Molecular Characterization of Oral Squamous Cell Carcinoma in Mexican Patients: A Genomic and Epidemiological Overview

Abstract

Background/Objectives: Oral squamous cell carcinoma (OSCC) is a major global malignancy caused by tobacco and alcohol consumption, human papillomavirus (HPV) infection, and genetic alterations. Emerging genomic insights have revealed recurrent mutations that influence tumorigenesis, prognosis, and the effectiveness of targeted therapies. Although prevalent, these mutations have not yet been described in the Mexican population. This study explored the molecular landscape of OSCC in Mexican patients, addressing the gaps in genomic research and postulating potential clinical implications. Methods: A prospective cohort study of 55 patients with OSCC was conducted (2018 to 2025). Whole-exome sequencing identified genomic alterations, tumor mutational burden, mutational signatures, disrupted signaling pathways, and the presence of HPV and Epstein–Barr Virus (EBV). Correlation of molecular alterations with prognostic and therapeutic indicators were performed. Results: TP53 (51%, p = <0.001), FAT1 (20%, p = 0.027), and KMT2C (18%, p = 0.003) were identified as potential predictors of response to immunotherapy. SBS 5 (p = 0.016) and ID-19 (p < 0.001) signatures, characteristic of the Mexican population, were correlated with prognosis and periodontal disease (p = 0.001). A genetically distinct OSCC subgroup (31%), primarily young women with advanced disease, lacked traditional risk factors and exhibited a high ID-19 prevalence (p = 0.011). CYTH4 mutations and NOTCH pathway activation were uniquely identified (p = 0.026). TP53, FAT1, KMT2C, SBS 5, and ID-19 were identified as potential biomarkers for risk stratification and therapy selection. The non-smoking, non-drinking subgroup exhibited NOTCH pathway activation, CYTH4 mutation, and ID-19 prevalence, suggesting alternative oncogenic mechanisms. Conclusions: These findings support molecular-driven OSCC classification and emphasize precision medicine for personalized treatment and prognosis improvement.