Proximal and Classic Epithelioid Sarcomas are Distinct Molecular Entities Defined by MYC/GATA3 and SOX17/Endothelial Markers, Respectively.

Autor:	Sigalotti L; Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy., Frezza AM; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Sbaraglia M; Surgical Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padua School of Medicine, Padua, Italy., Del Savio E; Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy., Baldazzi D; Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy., Valenti B; Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy., Bellan E; Department of Pathology, Azienda Ospedale Università Padova, Padua, Italy., De Benedictis I; Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy., Doni M; Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy., Gambarotti M; Department of Pathology, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy., Vincenzi B; Department of Medical Oncology, Università Campus Biomedico di Roma, Rome, Italy., Brunello A; Department of Oncology, Medical Oncology 1 Unit, Istituto Oncologico Veneto IOV, IRCCS, Padua, Italy., Baldi GG; Department of Medical Oncology, Hospital of Prato, Azienda USL Toscana Centro, Prato, Italy., Palmerini E; Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy., Pasquali S; Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Ciuffetti ME; Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy., Varano V; Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy., Cappello F; Department of Pathology, Azienda Ospedale Università Padova, Padua, Italy., Appolloni V; Italian Sarcoma Group, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Pastrello C; Division of Orthopaedic Surgery, Schroeder Arthritis Institute, Toronto, Canada., Jurisica I; Division of Orthopaedic Surgery, Schroeder Arthritis Institute, Toronto, Canada; Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, Toronto, Canada; Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, Canada; Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia., Gronchi A; Department of Sarcoma Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Stacchiotti S; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Casali PG; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology and Haemato-Oncology, University of Milan, Milan, Italy., Dei Tos AP; Surgical Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padua School of Medicine, Padua, Italy., Maestro R; Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy. Electronic address: rmaestro@cro.it.
Jazyk:	angličtina
Zdroj:	Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc [Mod Pathol] 2024 Nov 02; Vol. 38 (1), pp. 100647. Date of Electronic Publication: 2024 Nov 02.
DOI:	10.1016/j.modpat.2024.100647
Abstrakt:	Epithelioid sarcoma (ES) is a rare tumor hallmarked by the loss of INI1/SMARCB1 expression. Apart from this alteration, little is known about the biology of ES. Despite recent advances in treatment, the prognosis of ES remains unsatisfactory. To elucidate the molecular underpinnings of ES, and to identify diagnostic biomarkers and potential therapeutic vulnerabilities, we performed an integrated omics profiling (RNA sequencing and methylation array) of 24 primary, untreated ESs. Transcriptome and methylome analysis identified 2 distinct molecular clusters that essentially corresponded to the morphologic variants of ES, classic ES (C-ES) and the more aggressive proximal ES (P-ES). The P-ES group was characterized by hyperactivation of GATA3 and MYC pathways, with extensive epigenetic rewiring associated with EZH2 overexpression. Both DNA methylation and gene expression analysis indicated a striking similarity with the "MYC subgroup" of atypical teratoid/rhabdoid tumor, another SMARCB1-deficient tumor, implying a shared molecular background and potential therapeutic vulnerabilities. Conversely, the C-ES group exhibited an endothelial-like molecular profile, with expression of vascular genes and elevated proangiogenic SOX17 signaling. Immunohistochemistry validated the overexpression of the chromatin regulators GATA3 (9/12 vs 0/16) and EZH2 (7/7 vs 2/6) in P-ESs, and of the vascular factors SOX17 (8/8 vs 1/10) and N-cadherin (5/9 vs 0/10) in C-ESs. Therefore, these molecules emerge as potential diagnostic tools to fill the gap represented by the lack of ES subtype-specific biomarkers. In summary, our study shows that P-ES and C-ES represent distinct molecular entities defined by MYC/GATA3 and SOX17/endothelial molecular traits, respectively. Besides providing insights into the biology of ES, our study pinpoints subtype-specific biomarkers and potential therapeutic vulnerabilities. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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