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.
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.
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.
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.
Our data suggest that the polymorphism ERCC2Lys751Gln or a haplotype encompassing the variant allele is associated with risk of lung cancer in this population.
We found an increased risk of lung cancer among subjects carrying the ERCC2 751Gln/Gln genotype (odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.14 - 1.49).
In conclusion, the APE1 Asp148Glu polymorphism is highly predictive for lung cancer, and cumulative cigarette smoking modifies the associations between the XRCC1 Arg399Gln and the XPDLys751Gln polymorphisms and lung cancer risk.
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.
In conclusion, this study indicated no association between mRNA expression of the DNA-repair genes ERCC1 and XPD and risk of subsequent development of lung cancer.
We found that XPA A23G and XPC Lys939Gln polymorphisms may be risk factors for lung cancer and evidence that positive interactions between the polymorphisms in XPA/XPD and XPC/XPD may occur.
Moreover, one haplotype in ERCC2 was associated with a decreased risk of lung cancer (OR = 0.40, 95% CI 0.19-0.85) compared to the most common haplotype.
Together with data from the present study on DNA repair genes, we did not observe significant associations between any single variant genotype for several DNA-repair and chemical-metabolizing genes (XPD [or ERCC2], XRCC1, XRCC3, GSTM1, GSTT1, MPO, and mEH [or EPHX1]) and lung cancer.
Among men, carriers of the variant allele of XPDLys751Gln had a non-significantly increased risk of lung cancer in the youngest age interval (RR=6.38, 95% CI=0.74-54.90).
Combinations of polymorphisms in genes involved in the same repair pathway (XPA + XPD or XRCC1 + APE1) affected lung cancer risk only in patients with SCC.
These results support the hypothesis that both the XPD 751 C and 312 A are risk alleles and individuals with the XPD 751 CC and 312 AA genotypes are at higher risk of developing lung cancer.
XPD genotypes were determined using PCR-RFLP techniques, and the associations between genotypes and risk of lung cancer were estimated by odds ratios (ORs) and their 95% confidence intervals (CIs) calculated by unconditional logistic regression.
In this case-control study of 1091 Caucasian lung cancer patients and 1240 controls, we explored the gene-environment interactions between the XRCC1 Arg399Gln polymorphism, alone or in combination with the two ERCC2 polymorphisms, and cumulative smoking exposure in the development of lung cancer.