XRCC1 And ERCC1 Polymorphisms Are Related To Susceptibility And Survival Of CRC In Chinese Population

Objective: Colorectal cancer(CRC) is one of the common malignant tumors. Its incidence rate is increasing year by year. Studies showed that gene polymorphisms are related to tumorigenesis, chemotherapy drug sensitivity and toxicity reaction. Excision repair cross complementing 1(ERCC1) and X-ray repair cross-complementing gene 1(XRCC1) gene are the major mammalian DNA repair genes. Their proteins repair the damaged DNA caused by a variety of materials. They play an important role to maintain the individual’s genetic stability. Their gentic polymorphisms are associated with susceptibility, drug sensitivity and prognosis of cancer. The single nucleotide polymorphisms(SNPs) located at 3’untranslated region(3’UTR) and coding region of genes may affect the expression of genes and cancer susceptibility, drug sensitivity and prognosis. This study was to investigate the associations of ERCC1 and XRCC1 gene SNP of coding region and 3’UTR and colorectal cancer(CRC) susceptibility, oxaliplatin-based chemotherapy drug sensitivity and prognosis of CRC patients. Methods: Blood samples of 438 CRC patients and 438 healthy controls were collected before chemotherapy. Genotypes of ERCC1 rs3212986, rs762562, rs735482, rs2336219 and XRCC1 Gln399 Arg, Arg280 His, Arg194 Trp SNP were used by i MLDR method. ERCC1 and XRCC1 protein expression in CRC tissue were detected by immunohistochemistry(IHC) method. Hardy-Weinberg equilibrium analysis is used by the goodness of fit χ2 test. Genotypeand allele frequency distribution differences in Case-control group is tested by χ2 test or Fisher’s Exact Test. Unconditional logistic regression model was used to estimate the association of certain polymorphisms, CRC risk, and response to chemotherapy efficacy. The odds ratio(OR) with 95% confidence interval(CI) were adjusted according to age, sex, alcohol use, smoking status. Using Kaplan-Meier method, log-rank test and Cox regression models to assess gene polymorphism and CRC prognostic relevance. The linkage disequilibrium(LD) of the polymorphisms, haplotypes and their frequencies were estimated by using the SHEsis software(available at http://analysis.bio-x.cn/SHEsis Main.htm). The 2-tailed statistical tests were analyzed and P < 0.05 was considered significant. All data were analyzed with the SPSS v. 17.0(SPSS China, Beijing, China) statistical package. Results: ① XRCC1 Arg194 Trp and ERCC1rs2336219 are associated with CRC risk. Individuals carried Arg194 Trp Trp/Trp genotype and Trp allele had a significant increase of CRC risk(OR = 1.432,95% CI, 1.195~2.236, P = 0.021; OR = 1.314,95% CI, 1.125~1.646 P = 0.025). Compared with ERCC1rs2336219 GG genotype and G allele, AA genotype and A allele of ERCC1rs2336219 also exhibited a statistical increase of CRC risk(OR = 1.459,95% CI, 1.143~2.428, P = 0.008; OR = 1.312,95% CI, 1.063~1.627, P = 0.007).②Tumor location, depth of invasion, size, histological type, degree of differentiation and TNM stage were not associated with genetic polymorphisms(P> 0.05). the patients with Trp allele of Arg194 Trp showed significant increase of lymph node metastasis(P <0.05). ③XRCC1Arg194Trp and ERCC1 rs735482 polymorphism were associated with drug sensitivity. Arg194 Trp Trp allele and ERCC1 rs735482 C allele were related to oxaliplatin-based chemotherapy drug resistance. ④The XRCC1 Gln399 Arg, Arg280 His and Arg194 Trp were in strong LD. 194Arg/280Arg/399 Arg is the most commonhaplotype. The haplotype of 194Trp/280Arg/399 Arg was associated with a significant resistance compared with 194Arg/280Arg/399 Arg. ⑤XRCC1Arg194Trp and ERCC1 rs735482 were significantly associated with overall survival(OS) and event-free survival(EFS). carriers of Trp allele of XRCC1Arg194 Trp and C allele of ERCC1 rs735482 were associated with a higher relapse or metastasis risk. The patients with Trp allele of XRCC1Arg194 Trp and C allele of ERCC1 rs735482 had a higher risk of a shorter survival(HR=1.413, 95% CI 1.219~1.873, p= 0.004; HR=1.338, 95% CI 1.371~1.762, p=0.006). ⑥ IHC results showed that the expression of ERCC1 was associated with the rs735482 polymorphism. Medium to high levels of ERCC1 were detected in 62.2%(23/37) samples with rs735482 CC genotype, but only 24.4%(21/86) of tumor samples with rs735482 AA genotype. Conclusion: ①XRCC1 Arg194 Trp Trp/Trp genotype and ERCC1rs2336219 AA genotype significantly increased the risk of CRC. ②XRCC1Arg194Trp and ERCC1 rs735482 polymorphism were associated with oxaliplatin-based chemotherapy sensitivity, and prognosis of CRC patients. ③ERCC1 protein expression were significantly different in various ERCC1 rs735482 genotypes. ERCC1 polymorphism may affect protein levels to adjust drug sensitivity and prognosis of CRC patients.