Abstract 886: Germline variation in nucleotide excision repair genes and lung cancer risk in smokers

Abstract

Abstract Nucleotide excision repair (NER) is the primary mechanism for detecting and repairing bulky DNA lesions, which in the respiratory tract can be induced by tobacco smoke and other environmental exposures. By altering DNA repair capacity, single nucleotide polymorphisms (SNPs) in NER protein-encoding genes may affect lung cancer risk, especially in smokers. Although meta-analyses have suggested some associations between NER SNPs and lung cancer (e.g., ERCC2 rs13181 and XPA rs1800975), they are largely built upon studies that have examined a limited number of SNPs in a few genes in fairly small samples. To comprehensively assess the influence of NER gene variation on lung cancer risk, we genotyped 78 SNPs tagging the regions spanning ±2500 base pairs of the ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, LIG1, POLE, XPA and XPC genes in lung cancer cases and controls selected from the Beta-Carotene and Retinol Efficacy Trial, a randomized chemoprevention trial in smokers. Controls were matched to cases on age, sex, race, enrollment year, and baseline measures of smoking status and occupational asbestos exposure. Gene coverage by the tag SNPs selected using HapMap CEU data (dbSNP build 129, ≫5% minor allele frequency, pairwise r2 >0.8) ranged from 91.7% to 100%. To assess SNP-level associations, we computed odds ratios (OR) and 95% confidence intervals (CI) adjusted for matching variables using logistic regression. To assess gene-level associations, we computed global p-values for likelihood ratio tests comparing each model with all SNPs in a given gene to that with no SNPs. Analyses were limited to Caucasians (746 cases, 1477 controls). At the gene level, XPA (pglobal=0.008) and LIG1 (pglobal=0.039) were associated with lung cancer risk. Associations were detected for two of the nine XPA SNPs examined, rs3176683 (OR per G allele: 0.77, 95% CI: 0.58-1.00, p=0.05) and rs3176658 (OR per A allele: 0.83, 95% CI: 0.69-1.00, p=0.05), and three of the eleven LIG1 SNPs examined, rs156640 (OR per G allele: 1.2, 95% CI: 1.1-1.4, p=0.002), rs156641 (OR per A allele: 1.2, 95% CI: 1.1-1.4, p=0.003), and rs8100261 (OR per A allele: 0.87, 95% CI: 0.77-0.99, p=0.03). The two XPA SNPs (r2=0.01) exhibited stronger associations when included together in a single regression model. In diplotype analyses, lung cancer risk was lower for those carrying the homozygous major genotypes of rs3176683 and rs3176658, relative to both heterozygous genotypes (OR: 0.38, 95% CI: 0.17-0.87). Lung cancer risk was higher for those carrying the homozygous minor genotypes of rs156640 and rs156641 and homozygous major genotype of rs8100261, relative to the homozygous major genotypes of rs156640 and 156641 and homozygous minor genotype of rs8100261 (OR: 1.7, 95% CI: 1.2-2.3). Although reported ERCC2 rs13181 and XPA rs1800975 associations could not be confirmed, our data nonetheless support the hypothesis that germline variation in NER genes influences lung cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 886. doi:10.1158/1538-7445.AM2011-886