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

作者：Weisenberger Daniel J; Levine A Joan; Long Tiffany I; Buchanan Daniel D; Walters Rhiannon; Clendenning Mark; Rosty Christophe; Joshi Amit D; Stern Mariana C; Le Marchand Loic; Lindor Noralane M; Daftary Darshana; Gallinger Steven; Selander Teresa; Bapat Bharati; Newcomb Polly A; Campbell Peter T; Casey Graham; Ahnen Dennis J; Baron John A; Haile Robert W; Hopper John L; Young Joanne P; Laird Peter W; Siegmund Kimberly D^*

来源：Cancer Epidemiology Biomarkers & Prevention, 2015, 24(3): 512-519.

DOI：10.1158/1055-9965.EPI-14-1161

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 (P-trend < 0.001) and body mass index (BMI; P-trend = 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.

• 出版日期2015-3
• 单位河北医科大学