Sequence Variants of NAT1 and NAT2 and Other Xenometabolic Genes and Risk of Lung and Aerodigestive Tract Cancers in Central Europe James D. McKay, 1 Mia Hashibe, 1 Rayjean J. Hung, 1,3 Jon Wakefield, 1 Valerie Gaborieau, 1 Neonila Szeszenia-Dabrowska, 4 David Zaridze, 5 Jolanta Lissowska, 6 Peter Rudnai, 7 EleonoraFabianova, 8 DanaMates, 9 LenkaForetova, 10 VladimirJanout, 11 VladimirBencko, 12 Amelie Chabrier, 1 Janet Hall, 1 Paolo Boffetta, 1 Federico Canzian, 2 and Paul Brennan 1 1 IARC, Lyon, France; 2 German Cancer Research Center-Deutsches Krebsforschungszentrum, Heidelberg, Germany; 3 University of California at Berkeley, Berkeley, California; 4 Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland; 5 Institute of Carcinogenesis, Cancer Research Centre, Moscow, Russia; 6 Department of Cancer Epidemiology and Prevention, Cancer Center and Maria Sklodowska-Curie Institute of Oncology, Warsaw, Poland; 7 National Institute of Environmental Health, Budapest, Hungary; 8 Specialized Institute of Hygiene and Epidemiology, Banska Bystrica, Slovakia; 9 Institute of Public Health, Bucharest, Romania; 10 Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic; 11 Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic; and 12 Charles University of Prague, First Faculty of Medicine, Institute of Hygiene and Epidemiology, Prague, Czech Republic Abstract Tobaccosmokecontainsanextensivecocktailofhighly carcinogenic chemicals. Individuals with a slower elimination rate of the chemicals in tobacco smoke may have increased exposure to their carcinogenic properties compared with those with a faster rate. Polymorphisms that alter the function of the genes involved in the activation or the detoxification of the chemical carcinogens in tobacco smoke can potentially influence an individual’s risk of developing a tobacco- related cancer. To test this hypothesis, we have genotyped polymorphisms in 16 genes involved in metabolism of chemical carcinogens in a Central and Eastern European case-control study comprising 2,250 lung cases, 811 upper aerodigestive cancer (UADT) cases, and 2,704 controls. The N-acetyltransferase (NAT ) genes were the most implicated in risk, with the NAT1*10 haplotypeshowinganinverseassociation inlungcancer,inbothheterozygotecarriers[oddsratio (OR), 0.81; 95% confidence interval (95% CI), 0.70-0.93] and homozygote carriers (OR, 0.70; 95% CI, 0.48-1.01), suggesting a genotype dose response (P < 0.001). In UADT cancer, a similar inverse association was noted in NAT1*10 although only in heterozygotes (OR, 0.78; 95%CI, 0.65-0.95). In NAT2 , when considering the individuals inferred acetylator phenotypes based on their NAT2 diplotype, ‘‘slow’’ acetylators compared with intermediate or fast acetylators showed no association with risk. None of the other 14 genes provided robust evidence of an association for either lung or UADT cancer. We therefore conclude that, of the genetic variation studied, NAT1 genewasthemost likely candidate to influence the risk of developing a tobacco-related cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(1):141 – 7) Introduction Tobacco smoking is the predominant cause of lung and upper aerodigestive tract (UADT) cancers (1). The mutagenic chemical carcinogens in tobacco smoke are eliminated from the human body via a series of enzymes that metabolize the carcinogenic compounds. Genetic variation in functionally important regions of xenometa- bolic genes seem to influence the rate of action of these enzymes (2-4). An individual’s genetic profile of xen- ometabolic alleles will have a role in determining the rate at which carcinogens are eliminated and therefore the extent of carcinogen exposure. Individuals who have inherited alleles that result in higher degree of carcinogen exposure are expected to have a higher cancer risk relative to those who inherited lower exposure alleles (2-6). We hypothesized that polymorphisms in the genes encoding the proteins involved in either the activation (phase I) and/or the detoxification (phase II) of chemical carcinogens in tobacco smoke will influence risk of developing lung or UADT cancers. To test this hypothesis, we have genotyped polymorphisms in 16 xenometabolic genes in a large case-control study of lung cancer patients and UADT cancer cases. Materials and Methods Study Participants. The study was conducted in 15 centers in six countries of Central and Eastern Europe, including Czech Republic (Prague, Olomouc, Brno), Hungary (Borsod, Heves, Szabolcs, Szolnok, Cancer Epidemiol Biomarkers Prev 2008;17(1). January 2008 Received 6/18/07; revised 10/2/07; accepted 10/18/07. Grant support: National Cancer Institute R01 grant (contract no. CA 092039-01A2) and Association for International Cancer Research grant (contract no. 03-281). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: James McKay, IARC, 150 cours Albert Thomas, F-69372 Lyon Cedex 08, France. Phone: 33-4-727380993; Fax: 33-4-7273-8342. E-mail: mckay@iarc.fr Copyright D 2008 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-07-0553 141 on June 5, 2020. © 2008 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from