Polymorphisms of DNA repair genes and risk of non-small cell lung cancer.
ABSTRACT Lung cancer is a leading cause of cancer mortality with an inter-individual difference in susceptibility to the disease. The inheritance of low-efficiency genotypes involved in DNA repair and replication may contribute to the difference in susceptibility. We investigated 44 single nucleotide polymorphisms (SNPs) in 20 DNA repair genes including nucleotide excision repair (NER) genes XPA, ERCC1, ERCC2/XPD, ERCC4/XPF and ERCC5/XPG; base excision repair (BER) genes APE1/APEX, OGG1, MPG, XRCC1, PCNA, POLB, POLiota, LIG3 and EXO1; double-strand break repair (DSB-R) genes XRCC2, XRCC3, XRCC9, NBS1 and ATR; and direct damage reversal (DR) gene MGMT/AGT. The study included 343 non-small cell lung cancer (NSCLC) cases and 413 controls from Norwegian general population. Our results indicate that SNPs in the NER genes ERCC1 (Asn118Asn, 15310G>C, 8902G>T), XPA (-4G>A), ERCC2/XPD (Lys751Gln) and ERCC5/XPD (His46His); the BER genes APE1/APEX (Ile64Val), OGG1 (Ser326Cys), PCNA (1876A>G) and XRCC1 (Arg194Trp, Arg280His, Arg399Gln); and the DSB-R genes ATR (Thr211Met), NBS1 (Glu185Gln), XRCC2 (Arg188His) and XRCC9 (Thr297Ile) modulate NSCLC risk. The level of polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adducts in normal lung tissue from 211 patients was analysed. The variant alleles of XRCC1(Arg280His), XRCC1 (Arg399Gln), ERCC1(G8092T), ERCC5(His46His) and MGMT/AGT(Lys178Arg) were more frequent in patients with PAH-DNA adduct levels lower than the mean whereas the XRCC1(Arg194Trp) variant was more frequent in cases with higher adduct levels than the mean.
Article: DNA repair endonuclease ERCC1-XPF as a novel therapeutic target to overcome chemoresistance in cancer therapy.[show abstract] [hide abstract]
ABSTRACT: The ERCC1-XPF complex is a structure-specific endonuclease essential for the repair of DNA damage by the nucleotide excision repair pathway. It is also involved in other key cellular processes, including DNA interstrand crosslink (ICL) repair and DNA double-strand break (DSB) repair. New evidence has recently emerged, increasing our understanding of its requirement in these additional roles. In this review, we focus on the protein-protein and protein-DNA interactions made by the ERCC1 and XPF proteins and discuss how these coordinate ERCC1-XPF in its various roles. In a number of different cancers, high expression of ERCC1 has been linked to a poor response to platinum-based chemotherapy. We discuss prospects for the development of DNA repair inhibitors that target the activity, stability or protein interactions of the ERCC1-XPF complex as a novel therapeutic strategy to overcome chemoresistance.Nucleic Acids Research 08/2012; · 8.03 Impact Factor
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ABSTRACT: Many studies have examined the association between the XRCC3 Thr241Met gene polymorphism and lung cancer risk in various populations, but their results have been inconsistent. To assess this relationship more precisely, a meta-analysis was performed. The PubMed, Embase, Web of Science, and CNKI database was searched for case--control studies published up to July 2012. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated.Ultimately, 17 studies, comprising 4123 lung cancer cases and 5597 controls were included. Overall, for T allele carriers (TC + TT) versus the wild-type homozygotes (CC), the pooled OR was 0.95 (95% CI = 0.87-1.04 P = 0.228 for heterogeneity), for TT versus CC the pooled OR was 0.99 (95% CI = 0.86-1.15 P = 0.315 for heterogeneity). In the stratified analysis by ethnicity, histological types of lung cancer and smoking status, no any significantly risks were found for (C/T + T/T) vs C/C or T/T vs C/C. No publication bias was found by using the funnel plot and Egger's test.Overall, there is no evidence showing a significant correlation between XRCC3 Thr241Met polymorphism and lung cancer risk stratified analysis by ethnicity, histology and smoking status.Journal of Experimental & Clinical Cancer Research 01/2013; 32(1):1. · 2.15 Impact Factor
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ABSTRACT: Many carcinogens in tobacco smoke cause DNA damage, and some of that damage can be mitigated by the actions of DNA repair enzymes. In a case-control study nested within the Beta-Carotene and Retinol Efficacy Trial, a randomized chemoprevention trial in current and former heavy smokers, we examined whether lung cancer risk was associated with variation in 26 base excision repair, mismatch repair, and homologous recombination repair genes. Analyses were limited to Caucasians (744 cases, 1477 controls), and logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for individual SNPs and common haplotypes, with adjustment for matching factors. Lung cancer associations were observed (p<0.05) with SNPs in MSH5 (rs3131379, rs707938), MSH2 (rs2303428), UNG (rs246079), and PCNA (rs25406). MSH5 rs3131379 is a documented lung cancer susceptibility locus in complete linkage disequilibrium with rs3117582 in BAT3, and we observed associations similar in magnitude to those in prior studies (per A allele OR 1.37, 95% CI 1.13-1.65). UNG was associated with lung cancer risk at the gene level (p=0.02), and the A allele of rs246079 was associated with an increased risk (per A allele OR 1.15, 95% CI1.01-1.31). We observed stronger associations with UNG rs246079 among individuals who carried the risk genotypes (AG/AA) for MSH5 rs3131379 (pinteraction= 0.038). Our results provide additional evidence to suggest that the MSH5/BAT3 locus is associated with increased lung cancer risk among smokers, and that associations with other SNPs may vary depending upon MSH5/BAT3 genotype. Future studies to examine this possibility are warranted.International Journal of Molecular Epidemiology and Genetics 01/2013; 4(1):11-34.