Polymorphisms in the DNA repair genes XRCC1, APEX1, XRCC3 and NBS1, and the risk for lung cancer in never- and ever-smokers.

This case-control study examines the association between lung cancer and genetic polymorphisms in two base excision repair (BER) genes, XRCC1 and APEX1 and two genes involved in homologous recombination repair (HR), XRCC3 and NBS1. Never-smoking lung cancer patients were recruited, and also the next diagnosed ever-smoking case of the same gender and age group. Controls were recruited from the regional population register, frequency matched to cases by hospital catchment area, gender, age group and smoking category. As a result more than 70% of the study population were women. A total of 331 individuals were analysed. Presence of the XRCC1 399Gln allele was associated with a significantly decreased risk for lung cancer among non-smoking women (odds ratio (OR) 0.4, 95% confidence interval (CI) 0.2-0.9). No significant effect was seen with the APEX1 polymorphism. Women smokers carrying the XRCC3 241Met allele showed a significantly decreased risk for lung cancer (OR 0.3, CI 0.2-0.7). The NBS1 185Gln allele was significantly associated with an increased risk for lung cancer among non-smoking women (OR 2.2, CI 1.0-4.8) and low-dose smoking women (OR 4.8, CI 1.5-15.7). The protective effect of the variant XRCC3 241Met allele was strengthened when combined with the low-risk Glu185 allele of the NBS1 gene. Smokers (OR 0.38, CI 0.16-0.90) and women (OR 0.42, CI 0.21-0.85) with at least three low-risk alleles in these two HR genes showed a significantly decreased risk for lung cancer. Thus, in spite of a relatively small study population, this study, including a comparatively large number of never-smokers and women, presents several novel aspects on genetic susceptibility to lung cancer. Our results show that the genetic variation in XRCC1, XRCC3 and NBS1 influence lung cancer susceptibility among women, and that combinations of risk alleles in the two HR genes can enhance the effects.