Abstract LB-414: Variation in base excision repair genes and risk of smoking-related non-small cell lung cancer

Abstract

Abstract Base excision repair (BER) is the primary mechanism responsible for the repair of small base lesions in DNA caused by oxidation and alkylation. Given this role, functionally relevant polymorphisms in BER pathway genes may well affect the risk of smoking-related non-small cell lung cancer (NSCLC). We examined the association between 49 single nucleotide polymorphisms (SNPs) located in or near 5 different BER genes (XRCC1, LIG1, PARP1, MPG, and OGG1) and risk of NSCLC among Caucasians in a large case-control study. The study population consisted of 599 cases and 934 controls; all study participants were Caucasian and current or former cigarette smokers who had smoked at least 10.0 pack-years. SNPs were selected using various resources including literature review and data from the International HapMap project, and genotyping was conducted by Illumina Goldengate assay. Deviation from Hardy-Weinberg equilibrium was evaluated with the exact method. Associations between alleles and genotypes and NSCLC risk were examined using a Pearson Chi-square test and a Cochran-Armitage trend test, respectively. Per (minor) allele odds ratios (OR) and corresponding 95% confidence intervals (95% CI) were also calculated for each SNP. Six SNPs (rs3219073, rs747658, rs3219090, rs2048424, rs2666428, and rs8679) in PARP1 were statistically significantly (P<0.01) associated with NSCLC risk in our study population. SNP rs3219073 was in high linkage disequilibrium (r2≥0.8) with rs747658, as were rs3219090 and rs2048424 with rs2666428. The minor alleles of these SNPs were associated with a decreased risk of developing NSCLC (rs747658, OR: 0.7, 95%CI: 0.6-0.9, Ptrend=0.0005; rs2666428, OR: 0.8, 95%CI: 0.7-0.9, Ptrend =0.005). The C allele of SNP rs8679 (3′ UTR) was associated with an increased risk of NSCLC (OR: 1.3, 95%CI: 1.1-1.5, Ptrend =0.005). Additionally, SNPs rs3213255 and rs1799782 (Arg194Trp) in XRCC1 and SNP rs10500298 in LIG1 were also significantly associated with NSCLC risk. The minor alleles of rs3213255 and rs10500298 were associated with an increased risk (OR: 1.3, 95%CI: 1.1-1.5; OR: 1.2, 95%CI: 1.1-1.4, respectively), while the minor allele of rs1799782 was associated with a decreased risk (OR: 0.6, 95%CI: 0.4-0.9). PARP1 polymorphisms have previously been reported associated with other cancers, including breast cancer and colorectal cancer, but this is the first study to report associations with NSCLC risk. To conclude, our results suggest that common variation in PARP1, XRCC1 and LIG1 may be associated with risk of smoking-related NSCLC. 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 LB-414.