Polymorphisms and Haplotypes in the XRCC1 Gene and the Risk of Advanced Non-Small Cell Lung Cancer

Abstract

Introduction and Hypothesis: Single-nucleotide polymorphisms (SNPs) and haplotypes in the x-ray repair cross-complementing group 1 (XRCC1) gene, which is one of the base excision repair genes, are thought to be associated with the risk of non-small cell lung cancer (NSCLC). Methods: We genotyped three coding (Arg280His, Arg399Gln, and Gln632Gln) SNPs and six haplotype-tagging SNPs (htSNPs) for 140 advanced NSCLC cases and 217 healthy controls (all Koreans) using unconditional logistic regression analysis, and this was adjusted for age, gender, and the smoking status. The haplotypes were reconstructed according to the genotyping data and the linkage disequilibrium status of these nine SNPs. Results: The minor allele heterozygotes of the rs1001581 htSNP showed an increased risk of NSCLC (adjusted odds ratio = 2.118, p = 0.013), and the minor allele homozygotes of the rs2293036 htSNP showed a decreased risk of NSCLC (adjusted odds ratio = 0.363, p = 0.020). Seven possible haplotypes were demonstrated in this study (haplotype frequency >1%). The GGGGGGGGG haplotype, which is composed of nine major alleles, showed a protective effect for developing NSCLC (odds ratio = 0.433, p = 0.002); however, the GGGGGGAGG haplotype that contained the minor allele of the rs1001581 demonstrated an increased risk of NSCLC (odds ratio = 1.597, p = 0.044). The above associations were similarly noted for the never smokers, and so the smoking status might modify the associations between the x-ray repair cross-complementing group 1 (XRCC1) genetic variants and the risk of developing NSCLC. On 10-million permutation testing, only the GGGGGGGGG haplotype was significantly associated with a decreased risk of NSCLC in the total group (p = 0.001). Conclusions: This study presents several novel aspects of the genetic susceptibility to develop NSCLC. Larger studies that will focus on the role of the rs1001581 and rs2293036 htSNPs and haplotypes for developing NSCLC are needed in the future.