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Carcinogenesis Advance Access published online on March 26, 2007
Carcinogenesis, doi:10.1093/carcin/bgm067
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Folate related genes and the risk of tobacco-related cancers in Central Europe

Rayjean J. Hung1,2, Mia Hashibe1, James McKay1, Valerie Gaborieau1, Neonila Szeszenia-Dabrowska3, David Zaridze4, Jolanta Lissowska5, Peter Rudnai6, Eleonora Fabianova7, Ioan Mates8, Lenka Foretova9, Vladimir Janout10, Vladimir Bencko11, Amelie Chabrier1, Norman Moullan1, Federico Canzian12, Janet Hall1, Paolo Boffetta1 and Paul Brennan1

1 International Agency for Research on Cancer, Lyon, France
2 University of California at Berkeley, Berkeley, USA
3 Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland
4 Institute of Carcinogenesis, Cancer Research Centre, Moscow, Russia
5 Department of Cancer Epidemiology and Prevention, Cancer Center and Maria Sklodowska-Curie Institute of Oncology, Warsaw, Poland
6 National Institute of Environmental Health, Fodor József National Center for Public Health, Budapest, Hungary
7 Specialized Institute of Hygiene and Epidemiology, Banska Bystrica, Slovakia
8 University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania
9 Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic
10 Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic
11 Charles University of Prague, First Faculty of Medicine, Institute of Hygiene and Epidemiology, Prague, Czech Republic
12 German Cancer Research Center - Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany

Corresponding Author and Requests for reprints: Rayjean J. Hung, International Agency For Research on Cancer, 150 cours Albert Thomas, F-69372 Lyon Cedex 08, France, Tel: +33-4-7273-8391, Fax: +33-4-7273-8342, E-mail: 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-aerodigestive tract (UADT) cases, and 2899 controls were recruited with blood samples. The MTHFR C677T variant was associated with an increased risk of lung cancer with an OR for homozygote variant of 1.37 (95%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 UADT cancer, respectively. In conclusion, we identified a moderate effect of MTHFR C677T on lung cancer risk and a possible effect modification by folate intake which is consistent with the functional data. These results support an important role of folate in protecting against tobacco-related cancers.

Key Words: Folate • MTHFR • Lung cancer • genetic polymorphism • head and neck cancer

Received November 24, 2006; revised March 13, 2007; accepted March 15, 2007.


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