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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, Ptrend = 0.03) and between vitamin B6 and tumors showing MLH1 hypermethylation (highest versus lowest tertile: RR = 3.23, Ptrend = 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. © The Author 2008. Published by Oxford University Press. All rights reserved.

High alcohol consumption is related to colorectal cancer (CRC). Our objective was to study associations between alcohol consumption and risk of CRC according to characteristics of aetiological pathways: the chromosomal instability (CIN) and the microsatellite instability (MIN) pathway. We classified CIN+ tumours (tumours with either a truncating APC mutation, an activating K-ras mutation or overexpression of p53), MIN+ tumours (tumours lacking hMLH1 expression) and CIN-/MIN- tumours (tumours without these defects). In the Netherlands Cohort Study on diet and cancer, 120 852 men and women, aged 55-69 years, completed a questionnaire on risk factors for cancer at baseline (1986). Case-cohort analyses were conducted using 573 CRC cases with complete data after 7.3 years of follow-up, excluding the first 2.3 years. Adjusted incidence rate ratios (RR) and 95% confidence intervals (CI) were estimated. Compared with abstaining, alcohol consumption of ≥30 g/d was positively associated with the risk of CRC irrespective of genetic or molecular aberrations present, although statistical significance was not reached (RR 1.35 (95% CI 0.9-2.0) for the CIN+ tumours, RR 1.59 (95% CI 0.4-5.8) for the MIN+ tumours and RR 1.15 (95% CI 0.5-2.7) for the CIN-/MIN- tumours). Beer, wine and liquor consumption were, independent of their alcoholic content, not consistently associated with the risk of CRC within the defined subgroups. In conclusion, our results indicate that a daily alcohol consumption of ≥ 30 g is associated with an increase in risk of CRC, independent of the presence or absence of the studied characteristics of different aetiological pathways.