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Carcinogenesis Advance Access published online on January 27, 2007
Carcinogenesis, doi:10.1093/carcin/bgm021
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Development of lung cancer before the age of 50: the role of xenobiotic metabolism genes

Federica Gemignani1,2,*, Stefano Landi1,*, Neonilia Szeszenia-Dabrowska3, David Zaridze4, Jolanta Lissowska5, Peter Rudnai6, Eleonora Fabianova7, Dana Mates8, Lenka Foretova9, Vladimir Janout10, Vladimir Bencko11, Valérie Gaborieau2, Lydie Gioia-Patricola2, Ilaria Bellini1, Roberto Barale1, Federico Canzian12, Janet Hall13, Paolo Boffetta2, Rayjean J. Hung2,14 and Paul Brennan2

1 Genetics, Department of Biology, University of Pisa, Italy
2 International Agency for Research on Cancer, Lyon, France
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 Institute of Hygiene, Public Health, 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 (DKFZ), Heidelberg, Germany
13 Institut Curie, Paris, France
14 School of Public Health, University of California at Berkeley, Berkeley, USA

Correspondence and requests for reprints to: Paul Brennan, IARC, 150 cours Albert-Thomas, F-69372 Lyon, France; Fax: 33-4-72738342; E-mail: brennan{at}iarc.fr

OBJECTIVES: The role of genes coding for xenobiotic metabolism enzymes (XME) and the risk of lung cancer is unclear. Under the assumption that these genes may be more important among people having a diagnosis of lung cancer at younger ages, we have investigated the role of single nucleotide polymorphisms (SNPs) within phase I and phase II XME genes, and also genes involved in the metabolism of nucleic acids in a series of young onset patients and matched controls.

METHODS: We genotyped 299 lung cancer cases diagnosed before the age of 50 and 317 controls, from six countries of Central and Eastern Europe, by use of an oligonucleotide micro-array and arrayed primer extension technique (APEX) for 45 SNPs in 15 phase I XME genes, 46 SNPs in 17 phase II genes and 9 SNPs in 4 genes related to metabolism of nucleic acids.

RESULTS: Heterozygote carriers of SNPs in CYP1A2 1545T>C, -164C>A, and -740T>G, CYP2A6 -47A>C, MDR1 3435 T>C, NAT1 1088T>A, 1095A>C, GSTA2 S112T, GSTM3 V224I and MTHFR A222V had altered risk of developing lung cancer. Phenotypes reconstructed after haplotype analyses showed that the carriers of the combined NAT1 fast+ NAT2 fast phenotypes were at lower risk when compared to those with the combined NAT1 slow + NAT2 slow acetylator phenotypes. Finally, extensive EPHX1 metabolizers showed an increased risk as compared to the poor metabolizers.

Key Words: lung cancer • single nucleotide polymorphisms (SNPs) • xenobiotic metabolism • micro-array • phase I • phase II

* These authors contributed equally to the manuscript


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