Identification of Novel/Rare EWSR1 Fusion Partners in Undifferentiated Mesenchymal Neoplasms - Abstract

Sep 21, 2026

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Recurrent gene fusions in translocated sarcomas act as major oncogenic drivers and essential diagnostic markers. EWSR1 can fuse with many partner genes, and accurate fusion-partner identification is required because standard FISH break-apart assays cannot reveal the partner. The study analyzes three rare EWSR1 fusion cases in undifferentiated mesenchymal neoplasms using targeted RNA-seq, then confirms findings by RT-PCR and Sanger sequencing.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

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Introduction

Oncogenic gene fusions and sarcoma classification

Role of EWSR1 in translocated sarcomas

Study approach and case findings

Article Identification of Novel/Rare EWSR1 Fusion Partners in Undifferentiated Mesenchymal Neoplasms Carmen Salguero-Aranda 1,2,3,†, Elena Di Blasi 4, Lourdes Galán 1, Laura Zaldumbide 5, Gema Civantos 1, David Marcilla 1, Enrique de Álava 1,2,3, * and Juan Díaz-Martín 1,2,3, *,† Citation: Salguero-Aranda, C.; Di Blasi, E.; Galán, L.; Zaldumbide, L.; Civantos, G.; Marcilla, D.; de Álava, E.; Díaz-Martín, J. Identification of Novel/Rare EWSR1 Fusion Partners in Undifferentiated Mesenchymal Neoplasms. Int. J. Mol. Sci. 2024, 25, 1735. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms25031735 Academic Editor: Akiyoshi Takami Received: 11 December 2023 Revised: 23 January 2024 Accepted: 29 January 2024 Published: 1 February 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Instituto de Biomedicina de Sevilla, Department of Pathology, Hospital Universitario Virgen del Rocío, CSIC-Universidad de Sevilla, 41013 Seville, Spain; [csalguero-ibis@us.es](csalguero-ibis@us.es) (C.S.-A.) 2 Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III (CB16/12/00361; CIBERONC-ISCIII), 28029 Madrid, Spain 3 Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41004 Seville, Spain 4 Istituto Nazionale dei Tumori, Università degli Studi di Milano, 20133 Milan, Italy 5 Department of Pathology, Hospital Universitario Cruces, 48903 Barakaldo, Spain * Correspondence: [enrique.alava.sspa@juntadeandalucia.es](enrique.alava.sspa@juntadeandalucia.es) (E.d.Á .); [jdiaz-ibis@us.es](jdiaz-ibis@us.es) (J.D.-M.)† These authors contributed equally to this work. Abstract: Recurrent gene fusions (GFs) in translocated sarcomas are recognized as major oncogenicdrivers of the disease, as well as diagnostic markers whose identification is necessary for differential diagnosis. EWSR1 is a ‘promiscuous’ gene that can fuse with many different partner genes, defining different entities among a broad range of mesenchymal neoplasms. Molecular testing of EWSR1 translocation traditionally relies on FISH assays with break-apart probes, which are unable to identify the fusion partner. Therefore, other ancillary molecular diagnostic modalities are being increasingly adopted for accurate classification of these neoplasms. Herein, we report three cases with rare GFs involving EWSR1 in undifferentiated mesenchymal neoplasms with uncertain differential diagnoses, using targeted RNA-seq and confirming with RT-PCR and Sanger sequencing. Two GFs involved hormone nuclear receptors as 3′ partners, NR4A2 andRORB, which have not been previously reported. NR4A2 may functionally replace NR4A3, the usual 3′ partner in extraskeletal myxoid chondrosarcoma. The third GF, EWSR1::BEND2, has previously been reported in a subtype of astroblastoma and other rare entities, including a single case of a soft-tissue tumor that we discuss in this work. In conclusion, our findings indicate that the catalogue of mesenchymal neoplasm-bearing EWSR1 fusions continues to grow, underscoring the value of using molecular ancillary techniques with higher diagnostic abilities in the routine clinical setting. Keywords: EWSR1; gene fusion; sarcoma; targeted RNA-seq 1. Introduction Sarcomas are a highly heterogeneous and complex group of rare cancers encompassing more than 100 different morphological entities that originate in the mesenchymal tissues, which include connective tissues, muscles, and bones. They represent about 1% of malignancies, with an annual incidence of approximately 50–60 new cases per million people/year, and account for 2% of mortality due

FAQs

Why is identifying the EWSR1 fusion partner important for diagnosis?

EWSR1 is a promiscuous gene that forms fusions with many partners, and different partners define distinct entities. Standard FISH break-apart probes detect translocation but do not identify the fusion partner, which is necessary for differential diagnosis.

How were the rare EWSR1 fusions in the three cases confirmed?

The fusions were detected using targeted RNA-seq, followed by confirmation with RT-PCR and Sanger sequencing.

What is the main conclusion about the EWSR1 fusion catalogue?

The study indicates that the catalogue of mesenchymal neoplasm-associated EWSR1 fusions continues to expand, supporting the routine use of molecular ancillary techniques with stronger diagnostic capability.

Sep 21, 2026

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