Integrative Genomic Characterization of Oral Squamous Cell Carcinoma Identifies Frequent Somatic Drivers

TLDR

Survival rates for oral squamous cell carcinoma have remained stagnant, prompting the search for molecular targets. The study aimed to identify promising molecular targets in OSCC by conducting comprehensive genomic analysis. The authors performed integrated genomic profiling of gene expression, copy number, methylation, and point mutations in OSCC samples. Integrated analysis uncovered frequent somatic alterations, defining four major driver pathways (mitogenic signaling, Notch, cell cycle, TP53) and key genes FAT1 and CASP8, with Notch defects in 66 % of patients and a CASP8‑mutated subtype characterized by few copy‑number changes; overall, 80 % of patients had at least one targetable alteration, indicating potential for novel therapies.

Abstract

The survival of patients with oral squamous cell carcinoma (OSCC) has not changed significantly in several decades, leading clinicians and investigators to search for promising molecular targets. To this end, we conducted comprehensive genomic analysis of gene expression, copy number, methylation, and point mutations in OSCC. Integrated analysis revealed more somatic events than previously reported, identifying four major driver pathways (mitogenic signaling, Notch, cell cycle, and TP53) and two additional key genes (FAT1, CASP8). The Notch pathway was defective in 66% of patients, and in follow-up studies of mechanism, functional NOTCH1 signaling inhibited proliferation of OSCC cell lines. Frequent mutation of caspase-8 (CASP8) defines a new molecular subtype of OSCC with few copy number changes. Although genomic alterations are dominated by loss of tumor suppressor genes, 80% of patients harbored at least one genomic alteration in a targetable gene, suggesting that novel approaches to treatment may be possible for this debilitating subset of head and neck cancers.