Identification of Deleterious nsSNPs in Cell Cycle Regulatory Gene E2F1 and their Role in Susceptibility to Common Cancers in Himachal Pradesh Population

Abstract

Deregulated expression most of the E2Fs members have been observed in many human cancers. In this study, we examined the association damaging single nucleotide polymorphisms (SNPs) of E2F1 gene with risk of lung, cervical, head and neck cancer in 395 patients and 230 cancer-free-controls. Before conducting case-control association study, we prioritized SNP on the basis of computational analysis. In the computational analysis, six amino-acid variants (Cys227Phe, Arg252His, Val295Asp, Cys298Tyr, Arg56Trp, and Tyr59Cys) of E2F1 protein were most deleterious mutations. The analysis was on the basis of the effects of mutation on protein structure, function, and amino-acid conservation. Molecular dynamics simulations performed to investigate the deep insight about structural changes. In the statistical analysis of genotypes, the mutant genotype TT of rs3213172 (Arg252His) was associated with the elevated risk for lung cancer (LC) with an (odd ratio (OR) = 4.8; 95% confidence interval (CI) = 2.479-9.560, P lt0.001) in the homozygous model. This nsSNP was significantly associated with HNC and cervical cancer risk in genetic association analysis. The rs3213173 (Val276Met) polymorphism was associated with lung and cervical cancer risk in genotypic as well as allelic model. Current study revealed significant association of rs3213176 (Gly 393Ser) polymorphism with LC and HNC risk. The rs2071054 (C/T) polymorphism was also associated with HNC cancer risk in allelic model. Haplotypes of nsSNPs were significantly associated LC, HNC and cervical cancer risk. These results suggest that the rs3213172 (C/T), rs3213173 (C/T), rs3213176 (G/A) and rs2071054 (C/T) polymorphisms of E2F1 gene could be used as an effective biomarker for genetic susceptibility to LC, HNC and cervical cancer. Larger studies on different ethnic groups will provide better insight about these polymorphisms. newline