Protective role of ERCC4 SNP rs1800067 Minor Allele in Gallbladder Carcinogenesis.

Abstract Purpose: Gallbladder cancer (GBC) is the most aggressive tumor of the biliary tract. Since DNA damage is one of the common events in GBC, we hypothesized that nucleotide excision repair enzymes may be defective in GBC. We aimed to investigate the association of SNP rs1800067 (G/A) of ERCC4 with the disease predisposition in gallbladder cancer and its prognosis. We have also investigated the expression of ERCC4 in GBC patients and gallstone patients for any possible correlation with the SNP.Methods: In 350 GBC patients and 300 controls, ERCC4 SNP rs1800067 was genotyped by PCR-RFLP. Semi-quantitative RT-PCR was performed using ERCC4 and internal control β-actin primers in gallstone and tumor biopsy. We adopted the Kaplan-Meier plot and log-rank tests to explore the association of rs1800067 and prognosis of gallbladder cancer patients. Results: We demonstrate that the minor allele A is less frequent in GBC patients than healthy controls, suggesting the association of GA genotype with decreased risk of GBC. rs1800067 genotypes have significantly differential frequencies relative to clinical parameters. The relative expression of ERCC4 is significantly differentially expressed among early and late stages of tumors. Patients with combined GA+AA genotypes had longer overall survival in patients with early stages of tumors and with chemotherapy.Conclusion: Our results suggest that minor allele A is significantly associated with reduced risk of gallbladder carcinogenesis. The upregulation of relative mRNA expression of ERCC4 is an early event in the progression of gallbladder cancer.