A let-7 microRNA binding site polymorphism in the KRAS 3'UTR is associated with increased risk and reduced survival for gallbladder cancer in North Indian population.

Abstract

Gallbladder cancer is a lethal malignancy of hepato-biliary system with high incidence in North India, especially along gangetic plain. The let-7 microRNAs play a key role in regulating KRAS expression and a polymorphism in 3' untranslated region (rs61764370, T/G) of KRAS leads to its higher expression. This polymorphism is known to be associated with increased risk and prognosis of various cancers but its association with gallbladder cancer has not been evaluated. To address this research question, we evaluated whether rs61764370 variant is associated with gallbladder cancer susceptibility and clinical outcomes. In present case-control study, we enrolled 541 patients with gallbladder malignancy and 307 controls. Genomic DNA was obtained from peripheral blood and genotyping was performed using Taqman allelic discrimination assay. Heterozygous (TG) individuals are at a significant higher risk for GBC as compared with wild genotype (TT) (p=0.007, odds ratio=2.56, 95% CI 1.27-5.18). At allelic level, allele G has significant higher risk for GBC as compared with T allele (p=0.008, odds ratio=2.5, 95% CI 1.25-5.01). Survival analysis reveals decrease in overall survival for heterozygous genotype (p<0.0001, hazard ratio=3.42, 95% CI 1.21-4.20). Also, significant decrease in overall survival was observed for patient carrying allele G (p<0.0001, HR=2.89, 95% CI 1.21-4.20) as compared with allele C. We conclude that KRAS rs61764370 polymorphism is significantly associated with risk and prognosis of gallbladder malignancy in this endemic belt.