Association of genetic polymorphisms in DNA repair pathway genes with non-small cell lung cancer risk

Abstract

DNA repair function is believed to play an important role in cancer development and to be affected by genetic polymorphisms. Numerous epidemiological studies have examined the associations between single nucleotide polymorphisms (SNPs) in the DNA repair genes and lung cancer risk, but the results are inconsistent. The aim of this study was to investigate the associations of several SNPs in the DNA repair pathways and risk of non-small cell lung cancer (NSCLC) in a Chinese population. The study included 581 NSCLC cases and 603 healthy controls. The polymorphisms studied include XRCC1 (rs25487), hOGG1 (rs1052133), MUTYH (rs3219489) in the base excision repair (BER) pathway, XPA (rs1800975), ERCC2 (rs1799793 and rs13181) in the nucleotide excision repair (NER) pathway and XRCC3 (rs861539) in the double strand break repair (DSB) pathway. The associations between lung cancer risk and genetic polymorphisms were evaluated using the logistic regression models and subgroup analyses. Meta-analyses were conducted for the SNPs shown to be significantly associated with lung cancer risk in our study. Our findings showed that XPA -4G>A (rs1800975) had a significant association with lung cancer (OR=1.64; 95% CI: 1.03-2.60), and the association was more evident in squamous cell carcinoma (OR=1.69; 95% CI: 1.00-2.84). Three BER polymorphisms showed no independent effects on the risk of lung cancer. The stratified analysis showed higher lung cancer risk among the smokers carrying the variant XPA allele (OR=1.75; 95% CI: 1.15-2.65) and among the non-smokers carrying the variant ERCC2 allele of 312Asn (OR=2.10; 95% CI: 1.22-3.64). Meta-analysis showed that individuals with the variant AA genotype of XPA (-4G>A) had higher risk of lung cancer compared to those with the 'G' wild allele (OR=1.28; 95% CI: 1.12-1.47); and those with variant alleles of ERCC2 312Asn had higher risk compared to those with wild 312Asp alleles among nonsmokers (OR=1.58; 95% CI: 1.20-2.08). Although smoking is the dominant risk factor of lung cancer, XPA -4G>A (rs1800975) is also associated with the risk of NSCLC, especially for squamous cell carcinoma, among Asian young smokers. ERCC2 Asp/Asn (rs1799793) polymorphism may also affect lung cancer risk among nonsmokers. The NER pathway seems to have more strong influences on lung cancer than the BER pathway.