Functional ERCC1 And XPF Variants Are Associated With Susceptibility To Lung Cancer But Resistance To Platinum-Based Chemotherapy

Background & Aims The excision repair cross-complementation group 1 (ERCC1), combined with xeroderma pigmentsum group F (XPF), plays a pivotal role in DNA repair and has been linked to protection against carcinogenesis and resistance to platinum-based anticancer drugs. We tested whether functional genetic variants in the ERCC1 and XPF are associated with susceptibility to lung cancer and efficacy of platinum-chemotherapy in patients with small-cell lung cancer (SCLC).Methods Thirty individual DNA samples were sequenced to search for ERCC1 genetic variants, while the putative functional SNPs of XPF were selected from HapMap Project database. The functions of the variants were investigated by a series of biochemical assays. A case-control analysis was performed in 988 patients with lung cancer and 986 control subjects, and odds ratios and 95% confidence intervals were estimated by multivariate logistic regression. According to the genotypes, a comparison of chemotherapy outcome in 162 SCLC patients was executed. Overall survival was computed by Cox model adjusted for clinical factors.Results Five ERCC1 genetic variants, located in the promoter region (-433T>C), 5'UTR (262G>T), exon (3525C>T), the intron immediately 3' to the exon 3 (4855C>T), and 3'UTR (14443C>A), respectively, were identified. The 262G>T was proved altering the surrounding sequence's ability of binding nuclear proteins and then impacting the ERCC1 mRNA levels, while -433T>C was involved into the methylation regulation of CpG island. Multivariate logistic regression analysis showed that subjects with the -433CC or TC genotype had a 1.84-fold (95% CI = 1.37-2.45, P < 0.0001) increased risk for developing lung cancer compared with those with the -433TT genotype. A supermultiplicative joint effect between the -433T>C, 262G>T and smoking was observed. In contrast, the analysis of chemotherapy outcome of SCLC patients revealed that the 262GG genotype is associated with longer survival time compared with the 262GT or TT genotype [30 months (95% CI = 27-49) versus 19 months (95% CI = 15-22) or 17 months (95% CI = 14-24), P = 0.025 and 0.005, respectively]. Cox proportional model analyses showed that the adjusted hazard ratios of death for the 262GT and 262TT genotypes were 1.58 (95% CI = 0.96-2.62, P = 0.074) and 1.98 (95% CI = 1.13-3.47, P = 0.017), respectively, compared with that of the 262GG genotype, indicating that this variant may be an independent prognostic factor. Besides, three functional variants in an absolute linkage disequilibrium located in the XPF promoter, -673C>T, -357A>C and -30T>A, were proved affecting XPF expression. The case-control analysis showed that the -673TT genotype is associated with a decreased susceptibility to lung cancer (OR = 0.62, 95% CI = 0.42-0.91, P = 0.015), but not with the SCLC prognosis.Conclusions These findings are consistent with the notion that DNA repair is a double-edged sword in cancer and suggest that functional genetic variants in ERCC1 might serve as simple and less invasive biomarkers for susceptibility to lung cancer or personalized chemotherapy of platinum-based anticancer drugs.