Abstract 2677: Multi-omics profiling identifies two epithelioid sarcoma molecular subtypes with distinct signaling and immune characteristics

Abstract Background: Epithelioid sarcoma (EpS) is an aggressive sarcoma, characterized by the loss of SMARCB1 expression. EpS is traditionally classified as distal or proximal according to clinicopathological features, but its molecular bases remain largely unknown. Methods: To establish an EpS molecular classification, we combined multiple bulk omics profiling approaches to systematically characterize the genomic, transcriptional and methylome landscapes of EpS. We further investigated inter- and intra-patient heterogeneity and explored molecular subtype-specific transcriptomic signatures, using single-cell RNA sequencing on fresh samples. Results: We identified two molecular subtypes of EpS: “distal-like” and “proximal-like”. Distal-like tumors include all morphological distal subtypes and a subset of proximal and hybrid EpS. They express a specific single-cell derived epithelial-to-mesenchymal transition signature, which associates with improved patient survival and includes Desmoglein 2 (DSG2), which we identify as a potential routine immunohistochemichal biomarker to improve diagnosis. Distal-like EpS also display higher peri-tumoral CD8+ T cell infiltrates with specific tumor-immune cell interactions. Conversely, proximal-like EpS harbor a higher inter-tumoral molecular heterogeneity, with some cases resembling other SMARCB1-deficient tumors by DNA methylation profiling, and high intra-tumoral pro-tumoral macrophage infiltrates. Conclusion: Our study introduces a novel molecular classification of EpS with prognostic value, potential diagnostic markers and distinct tumor immune microenvironments, that extends beyond traditional clinicopathological classification. These insights pave the way for more personalized and effective treatment strategies for patients with EpS. Citation Format: Carine Ngo, Leo Colmet-Daage, Julien Vibert, Clémence Henon, Riwan Brillet, Jia Xiang Jin, Daniel Pissaloux, Clémence Astier, Jean-Yves Blay, Axel Le Cesne, Charles Honore, Matthieu Faron, Thomas Grünewald, Franck Bourdeaut, Franck Tirode, Sophie Postel-Vinay. Multi-omics profiling identifies two epithelioid sarcoma molecular subtypes with distinct signaling and immune characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2677.