Background. Genetic association studies on lung cancer aim to identify common low-risk susceptibility genes, however, most of such studies are underpowered and limited to single marker analysis. As lung cancer susceptibility is likely to have a polygenic basis, we have conducted a large multicenter case-control study to investigate multiple sequence variants in DNA repair and cell cycle control pathways that are essential for genome integrity and replication accuracy. Methods. A total of 2633 lung cancer cases and 2884 controls were recruited in Czech Republic, Hungary, Poland, Romania, Russia and Slovakia. Subjects completed a detailed lifestyle questionnaire and provided a blood sample. Initial results on 12 sequence variants in 8 candidate genes were available for 2092 cases and 1433 controls (MGMT C171T, Ile143Val, Lys178Arg; XPF Pro379Ser, Arg415Gln; XRCC2 Arg188His, XRCC3 Thr241Met, CCND1 G870A, CDKN2A Ala148Thr, TP53 Arg72Pro and a 16 bp repeat in TP53 intron3). We applied E-M algorithm to estimate the haplotype frequency for the multiple variants in MGMT, XPF, and TP53. Effect modifications of age of onset and smoking were evaluated. Combining with previously reported data on 6 additional polymorphisms in DNA repair pathway (OGG1 Ser326Cys, XRCC1 Arg194Trp, Arg280His, Arg399Gln, APEX Gln51His and XPD Lys751Gln), we conducted multigenic analyses on a total of 18 potential low-penetrance sequence variants. Cases with family history (as who had at least one first degree relative with lung cancer) were analyzed separately. Results. The results of MGMT haplotype analysis suggested that the haplotype of 171T-143Val-178Arg increased risk of lung cancer with OR of 1.24 (95%CI=1.02-1.50). XRCC3 Met/Met genotype conferred a protective effect overall (OR=0.75, 95%CI=0.59-0.95), and among cases with family history (OR=0.54, 95%CI=0.3-1.00). A 16 bp repeat in TP53 intron 3 and Arg72Pro was shown to be in linkage disequilibrium (D’=0.82), however, an increased risk of lung cancer was mainly observed in carriers of TP53 intron 3 homozygous variants (OR=1.93, 95%CI=1.26-2.96 overall, OR=2.65, 95%CI=1.16-6.09 for cases with family history). Multigenic analysis of the 18 polymorphisms suggested an increased risk with OR of 2.01 (95%CI=1.20-3.37) when the subjects carried at least 8 prior risk genotypes (Trend P =0.006). When the multigenic analysis was restricted to the 6 variants that showed a main effect in our study population under a multiplicative model, every increment in the number of prior risk genotypes conferred ORs of 1.30 (95%CI=1.17-1.44) overall and 1.26 (95%CI=0.99-1.61) among cases with family history. Conclusions. In summary, although common genetic polymorphisms may not individually confer a detectable increased risk of lung cancer, analyzing multiple alleles simultaneously may provide a more complete picture of cancer susceptibility.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]