There is increasing evidence that decreased nucleotide excision repair (NER) capacity may be associated with increased risk of cancer, including non-small cell lung cancer (NSCLC). We have studied the relationship of the NER pathway gene single nucleotide polymorphisms and haplotypes with NSCLC risk. Using a custom-designed Illumina GoldenGate assay 384 single nucleotide polymorphism (SNP) panel, we have screened for polymorphisms in nucleotide excision repair genes, cell cycle control genes, GSTP1 and ABCB1 and a set of ancestry informative markers in 797 Caucasian incident cases and 992 controls frequency matched for age (range 50-79) and gender. All subjects were ever smokers with a minimum 10 packyear smoking history. Our SNP selection strategy incorporates six SNP classes, i.e. haplotype tagSNPs defined by predicted LD scores; functional SNPs characterized by amino acid substitutions, SNPs that alter protein stability; evolutionary conservation across species; entromics and published epidemiological data. For the estimation of individual SNP and haplotype-specific associations with risk, unconditional logistic regression was used to estimate odds ratios and 95% confidence intervals in a dominant model adjusting for age, gender and packyear. A total of 26 unique SNPs in 14 genes were significantly associated with lung cancer risk. Haplotypes were reconstructed for each gene using HPlus and associations with risk were evaluated using the Cox proportional hazards model. The most frequent haplotype was used as the referent group for the estimation of hazard ratios (HR). Hazard ratios were calculated for common haplotypes i.e. those that were present at a frequency greater than 2% and were adjusted for age, gender and packyears. Among these 14 genes, 7 haplotypes were significant. These data suggest that NER pathway genotypes may serve to define an elevated risk subgroup. Supported in part by NIH 5P50 CA090440.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1868.