Carcinogenesis Advance Access originally published online on March 26, 2007
Carcinogenesis 2007 28(6):1334-1340; doi:10.1093/carcin/bgm067
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Folate-related genes and the risk of tobacco-related cancers in Central Europe
1 International Agency for Research on Cancer, 150 cours Albert Thomas, F-69372, 69008, Lyon Cedex 08, France
2 School of Public Health, University of California at Berkeley, Berkeley, CA 94720, USA
3 Department of Epidemiology, Institute of Occupational Medicine, Lodz, 90-950, Poland
4 Institute of Carcinogenesis, Cancer Research Centre, Moscow, 115-478, Russia
5 Department of Cancer Epidemiology and Prevention, Cancer Center and Maria Sklodowska-Curie Institute of Oncology, Warsaw, 02-781, Poland
6 National Institute of Environmental Health, Fodor József National Center for Public Health, Budapest, 1097, Hungary
7 Specialized Institute of Hygiene and Epidemiology, Banska Bystrica, 97556, Slovakia
8 Department of General and Esophageal Surgery, "St. Mary" Hospital, Bucharest, 020021, Romania
9 Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, CZ-65653, Brno, Czech Republic
10 Department of Preventive Medicine, Faculty of Medicine, Palacky University, CZ-77515, Olomouc, Czech Republic
11 First Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University of Prague, Prague, CZ-12800, Czech Republic
12 German Cancer Research Center—Deutsches Krebsforschungszentrum, D-69120, Heidelberg, Germany
* To whom correspondence should be addressed. Tel: +33 4 7273 8391; Fax: +33 4 7273 8342; Email: hung{at}iarc.fr
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.
Abbreviations: CI, confidence interval; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; OR, odds ratio
Received November 24, 2006; revised March 13, 2007; accepted March 15, 2007.
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