Core Epithelial‐to‐Mesenchymal Transition Gene Signature Predicts Metastasis and Poor Survival in Synovial Sarcoma

BACKGROUND: Synovial sarcoma (SS) is a rare soft tissue malignancy comprising 5%-10% of all sarcomas, typically affecting young adults. It is characterized by a pathognomonic SS18-SSX gene fusion, with variable histologic subtypes demonstrating epithelial and mesenchymal features. This study investigates the association between epithelial-to-mesenchymal transition (EMT) gene expression and metastatic potential in SS. METHODS: A retrospective, single-institution analysis was conducted using primary tumor specimens from 21 treatment-naïve SS patients. RNA sequencing was performed on formalin-fixed paraffin-embedded (FFPE) tissue to assess gene expression profiles. EMT scores were calculated using three independent methods: Hallmark EMT gene set from GSEA, the 76-gene EMT signature (76GS), and Kolmogorov-Smirnov (KS) testing. Patients were categorized into metastatic and nonmetastatic cohorts, and phenotype-specific survival analyses were conducted. RESULTS: Tumors from patients who developed metastases showed significant enrichment of EMT-related genes (GSEA NES 1.71, P = 0.025), oxidative phosphorylation, and immune-related pathways. EMT scores were consistently higher (more mesenchymal) in metastatic tumors across all scoring methods. Mesenchymal phenotype was associated with significantly worse overall survival (GSEA log-rank P = 0.0009). CONCLUSIONS: This study demonstrates a correlation between mesenchymal gene expression signatures and increased metastatic risk in SS. EMT status, derived from primary tumor profiling at diagnosis, may serve as a potential prognostic biomarker. These findings support further investigation into EMT as a stratification tool for tailoring treatment intensity and surveillance strategies in SS.