A functional BRCA1 coding sequence genetic variant contributes to risk of esophageal squamous cell carcinoma

As a tumor suppressor, breast cancer susceptibility gene 1 (BRCA1) plays a pivotal role in maintaining genomic stability. A functional rs799917 T>C polymorphism located in the BRCA1 coding sequence could influence miR-638-mediated regulation of BRCA1 expression. Therefore, we examined the association between this polymorphism and esophageal squamous cell carcinoma (ESCC) risk as well as its biological function. Genotypes were determined in two independent case-control studies consisted of 1128 ESCC patients and 1150 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The allele-specific regulation on BRCA1 expression by the polymorphism was investigated in vitro and in vivo. We found that the BRCA1 rs799917 CC genotype was significantly associated with increased ESCC risk compared with the TT genotype in both studies (Jinan population: OR = 1.28, 95% CI = 1.04-1.58, P = 0.020; Huaian population: OR = 1.46, 95% CI = 1.17-1.83, P = 0.001). Stratified analyses with pooled data indicated that a multiplicative interaction between rs799917 and smoking or drinking in intensifying ESCC risk was evident (gene-smoking: P interactio n = 5.8 × 10(-5); gene-drinking: P interaction = 7.1 × 10(-7)). In vitro experiments indicate that miR-638 could negatively regulate BRCA1 expression and enhance proliferation of ESCC cells. In vivo BRCA1 messenger RNA expression analyses showed that the rs799917 C allele carriers had significantly decreased BRCA1 expression in both normal and cancerous esophagus tissues compared with T allele carriers, suggesting that lower BRCA1 expression may lead to higher risk for malignant transformation of esophagus cells. These results suggest that BRCA1 functional rs799917 polymorphism is involved in susceptibility to developing ESCC, alone and in a gene-environment interaction manner.