Abstract
One-carbon metabolism plays an important role in colorectal carcinogenesis. Meta-analyses have suggested protective associations of folate and vitamin B6 intakes with colorectal cancer primarily based on studies in Caucasians, and genetic polymorphisms pertaining to the folate metabolism have been a matter of interest. Less investigated are the roles of methionine synthase (MTR) and thymidylate synthetase (TS) polymorphisms in colorectal carcinogenesis. In a study of 816 cases and 815 community controls in Japan, we investigated associations of dietary intakes of folate, methionine, vitamin B2, vitamin B6, and vitamin B12 with colorectal cancer risk. The associations with MTR 2756A>G, MTRR 66A>G, and TSER repeat polymorphism were examined in 685 cases and 778 controls. Methionine and vitamin B12 intakes were inversely associated with colorectal cancer risk, but the associations were totally confounded by dietary calcium and n-3 fatty acids. The other nutrients showed no association with the risk even without adjustment for calcium and n-3 fatty acids. The TSER 2R allele was dose-dependently associated with an increased risk. The MTR and MTRR polymorphisms were unrelated to colorectal cancer risk. There was no measurable gene-gene or gene-nutrient interaction, but increased risk associated with the TSER 2R allele seemed to be confined to individuals with high folate status. This study does not support protective associations for folate and vitamin B6. The TSER 2R allele may confer an increased risk of colorectal cancer. The role of the TSER polymorphism in colorectal carcinogenesis may differ by ethnicity.
Highlights
The one-carbon metabolism has drawn considerable attention in relation to colorectal carcinogenesis (Ulrich, 2005; Hubner and Houlston, 2009; Williams, 2012)
Dietary intakes of methionine and vitamin B12 were associated with a decreased risk of colorectal cancer risk, but the associations were confounded by dietary intakes of calcium and n-PUFA
B2, and vitamin B6 showed no association with colorectal cancer risk even when intakes of calcium and n-PUFA were not taken into consideration
Summary
The one-carbon metabolism has drawn considerable attention in relation to colorectal carcinogenesis (Ulrich, 2005; Hubner and Houlston, 2009; Williams, 2012). A folate metabolite, 5-methyl tetrahydrofolate (THF), provides the methyl group in the reaction by methionine synthase (MTR) to convert homocysteine to methionine, the precursor of S-adenosylmethionine (SAM). The substrate of MTHFR is required for conversion of deoxyuridylate to thymidylate by thymidylate synthase (TS). Depletion of the thymidylate pool results in uracil misincorporation into DNA, leading to single and double strand breaks (reviewed in Ulrich, 2005; Hubner and Houlston, 2009). Vitamin B2 is the precursor for a cofactor of MTHFR. Vitamin B6 is a cofactor for cystathionin beta-synthase (CBS) to convert homocystein to cystathionine and is required in the conversion of serine to glycine, recycling THF (derivative of 5-methyl THF after methyl-transfer to homocysteine) to 5, 10-methylene THF.
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