DNA repair genotype and lung cancer risk in the beta-carotene and retinol efficacy trial.

Many carcinogens in tobacco smoke cause DNA damage, and some of that damage can be mitigated by the actions of DNA repair enzymes. In a case-control study nested within the Beta-Carotene and Retinol Efficacy Trial, a randomized chemoprevention trial in current and former heavy smokers, we examined whether lung cancer risk was associated with variation in 26 base excision repair, mismatch repair, and homologous recombination repair genes. Analyses were limited to Caucasians (744 cases, 1477 controls), and logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for individual SNPs and common haplotypes, with adjustment for matching factors. Lung cancer associations were observed (p<0.05) with SNPs in MSH5 (rs3131379, rs707938), MSH2 (rs2303428), UNG (rs246079), and PCNA (rs25406). MSH5 rs3131379 is a documented lung cancer susceptibility locus in complete linkage disequilibrium with rs3117582 in BAT3, and we observed associations similar in magnitude to those in prior studies (per A allele OR 1.37, 95% CI 1.13-1.65). UNG was associated with lung cancer risk at the gene level (p=0.02), and the A allele of rs246079 was associated with an increased risk (per A allele OR 1.15, 95% CI1.01-1.31). We observed stronger associations with UNG rs246079 among individuals who carried the risk genotypes (AG/AA) for MSH5 rs3131379 (pinteraction= 0.038). Our results provide additional evidence to suggest that the MSH5/BAT3 locus is associated with increased lung cancer risk among smokers, and that associations with other SNPs may vary depending upon MSH5/BAT3 genotype. Future studies to examine this possibility are warranted.

Germ line variation in nucleotide excision repair genes and lung cancer risk in smokers.

Since nucleotide excision repair (NER) is primarily responsible for detecting and removing bulky DNA lesions induced by tobacco smoke in the respiratory tract, single nucleotide polymorphisms (SNPs) in NER protein-encoding genes may influence lung cancer risk, particularly in smokers. Studies testing this hypothesis have produced inconsistent results, with most analyzing a few SNPs in relatively small population samples. In a study nested in the Beta- Carotene and Retinol Efficacy Trial, we examined 79 tag and previously reported risk-associated SNPs in the ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, LIG1, POLE, XPA, and XPC genes in 744 lung cancer cases and 1,477 controls, all of whom were non-Hispanic white smokers. Using logistic regression, odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to estimate lung cancer risk associated with SNP genotypes and haplotypes, adjusting for case-control matching factors. Lung cancer risk was modestly associated with LIG1 rs156640 (OR per G allele, 1.23; 95% CI, 1.08-1.40), rs156641 (OR per A allele, 1.23; 95% CI, 1.08-1.40), and rs8100261 (OR per A allele, 0.83; 95% CI, 0.76-0.98); XPA rs3176658 (OR per A allele, 0.83; 95% CI, 0.69-1.00); and ERCC2 rs50871 (OR per C allele, 1.15; 95% CI: 1.01-1.30). Associations with LIG1 and XPA, but not ERCC2, haplotypes were found. The results of this study and others suggest that inherited variants in LIG1 and possibly other NER genes may predispose to smoking-related lung cancer. Given that chance likely accounts for one or more of the associations observed, replication of our findings is needed.