| Identifying genetic factors that contribute to lung cancer may lead to improved strategies for its early detection and treatment. Of particular relevance to the pathogenesis of this disease is nucleotide excision repair (NER), the DNA repair mechanism primarily responsible for recognizing and removing bulky DNA lesions induced by tobacco smoke, platinum-based chemotherapy agents, and other exogenous exposures. Studies examining whether genetic variations in the NER pathway influence lung cancer susceptibility and prognosis have produced inconclusive results, although most have analyzed a limited number of single nucleotide polymorphisms (SNPs) in a few genes in small population samples. A more comprehensive study nested in the Beta-Carotene and Retinol Efficacy Trial was conducted to evaluate associations of 79 tag and putative functional SNPs in the NER protein-encoding genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5 , LIG1, POLE, XPA, and XPC with lung cancer incidence and survival. Comparing 744 lung cancer cases to 1,477 controls, all of whom were non-Hispanic white smokers, estimates of lung cancer risk associated with SNP genotypes and haplotypes were calculated using logistic regression. For the 518 cases with non-small cell lung cancer and 132 cases with small cell lung cancer, probabilities of overall survival by SNP genotype were determined, and estimates of all-cause mortality risk associated with SNP genotypes and haplotypes were derived using Cox regression. Study results indicate that SNPs in LIG1 and possibly other NER genes may predispose to smoking-related lung cancer, and that SNPs in ERCC1, ERCC2, ERCC4, ERCC5, and XPC may modestly influence overall survival after lung cancer diagnosis, depending on tumor histology and receipt of chemotherapy. However, in light of study limitations, including that chance may account for one or more of the associations observed, these findings should be interpreted cautiously until validated in other large and well-characterized populations. |
