MOLECULAR PORTRAIT OF ORAL SQUAMOUS CELL CARCINOMA: GENETIC DRIVERS, BIOMARKERS, AND THERAPEUTIC TARGETS

Abstract

Oral squamous cell carcinoma (OSCC) remains one of the most burdensome malignancies of the head and neck region, with roughly 390,000 new cases and nearly 190,000 deaths estimated annually worldwide. Its five-year survival has stagnated near 50% despite refinements in surgery and radiotherapy. Histological grading and TNM staging alone fail to capture the molecular heterogeneity that governs tumor behavior and treatment response. This review synthesizes current evidence on the genomic architecture of OSCC, integrating data on somatic driver alterations, human papillomavirus (HPV)-defined molecular subtypes, and emerging biomarkers that inform diagnosis, prognosis, and therapeutic selection. We summarize the roles of TP53, PIK3CA, EGFR, NOTCH1, CDKN2A, and FAT1 as the principal genomic drivers, discuss how HPV status bifurcates OSCC into biologically distinct entities with divergent mutational burdens and clinical trajectories, and examine the evidence for tissue based next-generation sequencing panels, tumor mutational burden, microsatellite status, and circulating tumor DNA as complementary diagnostic and monitoring tools. We further review translation of this knowledge into practice through EGFR-directed therapy, PI3K/AKT/mTOR inhibition, and immune checkpoint blockade, highlighting advances alongside the persistent gap between genomic rationale and clinical benefit, and critically appraise biomarker reproducibility, the limited actionability of tumor-suppressor-dominated genomes, and barriers to implementing genomic and liquid-biopsy testing in routine care. Molecular profiling of OSCC has matured from a descriptive to an increasingly actionable discipline, but validated, minimally invasive panels for early detection and recurrence monitoring, together with rationally designed combination regimens, are needed before genomically guided care becomes standard for this disease.