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in translocated sarcomas are recognized as major oncogenic drivers of the disease, as well as diagnostic markers whose identification is necessary for differential diagnosis. EWSR1 is a \u2018promiscuous\u2019 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\u2032 partners, NR4A2 and RORB, which have not been previously reported. NR4A2 may functionally replace NR4A3, the usual 3\u2032 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.<\/jats:p>","DOI":"10.3390\/ijms25031735","type":"journal-article","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T08:44:08Z","timestamp":1706777048000},"page":"1735","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Identification of Novel\/Rare EWSR1 Fusion Partners in Undifferentiated Mesenchymal Neoplasms"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6010-8302","authenticated-orcid":false,"given":"Carmen","family":"Salguero-Aranda","sequence":"first","affiliation":[{"name":"Instituto de Biomedicina de Sevilla, Department of Pathology, Hospital Universitario Virgen del Roc\u00edo, CSIC-Universidad de Sevilla, 41013 Seville, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer, Instituto de Salud Carlos III (CB16\/12\/00361; CIBERONC-ISCIII), 28029 Madrid, Spain"},{"name":"Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41004 Seville, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Di Blasi","sequence":"additional","affiliation":[{"name":"Istituto Nazionale dei Tumori, Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6435-0822","authenticated-orcid":false,"given":"Lourdes","family":"Gal\u00e1n","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina de Sevilla, Department of Pathology, Hospital Universitario Virgen del Roc\u00edo, CSIC-Universidad de Sevilla, 41013 Seville, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1655-7458","authenticated-orcid":false,"given":"Laura","family":"Zaldumbide","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital Universitario Cruces, 48903 Barakaldo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gema","family":"Civantos","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina de Sevilla, Department of Pathology, Hospital Universitario Virgen del Roc\u00edo, CSIC-Universidad de Sevilla, 41013 Seville, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Marcilla","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina de Sevilla, Department of Pathology, Hospital Universitario Virgen del Roc\u00edo, CSIC-Universidad de Sevilla, 41013 Seville, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8400-046X","authenticated-orcid":false,"given":"Enrique","family":"de \u00c1lava","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina de Sevilla, Department of Pathology, Hospital Universitario Virgen del Roc\u00edo, CSIC-Universidad de Sevilla, 41013 Seville, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer, Instituto de Salud Carlos III (CB16\/12\/00361; CIBERONC-ISCIII), 28029 Madrid, Spain"},{"name":"Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41004 Seville, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3985-6434","authenticated-orcid":false,"given":"Juan","family":"D\u00edaz-Mart\u00edn","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina de Sevilla, Department of Pathology, Hospital Universitario Virgen del Roc\u00edo, CSIC-Universidad de Sevilla, 41013 Seville, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer, Instituto de Salud Carlos III (CB16\/12\/00361; CIBERONC-ISCIII), 28029 Madrid, Spain"},{"name":"Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41004 Seville, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,1]]},"reference":[{"key":"ref_1","unstructured":"Fletcher, C.D.M., Bridge, J., Hogendoorn, P.C.W., and Mertens, F. 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