Intake of dietary factors that serve as methyl group donors may influence promoter hypermethylation in colorectal
carcinogenesis. We investigated whether dietary
folate,
vitamin B2 and
vitamin B6,
methionine and alcohol were associated with mutL homologue 1 (MLH1) hypermethylation and the related molecular phenotypes of
MLH1 protein expression,
microsatellite instability (MSI) and BRAF mutations in patients with
colorectal carcinomas. Within the Netherlands Cohort Study on diet and
cancer (n = 120 852), 648 cases (367 men and 281 women) and 4059 subcohort members were available for data analyses from a follow-up period between 2.3 and 7.3 years after baseline. Gender-specific adjusted incidence rate ratios (RRs) were calculated over categories of dietary intake in case-cohort analyses. The intakes of
folate,
vitamin B2,
methionine and alcohol were not associated with risk of
tumors showing MLH1 hypermethylation, those lacking
MLH1 protein expression or with MSI. Among men, we observed strong positive associations between
folate and BRAF-mutated
tumors (RR = 3.04 for the highest versus lowest tertile of intake, P(trend) = 0.03) and between
vitamin B6 and
tumors showing MLH1 hypermethylation (highest versus lowest tertile: RR = 3.23, P(trend) = 0.03). Among women, the relative risks of
tumors with BRAF mutations or MLH1 hypermethylation were also increased in the highest tertiles of
folate and
vitamin B6 intake, respectively, but these did not reach statistical significance. The positive associations between
folate intake and
tumors harboring BRAF mutations and between
vitamin B6 intake and those showing MLH1 hypermethylation were most pronounced among men and may suggest that these
vitamins enhance
colorectal cancer risk through genetic as well as epigenetic aberrations.