Carcinogenesis Advance Access originally published online on April 21, 2007
Carcinogenesis 2007 28(8):1672-1679; doi:10.1093/carcin/bgm089
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Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet
Department of Internal Medicine, University of Utah Health Sciences Center, 375 Chipeta Way, Suite A, Salt Lake City, UT 84108, USA
1 Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
2 Kaiser Permanente Medical Center, Walnut Creek, CA 94596, USA
3 Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA
* To whom correspondence should be addressed. Tel: +801 581 4006; Fax: +801 581 3623; 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 methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), transcobalamin II (TCNII), methionine synthase (MTR), reduced folate carrier (RFC), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), dihydrofolate reductase (DHFR) and alcohol dehydrogenase 3 (ADH3) were evaluated. CIMP– or CIMP+ phenotype was based on five CpG island markers: MINT1, MINT2, MINT31, p16 and MLH1. 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 (two or more of five 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 versus 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.
Abbreviations: ADH3, alcohol dehydrogenase 3; CIMP, CpG island methylator phenotype; DHFR, dihydrofolate reductase; MTHFD1, methylenetetrahydrofolate dehydrogenase 1; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; RFC, reduced folate carrier; SAM, S-adenosylmethionine; TCNII, transcobalamin II; TS, thymidylate synthase
Received November 29, 2006; revised April 2, 2007; accepted April 2, 2007.
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