{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T07:40:57Z","timestamp":1773042057318,"version":"3.50.1"},"reference-count":41,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50 CA217694"],"award-info":[{"award-number":["P50 CA217694"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 CA008748"],"award-info":[{"award-number":["P30 CA008748"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017050","name":"Cycle for Survival","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genes Chromosomes &amp;amp; Cancer"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Extraskeletal myxoid chondrosarcoma (EMC) is a rare mesenchymal neoplasm of uncertain histogenesis, characterized by recurrent gene fusions involving <jats:italic>NR4A3<\/jats:italic> with various gene partners (<jats:italic>EWSR1<\/jats:italic>, <jats:italic>TAF15, FUS<\/jats:italic>, etc.). Although the impact of fusion variants has been linked to histology and prognosis, no study to date has comprehensively investigated the incidence and spectrum of secondary genetic alterations (SGAs) in EMC with regard to their association with fusion type and clinical impact. Our molecular database was searched for EMC tested on a hybridization capture\u2010based targeted matched tumor\u2010normal DNA NGS assay (MSK\u2010IMPACT, 341\u2010505 gene panel). All tumors had their fusion subtype confirmed either by Archer FusionPlex and\/or fluorescence in\u00a0situ hybridization (FISH). Clinicopathologic data was reviewed. Eighteen EMC patients (20 samples) were selected, with a mean age of 61\u2009years and a male: female ratio of 5:1. By molecular testing, the most common <jats:italic>NR4A3<\/jats:italic> fusion subtype involved <jats:italic>EWSR1<\/jats:italic> (14\/18, 78%), while two cases involved <jats:italic>TAF15<\/jats:italic> gene partner, and one each <jats:italic>TCF12<\/jats:italic> and <jats:italic>FUS<\/jats:italic> genes, respectively. All cases showed a low tumor mutation burden (TMB) (0\u20132, mean 0.83). Two\u2010thirds of cases had concurrent SGAs, while the remaining showed only the driver <jats:italic>NR4A3<\/jats:italic> fusion (0\u20138, mean 1.67 mut\/case). Among the detected SGAs, only <jats:italic>TP53<\/jats:italic> alterations were recurrent, seen in 2 cases with <jats:italic>EWSR1::NR4A3<\/jats:italic> and <jats:italic>TAF15::NR4A3<\/jats:italic> fusions, respectively. Other non\u2010recurrent alterations involved <jats:italic>CDKN1B<\/jats:italic>, <jats:italic>TERT<\/jats:italic>, and <jats:italic>MET<\/jats:italic> genes, among others. Non\u2010<jats:italic>EWSR1<\/jats:italic> fusion variant tumors showed a tendency for a higher number of SGAs compared to <jats:italic>EWSR1<\/jats:italic>\u2010rearranged tumors (mean 2.75 versus 1.36\u2009mut\/case). Patients with \u2265\u20091 SGA showed lower disease\u2010free survival (DFS) (<jats:italic>p<\/jats:italic>\u2009=\u20090.022) and poor overall survival (OS) (<jats:italic>p<\/jats:italic>\u2009=\u20090.014), while no statistically significant correlation was detected between OS and fusion subtypes. Most patients (83%) developed distant metastases, which did not correlate with the SGA status. This is the first study addressing the genomic landscape in EMC with regard to prognostication beyond fusion subtypes and histology. Similar to other translocation\u2010associated sarcomas, the number of co\u2010occurring SGAs in EMC is low; however, when present, they are associated with worse survival. Although a higher number of SGAs showed a trend to be associated with non\u2010<jats:italic>EWSR1<\/jats:italic> fusion variants, larger multi\u2010institutional studies are needed to further evaluate the correlation between fusion variants with SGAs and survival.<\/jats:p>","DOI":"10.1002\/gcc.70076","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T13:51:23Z","timestamp":1755611483000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Secondary Genetic Alterations in Extraskeletal Myxoid Chondrosarcoma"],"prefix":"10.1002","volume":"64","author":[{"given":"Yamato","family":"Suemitsu","sequence":"first","affiliation":[{"name":"Department of Pathology, Molecular and Cell\u2010Based Medicine Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8121-8322","authenticated-orcid":false,"given":"Hsin\u2010Yi","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Taipei Veterans General Hospital  Taipei Taiwan"},{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carla","family":"Saoud","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1139-2914","authenticated-orcid":false,"given":"Josephine K.","family":"Dermawan","sequence":"additional","affiliation":[{"name":"Robert J. Tomsich Pathology and Laboratory Medicine Institute Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meera","family":"Hameed","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Singer","sequence":"additional","affiliation":[{"name":"Department of Surgery Memorial Sloan Kettering Cancer Center  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William D.","family":"Tap","sequence":"additional","affiliation":[{"name":"Department of Medicine Memorial Sloan Kettering Cancer Center  New York New York USA"},{"name":"Department of Medicine Weill Cornell Medical College  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9717-8205","authenticated-orcid":false,"given":"Cristina R.","family":"Antonescu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,8,19]]},"reference":[{"key":"e_1_2_10_2_1","volume-title":"WHO Classifications of Tumours Soft Tissue Ande Bone 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