Exploring Genetic Mutations in EGFR Pathway via Whole Exome Sequencing Approach in Head and Neck Cancer

Abstract

Cancer is the second leading cause of lethality in developed countries but is now exceeding cardiovascular diseases and emerging as the leading cause of death in some regions of the world. Head and Neck cancer is the 7th most prevalent cancer all over the world and affects the upper aero-digestive tract including the larynx, pharynx, nasal cavity, oral cavity, and paranasal cavity. Among its most prevailing types, oral squamous cell carcinoma (OSCC) is the 8th most prevalent cancer worldwide and the 2nd most prevalent cancer in Pakistan. OSCC develops when several mutations arise in various genes (PIK3C2G, EIF4EBP1, RICTOR, BRAF, and MAPK3) that provide the Oral cells with a proliferative advantage. The aim of this research was the molecular characterization of OSCC tissue samples to determine the contribution of the EGFR pathway in OSCC development. To achieve our goal we employed the Whole Exome Sequencing (WES) of extracted DNA from a total of 6 OSCC tissue samples (3 tumors + 3 controls) followed by in silico analyses of targeted genes of EGFR pathway from WES-generated data by using several bioinformatics tools. Careful analysis showed non-synonymous SNV mutations in the catalytic domain and a region of PIK3C2G, HD domain of RICTOR, YXXXXL phi motif of EIF4EBP1, a region adjacent to RBD domain of BRAF, and the protein kinase domain of MAPK3 genes encoded proteins. In silico Analysis showed that mutations in all of these genes were recognized as highly deleterious and disease-causing. The overall conclusion is that mutations in these genes may contribute to the development of OSCC by deregulating the normal functioning of the EGFR signaling pathway. In the future, further transcriptome analysis and molecular docking can provide a profound perception that might accelerate the discovery of effective prognostic or diagnostic biomarkers and facilitate the development of new therapies against OSCC.