title: A common variant of the methylenetetrahydrofolate reductase gene (1p36) is associated with an increased risk of cancer.
abstract: Folate metabolism is thought to play an important role in carcinogenesis through its involvement in both DNA methylation and nucleotide synthesis. A common Ala(222)/Val variant in the methylenetetrahydrofolate reductase (MTHFR) gene leads to a disturbed folate metabolism and is associated with decreased genomic DNA methylation. We previously reported that the MTHFR Val/Val genotype was associated with increased cancer mortality in men from a population-based cohort of subjects ages > or = 85 years. To further explore the deleterious effects of the MTHFR genotype, we studied the association of the genotype with cancer risk in 860 men ages 65-84 years who were followed >10 years (Zutphen Elderly Study). During follow-up, 149 new cases of cancer occurred among the 793 men without cancer at baseline. The risk of developing cancer was 1.80-fold (95% confidence interval, 1.09-3.00) higher among men with the Val/Val genotype than among men with the Ala/Ala genotype. Except for lung cancer [relative risk (RR), 1.15], the risks of common forms of cancers were significantly increased among men with the Val/Val genotype [cancer of the prostate (RR, 3.48); the colorectum (RR, 3.65); the kidney and bladder (RR, 5.48)]. The risks of cancer were particularly increased among men with a lower folate and a higher alcohol intake and men of an older age. In conclusion, our current and previous studies in two independent populations indicate that a common Ala/Val variant in the MTHFR gene is a risk factor for cancer in elderly men from the general population. The mechanism underlying this association might involve genomic instability as a result of insufficient methylation of genomic DNA.
authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Centre, 2300 RA Leiden, the Netherlands. b.t.heijmans@lumnc.nl
authors.forename: Bastiaan T
authors.initials: BT
authors.lastname: Heijmans
authors.forename: Jolanda M A
authors.initials: JM
authors.lastname: Boer
authors.forename: H Eka D
authors.initials: HE
authors.lastname: Suchiman
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Cornelisse
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
authors.forename: Daan
authors.initials: D
authors.lastname: Kromhout
authors.forename: Edith J M
authors.initials: EJ
authors.lastname: Feskens
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000428:Alcohol Drinking; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D015331:Cohort Studies; D004032:Diet; D005492:Folic Acid / Q000008:administration & dosage / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D009369:Neoplasms / Q000209:etiology / Q000235:genetics*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D011446:Prospective Studies; D012907:Smoking
chemical_list: D005492:Folic Acid; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)