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Carcinogenesis Advance Access published online on April 21, 2007
Carcinogenesis, doi:10.1093/carcin/bgm089
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet

Karen Curtin, M.Stat.1, Martha L. Slattery, Ph.D.1, Cornelia M. Ulrich, Ph.D.2, Jeannette Bigler, Ph. D2, Theodore R. Levin, M.D.3, Roger K. Wolff, Ph.D.1, Hans Albertsen, Ph.D.1, John D. Potter, M.D., Ph.D.2 and Wade S. Samowitz, M.D.4

1 Department of Internal Medicine, University of Utah Health Sciences Center, 375 Chipeta Way, Suite A, Salt Lake City, Utah 84108
2 Fred Hutchinson Cancer Research Center, Seattle, Washington
3 Kaiser Permanente Medical Center, Walnut Creek, CA 94596
4 Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, Utah 84132

Correspondence to: Karen Curtin, M.Stat., Department of Internal Medicine, University of Utah Health Sciences Center, 375 Chipeta Way Suite A, Salt Lake City, UT 84108, Email: karen.curtin{at}hsc.utah.edu

This study investigated associations between CpG island methylator phenotype (CIMP) colon cancer and genetic polymorphisms relevant to one-carbon metabolism and thus, potentially the provision of methyl groups, and risk of colon cancer. Data from a large, population-based case-control study (916 incident colon cancer cases and 1972 matched controls) were used. Candidate polymorphisms in MTHFR, TS, TCNII, MTR, RFC, MTHFD1, DHFR, and ADH3 were evaluated. CIMP- or CIMP+ phenotype was based on 5 CpG island markers: MINT1, MINT2, MINT31, p16, and hMLH1. The influence of specific dietary factors (folate, methionine, vitamin B12 and alcohol) on these associations was also analyzed. We hypothesized that polymorphisms involved in the provision of methyl groups would be associated with CIMP+ tumors (2 or more of 5 markers methylated), potentially modified by diet. Few associations specific to CIMP+ tumors were observed overall, which does not support the hypothesis that the provision of methyl groups is important in defining a methylator phenotype. However, our data suggest that genetic polymorphisms in MTHFR 1298A>C, interacting with diet, may be involved in the development of highly CpG-methylated colon cancers. AC and CC genotypes in conjunction with a high-risk dietary pattern (low folate and methionine intake, and high alcohol use) were associated with CIMP+ (OR 2.1, 95%CI 1.3-3.4 vs. AA/high-risk; p-interaction 0.03). These results provide only limited support for a role of polymorphisms in one-carbon metabolism in the etiology of CIMP colon cancer.

Key Words: CIMP • CpG Island • Colon Cancer • MTHFR • one-carbon metabolism • diet

Received November 29, 2006; revised April 2, 2007; accepted April 2, 2007.


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