title: Folate-related genes and the risk of tobacco-related cancers in Central Europe.
abstract: Folate has been hypothesized to protect against aero-digestive cancers although the evidence is not yet conclusive due to possible confounding by other dietary factors. Sequence variants in folate pathway were suggested to be associated with plasma folate levels and are unlikely to be confounded by other lifestyle factors. We therefore investigated the effects of key folate genetic variants on the risk of aero-digestive cancers and their potential effect modification by folate intake in a multicenter study in Central Europe. A total of 2250 lung cases, 811 upper aero-digestive tract cases and 2899 controls were recruited with blood samples. The methylenetetrahydrofolate reductase (MTHFR) C677T variant was associated with an increased risk of lung cancer with an odds ratio (OR) for homozygote variant of 1.37 [95% confidence interval (CI) = 1.10-1.71]. The two MTHFR variants were in strong linkage disequilibrium, and 677T-1298A appeared to be the primary haplotype associated with cancer risk. The risk estimates for MTHFR 677T/677T genotype was more prominent among lung cancer patients with young onset (OR = 1.92, 95% CI = 1.12-3.29). When stratified by dietary intake of folate, the effect of the MTHFR 677T variant was more prominent among subjects with low intake of folate: the ORs for 677T/677T genotype among subjects with the lowest decile were 2.60 (95% CI = 1.39-4.88) and 4.14 (95% CI = 1.47-11.7) for lung and upper aero-digestive tract cancer, respectively. In conclusion, we identified a moderate effect of MTHFR C677T on lung cancer risk and a possible effect modification by folate intake that is consistent with the functional data. These results support an important role of folate in protecting against tobacco-related cancers.
authors: International Agency for Research on Cancer, 150 cours Albert Thomas, F-69372, 69008, Lyon Cedex 08, France. hung@iarc.fr
authors: Rayjean J
authors: RJ
authors: Hung
authors: Mia
authors: M
authors: Hashibe
authors: James
authors: J
authors: McKay
authors: Valerie
authors: V
authors: Gaborieau
authors: Neonila
authors: N
authors: Szeszenia-Dabrowska
authors: David
authors: D
authors: Zaridze
authors: Jolanta
authors: J
authors: Lissowska
authors: Peter
authors: P
authors: Rudnai
authors: Eleonora
authors: E
authors: Fabianova
authors: Ioan
authors: I
authors: Mates
authors: Lenka
authors: L
authors: Foretova
authors: Vladimir
authors: V
authors: Janout
authors: Vladimir
authors: V
authors: Bencko
authors: Amelie
authors: A
authors: Chabrier
authors: Norman
authors: N
authors: Moullan
authors: Federico
authors: F
authors: Canzian
authors: Janet
authors: J
authors: Hall
authors: Paolo
authors: P
authors: Boffetta
authors: Paul
authors: P
authors: Brennan
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D016022:Case-Control Studies; D005060:Europe; D005492:Folic Acid / Q000008:administration & dosage* / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase