Polymorphisms in the two helicases ERCC2/XPD and ERCC3/XPB of the transcription factor IIH complex and risk of lung cancer: a case-control analysis in a Chinese population.

The transcription factor IIH (TFIIH) helicases ERCC2/XPD and ERCC3/XPB are responsible for opening the DNA strand around the lesion site during nucleotide excision repair process. Genetic variants in these two genes may be markers for interindividual variability in DNA repair capacity and thus predisposition to cancer risk. In this case-control study of 1,010 incident lung cancer cases and 1,011 age and sex frequency-matched cancer-free controls in a Chinese population, we genotyped eight tagging polymorphisms of ERCC2 and ERCC3 using the high-throughput Taqman platform to determine their associations with risk of lung cancer. Although none of the eight polymorphisms was individually associated with lung cancer risk, we found that genetic variants in ERCC2 and ERCC3 jointly contributed to lung cancer risk in a dose-response manner. Compared with those with 0 to 1 "at-risk" locus, subjects carrying >1 at-risk loci were at increased risk for lung cancer [adjusted odds ratio (OR), 1.29; 95% confidence interval (95% CI), 0.98-1.70 for 2 at-risk loci; adjusted OR, 1.38; 95% CI, 1.02-1.85 for 3 at-risk loci; and adjusted OR, 1.51; 95% CI, 1.09-2.10 for > or =4 at-risk loci, respectively; P(trend) = 0.015]. This combined effect was slightly more evident in young subjects (<60 years), males, current smokers, and those with family history of cancer, particularly for histologic type of adenocarcinomas. No evidence for interaction was found. These findings indicate that these tagSNPs of the ERCC2 and ERCC3 along with their surrounding regions may serve as biomarkers of susceptibility to lung cancer, which warrant further validation by other population-based and phenotypic studies to determine the biological relevance of these tagSNPs.