We included polymorphisms in the XPC, XPA and XPD genes involved in the nucleotide excision DNA repair pathway and analysed possible interactions with smoking and dietary intake of fruit and vegetables in relation to risk for lung cancer.
Two of the genetic polymorphisms, XRCC1Arg399Gln and XPDLys751Gln have been extensively studied in the association with lung cancer risk, although published studies have been inconclusive.
Using a panel of 20 lung cancer cell lines, including 15 NSCLC and 5 small cell lung cancers (SCLC), the mRNA expression levels for the RRM1, ERCC1 and ERCC2 genes were examined by quantitative real-time reverse transcription PCR.
From MDR analysis, in Latinos, smoking and 3 SNPs (ERCC2rs171140, ERCC5 rs17655 and LIG1 rs20581) together had a prediction accuracy of 67.4% (p = 0.001) for lung cancer.
Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79-0.99 and homozygote OR, 0.84; 95% CI, 0.71-1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPDK751Q (heterozygote OR, 0.99; 95% CI, 0.89-1.10 and homozygote OR, 1.19; 95% CI, 1.02-1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% CI, 1.00-1.29 and homozygote OR, 1.20; 95% CI, 1.02-1.42) based on 3,610 cases and 5,293 controls from 6 studies.
Requiring more stringent P values to account for multiplicity of comparisons, only the associations of ERCC2 codon 751 (recessive model) and of XRCC1 -77 T>C (dominant model) with lung cancer had P <or= .0001 and retained P <or= .001 even when the first published studies on the respective associations were excluded.
Although none of the six htSNPs was individually associated with lung cancer risk, we found that two ERCC2 haplotypes were associated with risk of lung cancer.
Previous studies have suggested that certain genetic polymorphisms, specifically the Xeroderma pigmentosum group D (XPD) gene codon 751 and the X-ray repair cross-complementing group 1 (XRCC1) gene codon 399 polymorphisms, were associated with an increased risk of lung cancer, and, in some studies, with a greater risk for mutations in the p53 tumor suppressor gene in lung tumors.
This meta-analysis suggests that the XPDLys751Gln and Asp312Asn gene polymorphisms are associated with lung cancer risk, the C allele of XPDLys751Gln genotype is an increased risk factor for developing lung cancer among Caucasians and in smokers, and the A allele of XPD 312 genotype is also an increased risk factor among Asians and in smokers.
These data suggest that common genetic variations in ERCC1 may influence increased risk of smoking-related lung cancer and one of the causative effectors may locate around or within ERCC2.
In conclusion, this meta-analysis suggests that the two ERCC2 polymorphisms may contribute to lung cancer susceptibility serving as low-penetrance risk factors.
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; ERCC2rs1799793; MBD4 rs140693; XRCC1 rs25487, and PMS1 rs5742933.
These associations were: two SNPs rs1799793 and rs13181 in the ERCC2 gene and lung cancer (recessive model) and rs1805794 in the NBN gene and bladder cancer (dominant model).
A pertinent combination of multiple "at-risk" genotypes of CYP1A1 rs4646903, the GSTM1 deletion polymorphism and ERCC2rs13181 was at a 5.94-fold (95% CI = 2.77-12.7) increased risk of lung cancer.
Furthermore, single nucleotide polymorphisms (SNPs) and haplotypes in the ERCC2 gene are thought to be associated with the risk of developing lung cancer and clinical outcomes.
In total, significantly increased risk of developing lung cancer was found in the following combinations of genotypes: XPD Lys/Gln+XPC Lys/Lys (OR = 1.62; p = 0.04), XRCC1 Gln/Gln+hOGG1 Ser/Ser (OR = 2.14; p = 0.02).
In conclusion, this meta-analysis suggested ERCC2Asp312Asn polymorphism may increase the risk of lung cancer among Asians, whereas not among Caucasians.
The haplotype ERCC2rs3916874(G) and rs238415(C) [OR (95% CI)=1.26 (1.02-1.57), P=0.03] in block 1 and the haplotype PPP1R13L rs4803817(A), CD3EAP rs1046282(T), rs735482(C), ERCC1 rs3212980(A), rs3212964(G) [OR (95% CI)=3.56 (1.55-8.18), P=0.005] in block 3 were associated with lung cancer risk.
Gln/Gln alleles of both XRCC1 and XPD genes appear to amplify the effects of household exposure, smoking and betel quid chewing on lung cancer risk in the study population.
We found a significantly increased risk of lung cancer development in XPD genotype Lys/Gln (OR=1.94; 95% CI=1.10-3.43; p=0.015) and in the gene combinations: XPD Lys/Gln+XPC Lys/Gln (OR=6.5; 95% CI=1.53-27.49; p=0.009) and XPD Lys/Gln+XPC Gln/Gln(OR=5.2; 95% CI=1.07-25.32; p=0.04).