Whole-exome sequencing analysis of NSCLC reveals the pathogenic missense variants from cancer-associated genes

Udhaya Kumar S; Ambritha Balasundaram; Hephzibah Cathryn R; Rinku Polachirakkal Varghese; Siva R; Gnanasambandan R; Salma Younes; Hatem Zayed; George Priya Doss C

doi:10.1016/j.compbiomed.2022.105701

Whole-exome sequencing analysis of NSCLC reveals the pathogenic missense variants from cancer-associated genes

Comput Biol Med. 2022 Sep:148:105701. doi: 10.1016/j.compbiomed.2022.105701. Epub 2022 Jun 7.

Authors

Udhaya Kumar S¹, Ambritha Balasundaram¹, Hephzibah Cathryn R¹, Rinku Polachirakkal Varghese¹, Siva R¹, Gnanasambandan R¹, Salma Younes², Hatem Zayed², George Priya Doss C³

Affiliations

¹ Laboratory of Integrative Genomics, Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
² Department of Biomedical Sciences, College of Health and Sciences, Qatar University, QU Health, Doha, 2713, Qatar.
³ Laboratory of Integrative Genomics, Department of Integrative Biology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India. Electronic address: georgepriyadoss@vit.ac.in.

PMID: 35753820
DOI: 10.1016/j.compbiomed.2022.105701

Abstract

Background: Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer. NSCLC accounts for 84% of all lung cancer cases. In recent years, advances in pathway understanding, methods for discovering novel genetic biomarkers, and new drugs designed to inhibit the signaling cascades have enabled clinicians to personalize therapy for NSCLC.

Objectives: The primary aim of this study is to identify the genes associated with NSCLC that harbor pathogenic variants that could be causative for NSCLC. The second aim is to investigate their roles in different pathways that lead to NSCLC.

Methods: We examined exome-sequencing datasets from 54 NSCLC patients to characterize the variants associated with NSCLC.

Results: Our findings revealed that 17 variants in 14 genes were considered highly pathogenic, including CDKN2A, ERBB2, FOXP1, IDH1, JAK3, KMT2D, K-Ras, MSH3, MSH6, POLE, RNF43, TCF7L2, TP53, and TSC1. Gene set enrichment analysis revealed the involvement of transmembrane receptor protein tyrosine kinase activity, protein binding, ATP binding, phosphatidylinositol-4,5-bisphosphate 3-kinase, and Ras guanyl-nucleotide exchange factor activity. Pathway analysis of these genes yielded different cancer-related pathways, including colorectal, prostate, endometrial, pancreatic, PI3K-Akt signaling pathways, and signaling pathways regulating pluripotency of stem cells. Module 1 from protein-protein interactions (PPIs) identified genes that harbor pathogenic SNPs. Three of the most deleterious SNPs are ERBB2 (rs1196929947), K-Ras (rs121913529), and POLE (rs751425952). Interestingly, one patient has a pathogenic K-Ras variant (rs121913529) co-occurred with the missense variant (rs752054698) inTSC1 gene.

Conclusion: This study maps highly pathogenic variants associated with NSCLC and investigates their contributions to the pathogenesis of NSCLC. This study sheds light on the potential applications of precision medicine in patients with NSCLC.

Keywords: Non-small cell lung cancer; Non-synonymous single nucleotide polymorphisms; PPI network; Pathogenic variants; Pathway enrichment analysis; Precision medicine; Whole-exome sequencing.

MeSH terms

Carcinoma, Non-Small-Cell Lung*
Exome Sequencing
Forkhead Transcription Factors
Humans
Lung Neoplasms*
Male
Phosphatidylinositol 3-Kinases
Polymorphism, Single Nucleotide
Repressor Proteins

Substances

FOXP1 protein, human
Forkhead Transcription Factors
Repressor Proteins