CONCLUSIONS Taken together, T-77C and Arg399Gln polymorphisms of the XRCC1 gene, as well as the 186C>T and Val158Met polymorphisms of the COMT gene, increased the risk of lung cancer in non-smoking women, with the factors of occupation type, cooking-oil fumes, and soot exposures representing key contributing factors.
Our meta-analysis on 2861 cases (lung cancer patients) and 2783 controls from eight eligible studies in Chinese populations showed that for the XRCC1Arg194Trp polymorphism, compared with the Arg/Arg homozygous genotype, the variant Arg/Trp and Trp/Trp genotypes combined was not associated with lung cancer risk (OR=1.06, 95% confidence interval [CI]=0.89-1.27) (Z=0.70, P=0.48), nor was Arg280His (OR=0.63, 95% CI=0.28-1.41) (Z=1.12, P=0.26); however, for the XRCC1Arg399Gln polymorphism, the combination of variant Arg/Gln and Gln/Gln genotypes was borderline significantly associated with lung cancer risk (OR=1.16, 95% CI=1.00-1.36) (Z=1.90, P=0.06), compared with the Arg/Arg homozygous genotype.
On the other hand, individuals homozygous for the XRCC1 399Gln allele presented no risk of developing lung cancer (OR = 0.87; 95%CI = 0.57-1.31) except for individuals carriers of 399Gln/Gln genotype and without family history of cancer (OR = 0.57; 95%CI = 0.33-0.98) and no association was found between XRCC3 Thr241Met polymorphism and lung cancer risk (OR = 0.92; 95%CI = 0.56-1.50), except for the 241Met/Met genotype and squamous cell carcinoma risk (OR = 0.47; 95%CI = 0.23-1.00).
A polymorphism at codon 399 of the XRCC1 gene (Arg to Gln) is associated with increased DNA adduct binding and an increase in sister chromatid exchanges after exposure to tobacco carcinogens and may be linked with an increased risk of lung cancer.
To analyze the relationship of GSTT1, GSTM1, XRCC1 (rs25487), ERCC1 (rs11615, rs3212986), ERCC2 (rs13181), XRCC3 (rs861539), OGG1 (rs1052133), and Alpha-1-Antitrypsin mutations (AAT) with the risk of lung cancer in never-smokers, and ascertain if there is an effect modification between these polymorphisms and residential radon exposure.
These preliminary results suggested that the XRCC1 c.482C>T and c.1686C>G genetic variants might play genetic effects on the susceptibility to lung cancer in the studied population.
In conclusion, this meta-analysis has demonstrated that codon 194, codon 399 and -77 T > C polymorphisms of XRCC1 gene might have contributed to individual susceptibility to lung cancer.
However, the XRCC1Arg194Trp and Arg280His variants were each associated with a reduced risk of lung cancer among subjects in the highest quartile of pack-years of smoking compared with common allele homozygotes (ORs of 0.65 [95% CI = 0.46 to 0.93] and 0.56 [95% CI = 0.36 to 0.86], respectively).
We found no direct association between lung cancer risk and any of the DNA repair genotypes studied, however, the association between XPD codon 751 genotype and lung cancer was modified by alpha-tocopherol supplementation, and the association between XRCC1 codon 399 genotype and lung cancer was modified by the amount of smoking.
In an effort to develop a biomarker for lung cancer risk, we evaluated the transcript expressions of 14 antioxidant, DNA repair, and transcription factor genes in normal bronchial epithelial cells (HUGO names CAT, CEBPG, E2F1, ERCC4, ERCC5, GPX1, GPX3, GSTM3, GSTP1, GSTT1, GSTZ1, MGST1, SOD1, and XRCC1).
Multivariate logistic regression analysis found that an increased risk of lung cancer was associated with the variant XRCC1 -77 genotypes (TC and CC) compared with the TT genotype (OR=1.46, 95% CI=1.18-1.82; P=0.001) and the increased risk was more pronounced in smokers (OR=1.63, 95% CI=1.20-2.21) than in non-smokers (OR=1.28, 95% CI=0.94-1.76).
These findings further suggest that the polymorphisms XRCC1Arg194Trp and Pro206Pro or the haplotype encompassing the variant alleles may contribute to susceptibility of lung cancer in a Chinese population.
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.
This meta-analysis aimed to summarize published data on the association between the commonest SNPs of XRCC1 (rs1799782" genes_norm="7515">Arg194Trp, C > T, rs1799782 and Arg399Gln, G > A, rs25487) and clinical outcome of lung cancer patients.
Lung cancer risk associated with individual SNPs was seen for GSTP1 [A allele; odds ratio (OR) = 1.85; 95% confidence interval (CI), 1.04-3.27] and XRCC1 (A/A genotype; OR = 1.68; 95% CI, 1.01-2.79) in white women and CYP1B1 (G allele; OR = 11.1; 95% CI, 1.18-104) in black women smokers.
In the present study, we investigated the polymorphisms of the following selected members of the base and nucleotide excision repair genes: XPC (Lys939Gln), XPD (Lys751Gln), XRCC1(Arg399Gln), and hOGG1(Ser326Ser), and the risk they present toward the development of lung cancer, with emphasis on the effect of chromium exposure.
Meta-analysis of 18 studies with high quality also found that there was an obvious association between XRCC1Arg399Gln polymorphism and increased risk of lung cancer under three genetic models.
XRCC1 is an important scaffold protein involved in base excision repair that is regulated by ERK1/2 and AKT signals and plays an important role in the development of lung cancer.
On the other hand, among several XRCC1 gene polymorphisms, codon 399 polymorphism was reported to reduce the risk of bladder cancer and raise the risk of lung cancer.