Computational Approach to Identify Mutations in Genes of Notch Signaling Pathway and Its Association with OSCC

Abstract

Derailments in signal transduction pathways are associated with the development of tumors. One such vital pathway is the Notch signaling pathway which is associated with various processes of carcinogenesis such as proliferation of cells, cell renewal, angiogenesis and oncogenic microenvironment preservation. Interestingly, Notch also plays a pivotal role in tumor development by acting as an oncogene as well as tumor suppressor gene. In view of this fact, the present study was designed to analyze mutations in Notch signalling pathway which might have a crucial role in the etiology of oral squamous cell carcinoma (OSCC) using computational approach. The Cancer Gene Atlas data set hosted in the cBioportal was used in the present study. These samples were queried for the presence of mutations in Notch signalling genes which included a predefined list of 55 genes. Further, the Oncoprint data obtained was compared to that of gnomAD database which identified novel and reported mutations in the genes analyzed. Additionally, I-Mutant and MutPred analysis was carried out to determine the stability and pathogenicity of the variations recorded. Among 55 genes analysed, SPEN gene was shown to possess the highest frequency of mutation (5%) followed by FBXW7, Notch1, EP300, NUMB, and RBPJL genes. Most of the mutations identified were novel as assessed using the control dataset from the gnomAD database. The stability of the protein was found to decrease upon nucleotide substitution. Finally, the MutPred score revealed that most of the mutant proteins were pathogenic.  Several novel mutations have been identified in the pathway analyzed. Functional analysis of these variants using experimental approaches would aid in dissecting their association with OSCC.