Potentially functional polymorphisms in DNA repair genes and non‐small‐cell lung cancer survival: A pathway‐based analysis

To assess systematically whether potentially functional polymorphisms in DNA repair genes influence the clinical behavior of non‐small‐cell lung cancer (NSCLC), we examined the impact of a comprehensive panel of 218 signal nucleotide polymorphisms (SNP) in 50 candidate DNA repair genes on overall survival of NSCLC in a case‐cohort of 568 lung cancer patients. SNPs associated with lung cancer prognosis primarily mapped to 14 genes in different repair pathways, and 6 SNPs were remained in the final model after multivariate stepwise Cox regression analysis: ATM rs189037; MRE11A rs11020802; ERCC2 rs1799793; MBD4 rs140693; XRCC1 rs25487, and PMS1 rs5742933. In the combined analysis of these 6 SNPs, an increasing number of unfavorable loci was associated with a poorer prognosis ( P for trend: <0.0001) and patients having 2–4 unfavorable loci had a 1.99‐fold elevated risk of death 95% confidence interval (CI) = 1.58–2.50, compared with those carrying 0–1 unfavorable loci, and this elevated risk was more evident among stages I–II patients (hazard ratio = 3.04, 95% CI = 1.86–4.98, P for heterogeneity: 0.07). Furthermore, a significant effect of SNPs in nucleotide excision repair pathway on lung cancer survival was observed among 185 stages III–IV patients treated with platinum‐based chemotherapy without surgical operation: XPC rs2228000 (Ala499Val; P  = 0.002) and ERCC1 rs11615 (Asn118Asn; P  = 0.012). Our data indicate that potentially functional polymorphisms in DNA repair genes may serve as candidate prognostic markers of clinical outcome of NSCLC. © 2011 Wiley Periodicals, Inc.