title: Dietary folate and APC mutations in sporadic colorectal cancer.
abstract: Folate deficiency has been associated with colorectal cancer risk and may be involved in colorectal carcinogenesis through increased chromosome instability, gene mutations, and aberrant DNA methylation. Within the Netherlands Cohort Study on diet and cancer, we investigated the associations between dietary folate intake and colorectal cancer risk with (APC(+)) and without (APC(-)) truncating APC mutations, accounting for hMLH1 expression and K-ras mutations. In total, 528 cases and 4200 subcohort members were available for data analyses of the study cohort (n = 120,852) from a follow-up period between 2.3 and 7.3 y after baseline. Adjusted gender-specific incidence rate ratios (RR) over tertiles of folate intake were calculated in case-cohort analyses for colon and rectal cancer. Although relatively high folate intake was not associated with overall colorectal cancer risk, it reduced the risk of APC(-)colon tumors in men (RR 0.58, 95% CI 0.32-1.05, P(trend) = 0.06 for the highest vs. lowest tertile of folate intake). In contrast, it was positively associated with APC(+) colon tumors in men (highest vs. lowest tertile: RR 2.77, 95% CI 1.29-5.95, P(trend) = 0.008) and was even stronger when the lack of hMLH1 expression and K-ras mutations were excluded (RR 3.99, 95% CI 1.43-11.14, P(trend) = 0.007). Such positive associations were not observed among women; nor was folate intake associated with rectal cancer when APC mutation status was taken into account. Relatively high folate consumption reduced the risk of APC(-) colon tumors, but folate intake was positively associated with APC(+) colon tumors among men. These opposite results may indicate that folate enhances colorectal carcinogenesis through a distinct APC mutated pathway.
authors.affiliation: Research Institute Growth and Development (GROW), Department of Epidemiology, Maastricht University, Maastricht, The Netherlands. stefan.devogel@epid.unimaas.nl
authors.forename: Stefan
authors.initials: S
authors.lastname: de Vogel
authors.forename: Manon
authors.initials: M
authors.lastname: van Engeland
authors.forename: Margreet
authors.initials: M
authors.lastname: Lüchtenborg
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: de Bruïne
authors.forename: Guido M J M
authors.initials: GM
authors.lastname: Roemen
authors.forename: Marjolein H F M
authors.initials: MH
authors.lastname: Lentjes
authors.forename: R Alexandra
authors.initials: RA
authors.lastname: Goldbohm
authors.forename: Piet A
authors.initials: PA
authors.lastname: van den Brandt
authors.forename: Anton F P M
authors.initials: AF
authors.lastname: de Goeij
authors.forename: Matty P
authors.initials: MP
authors.lastname: Weijenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D004032:Diet; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D017491:Genes, APC; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D018579:Patient Selection; D016016:Proportional Hazards Models; D012004:Rectal Neoplasms / Q000235:genetics; D011795:Surveys and Questionnaires
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D005492:Folic Acid; D000070957:MutL Protein Homolog 1