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

TL;DR

Loss of the Y chromosome in oral pre-cancerous conditions is linked to higher cancer risk and could help in early diagnosis and treatment.

Contribution

This study identifies LOY/EDY as a potential biomarker and therapeutic target in oral cancer progression.

Findings

LOY is common in men with oral potentially malignant disorders and is associated with higher cancer risk.

EDY-positive cells show increased oncogenic activity and altered signaling pathways.

Loss of KDM5D and epigenetic changes may drive malignant progression in these disorders.

Abstract

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.

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.

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.

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.

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