Genomic landscape of oral squamous cell carcinoma highlights prognostic significance of NOTCH1 mutations and subsite-specific differences

We performed comprehensive genomic profiling (CGP) in 136 surgically resected cases of oral squamous cell carcinoma (OSCC). By leveraging biospecimens from the institutional biobank, we included early-stage tumors that are typically excluded from insurance-approved testing in Japan, thereby enabling characterization of the genomic landscape across all clinical stages. Through exploratory analysis, we identified NOTCH1 mutations as a robust, independent favorable prognostic marker for overall survival (OS) and relapse-free survival (RFS). Notably, the protective effect of NOTCH1 mutation was most pronounced in stage IV disease (p = 0.029), suggesting its utility as a clinically actionable biomarker for stratifying high-risk patients. Additionally, tongue cancers exhibited higher frequencies of EGFR amplification and HRAS mutation compared to non-tongue cancers, a pattern validated using the nationwide C-CAT database. This subsite-dependent genomic heterogeneity underscores the necessity of integrating anatomical context into molecular profiling to inform tailored therapeutic strategies. Taken together, our study delineates the OSCC genomic landscape with unprecedented resolution across clinical stages. It highlights NOTCH1 mutations as a favorable prognostic biomarker and emphasizes the clinical value of incorporating both genetic and anatomical stratification to optimize individualized care for OSCC patients.