Whole exome sequencing based coding variation in nasopharyngeal cancer from tribal population of North-East India

Abstract

Genome-wide association studies (GWAS) have emerged due to the advent of high-throughput genotyping tools in the study of genetic architecture. Next-generation sequencing techniques, particularly whole exome sequencing (WES) in single nucleotide polymorphism (SNP) analysis, have been used to identify unusual coding variations. Across various demographic groups worldwide, coding differences have varied impacts on the evolution of NPC. However, certain loci related to NPC susceptibility are shared by multiple population types, with the North Eastern (NE) region exhibiting ethnicity-specific cancer variations. In this study, we focused on the major North Eastern tribal populations (Mizoram, Manipur, and Nagaland) to identify NPC-focused germline coding variations through WES. To better understand the genetic association of coding variants with NPC, WES was performed on 15 samples from affected patients and healthy individuals from three different ethnic groups (N = 9 cases and N = 6 controls). Variants were called using the Ion Proton™ platform, and case-control variants were screened for their association studies. All variants were filtered using Haploview, and PLINK software was used to assess the statistical significance of the passed case-control variants. Furthermore, the filtered variants, along with significant variants, were analyzed using different bioinformatics tools and compared with other clinical databases. A total of 60,387 (61.50 %) variations were discovered, of which 578 (p-value ≤0.05) were determined to be significant coding variants. These variants were then processed and filtered using several in silico techniques. The coding regions (exonic) of 10 genes, including CR1, GBP3, QPCT, ADGRV1, ADGB, ALG9, DLAT, CCT6B, GP6, and LRRN4, revealed ten SNPs, all of which are thought to be strongly linked with the NPCs of the three main NER tribes. It is anticipated that protein stability varies as a result of mutation, based on different in silico software such as I-mutant 3.0, MUpro, MutPred, Consurf, Netsurf 3.0, ProtParam tool, and HOPE, where the protein's structural and functional analyses are verified. Nearly all of the 10 nsSNPs exhibit intolerant alterations, indicating their functional significance in crucial areas and potential impact on the stability and function of the corresponding protein. In comparison to the current accepted genetic testing methodology, our work reveals greater sensitivity and specificity for the identification of harmful germline mutations.