activating Mutation in Colorectal Carcinoma: Associations with Molecular Features and Survival , 2013, PloS one.

[7]  P. Laird,et al.  Genome-scale analysis of aberrant DNA methylation in colorectal cancer. , 2012, Genome research.

[8]  Jennifer Herrick,et al.  Association of smoking, CpG island methylator phenotype, and V600E BRAF mutations in colon cancer. , 2006, Journal of the National Cancer Institute.

[9]  B E Ainsworth,et al.  Compendium of physical activities: an update of activity codes and MET intensities. , 2000, Medicine and science in sports and exercise.

[10]  References , 1971 .

[11]  M. Loda,et al.  CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations. , 2006, The Journal of molecular diagnostics : JMD.

[12]  P. Boyle,et al.  ABC of colorectal cancer: Epidemiology , 2000, BMJ.

[13]  Joanne P Young,et al.  KRAS mutations in ovarian low-grade endometrioid adenocarcinoma: association with concurrent endometriosis. , 2012, Human pathology.

[14]  Peter A. Jones,et al.  The fundamental role of epigenetic events in cancer , 2002, Nature Reviews Genetics.

[15]  J. Potter,et al.  The Association of Tumor Microsatellite Instability Phenotype with Family History of Colorectal Cancer , 2009, Cancer Epidemiology Biomarkers & Prevention.

[16]  J. Baron,et al.  The Association of Lifestyle and Dietary Factors with the Risk for Serrated Polyps of the Colorectum , 2009, Cancer Epidemiology, Biomarkers & Prevention.

[17]  D. Sargent,et al.  Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147. , 2014, Journal of the National Cancer Institute.

[18]  Reiko Nishihara,et al.  Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. , 2013, Journal of the National Cancer Institute.

[19]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[20]  Aung Ko Win,et al.  Risk Factors for Colorectal Cancer in Patients with Multiple Serrated Polyps: A Cross-Sectional Case Series from Genetics Clinics , 2010, PloS one.

[21]  M. Röösli,et al.  Modulation of Age- and Cancer-Associated DNA Methylation Change in the Healthy Colon by Aspirin and Lifestyle , 2014, Journal of the National Cancer Institute.

[22]  B. Leggett,et al.  Promoter Hypermethylation Frequency and BRAF Mutations Distinguish Hereditary Non-Polyposis Colon Cancer from Sporadic MSI-H Colon Cancer , 2004, Familial Cancer.

[23]  H. Aburatani,et al.  Three DNA Methylation Epigenotypes in Human Colorectal Cancer , 2009, Clinical Cancer Research.

[24]  N. Matsubara,et al.  BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum , 2004, Gut.

[25]  R. Wolff,et al.  Diet and lifestyle factor associations with CpG island methylator phenotype and BRAF mutations in colon cancer , 2007, International journal of cancer.

[26]  W. Willett,et al.  Prospective study of fruit and vegetable consumption and incidence of colon and rectal cancers. , 2000, Journal of the National Cancer Institute.

[27]  R. Wolff,et al.  Diet, physical activity, and body size associations with rectal tumor mutations and epigenetic changes , 2010, Cancer Causes & Control.

[28]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[29]  J. Cerhan,et al.  Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. , 2010, Journal of the National Cancer Institute.

[30]  M. Bondy,et al.  What Can We Learn about Disease Etiology from Case-Case Analyses? Lessons from Breast Cancer , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[31]  Rebecca L. Siegel Mph,et al.  Colorectal cancer statistics, 2014 , 2014 .

[32]  E. Giovannucci,et al.  Primary prevention of colorectal cancer. , 2010, Gastroenterology.

[33]  David J. Kerr,et al.  ABC of colorectal cancer , 2011 .

[34]  G. Kang.  Four molecular subtypes of colorectal cancer and their precursor lesions. , 2011, Archives of pathology & laboratory medicine.

[35]  Nakamura Masato.  [Aspirin for the prevention of colorectal cancer]. , 2015, Gan to kagaku ryoho. Cancer & chemotherapy.

[36]  Hereditary nonpolyposis colorectal cancer (Lynch syndrome): An updated review , 1996, Cancer.

[37]  Sabha Rasool,et al.  A comparative overview of general risk factors associated with the incidence of colorectal cancer , 2013, Tumor Biology.

[38]  P. Laird,et al.  Epigenetic Subgroups of Esophageal and Gastric Adenocarcinoma with Differential GATA5 DNA Methylation Associated with Clinical and Lifestyle Factors , 2011, PloS one.

[39]  John D Potter,et al.  Colon Cancer Family Registry: An International Resource for Studies of the Genetic Epidemiology of Colon Cancer , 2007, Cancer Epidemiology Biomarkers & Prevention.

[40]  A. Sparks,et al.  The Genomic Landscapes of Human Breast and Colorectal Cancers , 2007, Science.

[41]  M. O'brien,et al.  BRAF and KRAS Mutations in Hyperplastic Polyps and Serrated Adenomas of the Colorectum: Relationship to Histology and CpG Island Methylation Status , 2004, The American journal of surgical pathology.

[42]  N. Cho,et al.  Prognostic implications of CpG island hypermethylator phenotype in colorectal cancers , 2009, Virchows Archiv.

[43]  A. Jemal,et al.  Colorectal cancer statistics, 2014 , 2014, CA: a cancer journal for clinicians.

[44]  Minoru Toyota,et al.  Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer , 2007, Proceedings of the National Academy of Sciences.

[45]  R. Luben,et al.  MLH1 Promoter Methylation, Diet, and Lifestyle Factors in Mismatch Repair Deficient Colorectal Cancer Patients From EPIC-Norfolk , 2011, Nutrition and cancer.

[46]  P. Laird,et al.  CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer , 2006, Nature Genetics.

[47]  M. Loda,et al.  Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample. , 2007, The Journal of molecular diagnostics : JMD.

[48]  D. Kerr,et al.  Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  P. Laird,et al.  Analysis of the Association between CIMP and BRAFV600E in Colorectal Cancer by DNA Methylation Profiling , 2009, PloS one.

[50]  H. Lynch,et al.  Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) , 2004 .

[51]  D. English,et al.  Ethnicity and Risk for Colorectal Cancers Showing Somatic BRAF V600E Mutation or CpG Island Methylator Phenotype , 2008, Cancer Epidemiology Biomarkers & Prevention.

[52]  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.

[53]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of human colon and rectal cancer , 2012, Nature.

[54]  N. Matsubara,et al.  Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  Y. Hu,et al.  DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer , 2010, Oncogene.

[56]  J. Hardcastle,et al.  Colorectal cancer , 1993, Europe Against Cancer European Commission Series for General Practitioners.

[57]  M. Tzardi,et al.  BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients’ outcome , 2010, British Journal of Cancer.