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Inherited Predisposition of Lung Cancer: A Hierarchical Modeling Approach to DNA Repair and Cell Cycle Control Pathways

¹ IARC, Lyon, France; ² University of California at Berkeley, Berkeley, California; ³ Ecole Nationale de la Statistique et de l'Analyse de l'Information, Bruz, France; ⁴ Department of Preventive Medicine, University of Southern California, Los Angeles, California; ⁵ Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland; ⁶ Institute of Carcinogenesis, Cancer Research Centre, Moscow, Russia; ⁷ Department of Cancer Epidemiology and Prevention, Cancer Center and Maria Sklodowska-Curie Institute of Oncology, Warsaw, Poland; ⁸ National Institute of Environmental Health, Fodor József National Center for Public Health, Budapest, Hungary; ⁹ Specialized Institute of Hygiene and Epidemiology, Banska Bystrica, Slovakia; ¹⁰ Institute of Public Health, Bucharest, Romania; ¹¹ Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic; ¹² Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic; ¹³ Charles University of Prague, First Faculty of Medicine, Institute of Hygiene and Epidemiology, Prague, Czech Republic; ¹⁴ German Cancer Research Center-Deutsches Krebsforschungszentrum, Heidelberg, Germany; and ¹⁵ Institut National de la Sante et de la Recherche Medicale U612, Institute Curie-Recherche, Orsay, France

Requests for reprints: Rayjean J. Hung, IARC, 150 cours Albert Thomas, F-69372 Lyon Cedex 08, France. Phone: 33-4-7273-8023; Fax: 33-4-7273-8342. E-mail: hung{at}iarc.fr

The DNA repair systems maintain the integrity of the human genome and cell cycle checkpoints are a critical component of the cellular response to DNA damage. We hypothesized that genetic variants in DNA repair and cell cycle control pathways will influence the predisposition to lung cancer, and studied 27 variants in 17 DNA repair enzymes and 10 variants in eight cell cycle control genes in 1,604 lung cancer patients and 2,053 controls. To improve the estimation of risks for specific variants, we applied a Bayesian approach in which we allowed the prior knowledge regarding the evolutionary biology and physicochemical properties of the variant to be incorporated into the hierarchical model. Based on the estimation from the hierarchical modeling, subjects who carried OGG1 326C/326C homozygotes, MGMT 143V or 178R, and CHEK2 157I had an odds ratio of lung cancer equal to 1.45 [95% confidence interval (95% CI), 1.05-2.00], 1.18 (95% CI, 1.01-1.40), and 1.58 (95% CI, 1.14-2.17). The association of CHEK2 157I seems to be overestimated in the conventional analysis. Nevertheless, this association seems to be robust in the hierarchical modeling. None of the pathways seem to have a prominent effect. In general, our study supports the notion that sequence variation may explain at least some of the variation of inherited susceptibility. In particular, further investigation of OGG1, MGMT, and CHEK2 focusing on the genetic regions where the present markers are located or the haplotype blocks tightly linked with these markers might be warranted. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2736–44)