Loss of the Y Chromosome in Oral Potentially Premalignant Disorders Predicts Malignant Progression: An Integrative Cross-Species Multi-Cohort Bioinformatic Study.

Abstract

BACKGROUND: The loss of the Y chromosome (LOY) and the extreme down-regulation of Y chromosome gene expression (EDY) are frequently observed in oral squamous cell carcinoma (OSCC). However, their roles in oral potentially malignant disorders (OPMDs) are unclear. METHODS: A comprehensive bioinformatic analysis was performed using publicly available datasets from chemically induced mouse OSCC models and human cohorts. The analysis included LOY/EDY detection, gene set variation analysis (GSVA), PROGENy pathway profiling, cell-to-cell communication inference, and epigenetic correlation studies. RESULTS: LOY was prevalent among men with OPMD, and EDY was identified in both mouse models and human OPMDs. The presence of LOY/EDY was associated with a higher risk of OPMD progression to OSCC. Single-cell analysis revealed that EDY-positive epithelial cells exhibited elevated oncogenic pathway activity and enhanced IL17-IL17RC signaling, possibly due to the loss of KDM5D in epithelial cells and altered epigenetic regulation. CONCLUSIONS: LOY/EDY can be detected in OPMD and promotes malignant progression by altering oncogenic signaling and epithelial cell interactions. LOY/EDY may serve as both a diagnostic biomarker and a therapeutic target, improving clinical management and patient outcomes.