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DNA Repair and Cell Cycle Control Genes and the Risk of Young-Onset Lung Cancer

¹ Dip. Biologia-Genetics, University of Pisa, Pisa, Italy; ² IARC, Lyon, France; ³ German Cancer Research Center, Heidelberg, Germany; 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, Fodor József National Center for Public Health, Budapest, Hungary; ⁸ Specialized Institute of Hygiene and Epidemiology, Banska Bystrica, Slovakia; ⁹ Institute of Hygiene, 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; ¹² Charles University of Prague, First Faculty of Medicine, Institute of Hygiene and Epidemiology, Prague, Czech Republic; and ¹³ School of Public Health, University of California at Berkeley, Berkeley, California

Requests for reprints: Paul Brennan, IARC, 150 cours Albert-Thomas, F-69372 Lyon Cedex 08, France. Phone: 33-4-72738391; Fax: 33-4-72738342; E-mail: brennan{at}iarc.fr.

Exposure to tobacco smoke and to mutagenic xenobiotics can cause various types of DNA damage in lung cells, which, if not corrected by DNA repair systems, may lead to deregulation of the cell cycle and, ultimately, to cancer. Genetic variation could thus be an important factor in determining susceptibility to tobacco-induced lung cancer with genetic susceptibility playing a larger role in young-onset cases compared with that in the general population. We have therefore studied 102 single-nucleotide polymorphisms (SNP) in 34 key DNA repair and cell cycle control genes in 299 lung cancer cases diagnosed before the age of 50 years and 317 controls from six countries of Central and Eastern Europe. We have found no association of lung cancer risk with polymorphisms in genes related to cell cycle control, single-strand/double-strand break repair, or base excision repair. Significant associations (P < 0.05) were found with polymorphisms in genes involved in DNA damage sensing (ATM) and, interestingly, in four genes encoding proteins involved in mismatch repair (LIG1, LIG3, MLH1, and MSH6). The strongest associations were observed with heterozygote carriers of LIG1 –7C>T [odds ratio (OR), 1.73; 95% confidence interval (95% CI), 1.13-2.64] and homozygote carriers of LIG3 rs1052536 (OR, 2.05; 95% CI, 1.25-3.38). Consideration of the relatively large number of markers assessed diminishes the significance of these findings; thus, these SNPs should be considered promising candidates for further investigation in other independent populations. (Cancer Res 2006; 66(22): 11062-9)

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