A Novel Polymorphism in Codon 25 of theKRASGene Associated with Gallbladder Carcinoma Patients of the Eastern Part of India

Abstract

Gallbladder cancer (GBC) is more prevalent than other cancers in North India. The asymptomatic nature of the disease is a problem in the diagnosis and treatment. Analysis of oncogenes or tumor suppressor genes could be of importance in this regard. KRAS is the most frequently mutated member and is said to be one of the most activated oncogenes. The present study was aimed to determine the role of intragenic variants in the KRAS gene, in the progression of GBC in the eastern part of India. Sixty gallbladder carcinoma subjects (13 men and 47 women) with histologically proven diagnosis and 90 individuals (14 men and 76 women) who have no diagnosed cancer were included in the present study. All single-nucleotide polymorphisms present in exons 1 and 2 were analyzed by polymerase chain reaction followed by sequencing. We could not find the most frequently reported mutations at codons 12, 13, and 61 of the KRAS gene that occur in human malignancies. However, in this study, we detected one novel polymorphism at codon 25 (CAG>CAT; Gln25His) in exon 1 of the KRAS gene in both germline and tissue DNA. Multivariable logistic regression analysis with adjustment for age and sex revealed that the Gln25His variant of the KRAS gene was significantly associated with GBC. In silico analysis has validated the KRAS p.Q25H polymorphism as a disease-causing variant. Further, screening of the DNA samples in a cohort of ancestral tribal populations from various parts of the country without information on the phenotype, however, revealed the presence of the previously reported codon 12 and 25 polymorphisms, thereby indicating that the novel variant is population specific in the region.

Overview of current targeted therapy in gallbladder cancer

“… 156 , 158 – 160 Gln25His polymorphism of KRAS gene was identified to connect with GBC pathogenesis. 161 Consistent with this result, KRAS rs61764370 polymorphism was intimately associated with risk and prognosis of cancers in 307 healthy controls and 541 GBCs in Indians. 162 With regard to BRAF mutation frequency in GBC, it is still inconsistent, as no BRAF mutations were reported in the United States and Chile patients, but 33% of patients with BRAF mutations were present in Europe.…”

Candidate gene studies in gallbladder cancer: A systematic review and meta-analysis

“…The angiogenesis pathway gene KRAS Gln25His polymorphism was significantly associated with GBC risk (OR= 2.81; P =0.003) in a multivariable study from Eastern India [57]. The polymorphisms in other genes such as angiogenesis pathway ( ACE ), signaling ( TLR ), miRNA, apoptosis ( CASP8 ) or methylation ( DNMT3B ) pathway were significantly associated with GBC (additive model) [58-62].…”