title: Associations of dietary methyl donor intake with MLH1 promoter hypermethylation and related molecular phenotypes in sporadic colorectal cancer.
abstract: 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.
authors.affiliation: Department of Epidemiology, GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands. stefan.devogel@epid.unimaas.nl
authors.forename: Stefan
authors.initials: S
authors.lastname: de Vogel
authors.forename: Brenda W C
authors.initials: BW
authors.lastname: Bongaerts
authors.forename: Kim A D
authors.initials: KA
authors.lastname: Wouters
authors.forename: Arnold D M
authors.initials: AD
authors.lastname: Kester
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Schouten
authors.forename: Anton F P M
authors.initials: AF
authors.lastname: de Goeij
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: de Bruïne
authors.forename: R Alexandra
authors.initials: RA
authors.lastname: Goldbohm
authors.forename: Piet A
authors.initials: PA
authors.lastname: van den Brandt
authors.forename: Manon
authors.initials: M
authors.lastname: van Engeland
authors.forename: Matty P
authors.initials: MP
authors.lastname: Weijenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004032:Diet; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008715:Methionine / Q000008:administration & dosage*; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation / Q000235:genetics; D009426:Netherlands / Q000453:epidemiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D012256:Riboflavin / Q000008:administration & dosage; D011795:Surveys and Questionnaires; D014805:Vitamin B 12 / Q000008:administration & dosage; D025101:Vitamin B 6 / Q000008:administration & dosage
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D025101:Vitamin B 6; D005492:Folic Acid; D008715:Methionine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1; D014805:Vitamin B 12; D012256:Riboflavin