HapMap-based study of a region encompassing ERCC1 and ERCC2 related to lung cancer susceptibility in a Chinese population

Abstract

DNA repair genes play a crucial role in carcinogenesis. The paper aims to explore if common variants in ERCC1 are involved in lung cancer susceptibility. A Chinese case–control study included 339 lung cancer cases and 358 controls using five haplotype-tagging SNPs (htSNPs) (rs3212980, rs3212964, rs3212961, rs11615 and rs2298881) from the HapMap database, capturing 95% of the common haplotypic diversity of ERCC1. A combined analysis of eleven htSNPs covering ERCC2 and ERCC1 was performed. No significant association between individual htSNPs and lung cancer susceptibility was observed. There were interactions between rs3212961 and rs2298881and smoking duration ( P = 0.03 and P = 0.01, respectively). Thus, the variant alleles of rs3212961 [OR (95% CI) = 1.81(1.03–3.17), P = 0.04] and rs2298881 [OR (95% CI) = 2.16(1.26–3.70), P = 0.005] were associated with risk of lung cancer among long-term smokers (>20 years) but not among never smokers and short-term smokers. No significant associations with lung cancer susceptibility were observed for global or individual haplotypes defined by five htSNPs of ERCC1. A highly differential distribution of haplotypes based on eleven htSNPs covering ERCC2 and ERCC1 were found (global test P =4.3 × 10 −5). After Bonferroni correction, haplotypeER2 + 1–1 [OR (95% CI) = 3.63 (1.39–9.47), P = 0.005, marginally] and haplotypeER2 + 1–8 [OR (95% CI) = 4.46 (2.03–9.79), P = 5.6 × 10 −5, strongly] were associated with increased risk of lung cancer. The diplotype analysis with haplotypeER2 + 1–8 was also statistically significant ( P < 0.001). Haplotype analysis of pathological subtypes revealed that htSNPs of both genes may mainly influence the risk of lung adenocarcinoma. Strong linkage disequilibrium exist in two regions encompassing ERCC2 and ERCC1. These data suggest that common genetic variations in ERCC1 may influence increased risk of smoking-related lung cancer and one of the causative effectors may locate around or within ERCC2.