Abstract LB-417: Polymorphisms and haplotypes in XRCC1 and risk of advanced non-small cell lung cancer

Abstract

Abstract Background: Base excision repair (BER) is the primary DNA damage repair mechanism for repairing small base lesions resulting from oxidation and alkylation damage. Genetic variants in XRCC1, one of the BER genes, may be associated with smoking-related cancers. We tested the hypothesis that single nucleotide polymorphisms (SNPs) and/or hyplotypes in XRCC1 are related with the risk of non-small-cell lung cancer (NSCLC). Methods: We genotyped 3 known coding SNPs (Arg280His (rs25489), Arg399Gln (rs25487), and Gln632Gln (rs3547)) and 6 haplotype-tagging SNPs (htSNP) by Sequenom's (San Diego, CA, USA) high-throughput matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in 140 NSCLC patients and 217 controls from Korea. Analyses of individual SNPs and hyplotypes were performed using unconditional logistic regression adjusted for age, sex, and smoking status. Haplotypes were reconstructed according to the genotyping data and linkage disequilibrium status of these 9 SNPs using the Haploview version 4.1 software (Broad Institute of MIT and Harvard, Cambridge, MA, USA). Results: Minor allele heterozygotes of htSNP rs1799778 was increased risk of advanced NSCLC (adjusted OR, 2.118, 95% CI, 1.175-3.818, P= 0.013) and minor allele homozygote of htSNP rs2293036 was decreased risk of advanced NSCLC (adjusted OR, 0.363, 95% CI, 0.254-0.854, P = 0.020). Seven possible haplotypes were demonstrated in this study (Haplotype frequency >1%). The frequency of GGGGGGGGG haplotype composed of major alleles among selected all SNPs, was 0.109 and this haplotype showed protective effect of NSCLC risk (OR, 0.433; 95% CI, 0.246-0.740; P = 0.002). The association between the GGGGGGGGG haplotype and decreased risk of NSCLC was stable on permutation testing (P = 0.021). According to the smoking status, statistically significant associations between the rs1001581 polymorphisms and increased risk of NSCLC and the GGGGGGGGG haplotype and decreased risk of NSCLC risk were observed among never smokers (Adjusted P for trend = 0.005, P = 0.016), however, no association was noted among ever smokers. Conclusions: These findings suggest that the GGGGGGGGG haplotype composed of major alleles in all selected SNPs showed protective role against development of NSCLC and the rs1001581 polymorphisms showed increased risk of NSCLC in Koreans, especially nonsmokers, and smoking status modifies the associations between the XRCC1 genetic variants and NSCLC risk. Thus, this study presents several novel aspects on genetic susceptibility to NSCLC and larger studies of the role of the rs1001581 and haplotypes for NSCLC risk would be needed. 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-417.