Clinically Relevant Mutational Signatures and Prognostic Biomarkers in Taiwanese Oral Squamous Cell Carcinoma.

Abstract

Oral squamous cell carcinoma (OSCC), primarily caused by high exposure to betel quid, tobacco, and alcohol, remains a major public health burden in Taiwan. Although key mutations have been identified in OSCC, the population-specific mutational landscape and its clinical relevance remain underexplored. A total of 106 OSCC tumors from Taiwanese patients were subjected to targeted gene sequencing with the Oncomine Comprehensive Assay v3 platform. High-confidence exonic, nonsynonymous variants were identified from 161 cancer-related genes. The resulting mutational landscape was compared with publicly available data from The Cancer Genome Atlas. Gene- and pathway-level alterations were further correlated with clinicopathological parameters. A total of 317 exonic, nonsynonymous variants were identified in 73 OSCC-related genes, of which 52 were classified as driver genes. In addition to commonly mutated genes (e.g., TP53, CDKN2A, NOTCH1, HRAS, and PIK3CA), PIK3R1 and MSH6 exhibited high mutation frequencies. A higher number of mutated genes per tumor was significantly correlated with poorer local-relapse-free survival (hazard ratio: 1.17, 95% CI: 1.04-1.31, p = 0.010). In the 83 advanced-stage OSCC tumors, TP53 mutation was strongly associated with positive cervical lymph nodal metastasis (p < 0.001). An inverse relationship was noted between nodal metastasis and NOTCH1, HRAS, and PIK3CA mutations, possibly due to the mutually exclusive pattern observed between TP53 and NOTCH1/HRAS mutations. Alteration of the cell cycle oncogene pathway was significantly associated with poor survival in advanced-stage OSCC patients, which was subsequently confirmed as an independent prognostic factor for disease-specific survival (hazard ratio: 3.2, 95% CI: 1.05-9.75, p = 0.040) in 89 patients with advanced-stage OSCC from The Cancer Genome Atlas. This study uniquely illustrates the mutational landscape of OSCC in Taiwanese patients, highlighting clinically relevant genomic alterations that hold promise as prognostic biomarkers and candidates for targeted intervention.