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.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
We conclude that KRAS rs61764370 polymorphism is significantly associated with risk and prognosis of gallbladder malignancy in this endemic belt.
Department of Surgical Gastroenterology, King George's Medical University, Lucknow, 226003, India.|Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, 221005, India.
Hasan Raza
HR
Kazmi
Department of Surgical Gastroenterology, King George's Medical University, Lucknow, 226003, India. abhijitchandra@hotmail.com.
Abhijit
A
Chandra
Department of Surgical Gastroenterology, King George's Medical University, Lucknow, 226003, India.
Saket
S
Kumar
Cell and Molecular Biology Department, Aurigene Discovery Technologies Limited, Bangalore, 560095, India.
Leena Khare
LK
Satyam
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226003, India.
Annapurna
A
Gupta
Department of Surgical Gastroenterology, King George's Medical University, Lucknow, 226003, India.
Jaya
J
Nigam
Department of Surgical Gastroenterology, King George's Medical University, Lucknow, 226003, India.
Meenu
M
Srivastava
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226003, India.
Balraj
B
Mittal
D020413:3' Untranslated Regions / Q000235:genetics*; D000328:Adult; D000368:Aged; D001665:Binding Sites / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007194:India / Q000453:epidemiology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D016019:Survival Analysis
D020413:3' Untranslated Regions; C117307:KRAS protein, human; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; D016283:Proto-Oncogene Proteins p21(ras)
Gallbladder cancer; KRAS; let-7; rs61764370