METHYLENETETRAHYDROFOLATE REDUCTASE POLYMORPHISM, DIETARY INTERACTIONS, AND RISK OF COLORECTAL-CANCER

Folate derivatives are important in experimental colorectal carcinogen esis; low folate intake, particularly with substantial alcohol intake, is associated with increased risk. The enzyme 5,10-methylenetetrahydr ofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenete trahydrofolate, required for purine and thymidine syntheses, to 5-meth yltetrahydrofolate, the primary circulatory form of folate necessary f or methionine synthesis, A common mutation (677C-->T) in MTHFR reduces enzyme activity, leading to lower levels of 5-methyltetrahydrofolate. To evaluate the role of folate metabolism in human carcinogenesis, we examined the associations of MTHFR mutation, plasma folate levels, an d their interaction with risk of colon cancer. We also examined the in teraction between genotype and alcohol intake. We used a nested case-c ontrol design within the Physicians' Health Study, Participants were a ges 40-84 at baseline when alcohol intake was ascertained and blood sa mples were drawn, During 12 years of follow-up, we identified 202 colo rectal cancer cases and matched them to 326 cancer-free controls by ag e and smoking status. We genotyped for the MTHFR polymorphism and meas ured plasma folate levels. Men with the homozygous mutation (15% in co ntrols) had half the risk of colorectal cancer [odds ratio (OR), 0.49; 95% confidence interval (CI), 0.27-0.87] compared with the homozygous normal or heterozygous genotypes. Overall, we observed a marginal sig nificant increased risk of colorectal cancer (OR, 1.78; 95% CI, 0.93-3 .42) among those whose plasma folate levels indicated deficiency (< 3 ng/ml) compared with men with adequate folate levels, Among men with a dequate folate levels, we observed a S-fold decrease in risk (OR, 0.32 ; 95% CI, 0.15-0.68) among men with the homozygous mutation compared w ith those with the homozygous normal or heterozygous genotypes. Howeve r, the protection due to the mutation was absent in men with folate de ficiency, In men with the homozygous normal genotype who drank little or no alcohol as reference, those with the homozygous mutation who dra nk little or no alcohol had an 8-fold decrease in risk (OR, 0.12; 95% CI, 0.03-0.57), and for moderate drinkers, a 2-fold decrease in risk ( OR, 0.42; 95% CI, 0.15-1.20); no decrease in risk was seen in those dr inking 1 or more drinks/day. Our findings provide support for an impor tant role of folate metabolism in colon carcinogenesis. In particular, these results suggest that the 677C-->T mutation in MTHFR reduces col on cancer risk, perhaps by increasing 5,10-methylenetetrahydrofolate l evels for DNA synthesis, but that low folate intake or high alcohol co nsumption may negate some of the protective effect.