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Most fusions in RMS result in aberrant transcription factors, such as <jats:italic>PAX3<\/jats:italic>\/<jats:italic>7::FOXO1<\/jats:italic> in alveolar RMS (ARMS) and fusions involving <jats:italic>VGLL2<\/jats:italic> or <jats:italic>NCOA2<\/jats:italic> in infantile spindle cell RMS. However, recurrent fusions driving oncogenic kinase activation have not been reported in RMS. Triggered by an index case of an unclassified RMS (overlapping features between ARMS and sclerosing RMS) with a novel <jats:italic>FGFR1::ANK1<\/jats:italic> fusion, we reviewed our molecular files for cases harboring <jats:italic>FGFR1<\/jats:italic>\u2010related fusions. One additional case with an <jats:italic>FGFR1::TACC1<\/jats:italic> fusion was identified in a tumor resembling embryonal RMS (ERMS) with anaplasia, but with no pathogenic variants in <jats:italic>TP53<\/jats:italic> or <jats:italic>DICER1<\/jats:italic> on germline testing. Both cases occurred in males, aged 7 and 24, and in the pelvis. The 2nd case also harbored additional alterations, including somatic <jats:italic>TP53<\/jats:italic> and <jats:italic>TET2<\/jats:italic> mutations. Two additional RMS cases (one unclassified, one ERMS) with <jats:italic>FGFR1<\/jats:italic> overexpression but lacking <jats:italic>FGFR1<\/jats:italic> fusions were identified by RNA sequencing. These two cases and the <jats:italic>FGFR1::TACC1<\/jats:italic>\u2010positive case clustered together with the ERMS group by RNAseq. This is the first report of RMS harboring recurrent <jats:italic>FGFR1<\/jats:italic> fusions. However, it remains unclear if <jats:italic>FGFR1<\/jats:italic> fusions define a novel subset of RMS or alternatively, whether this alteration can sporadically drive the pathogenesis of known RMS subtypes, such as ERMS. Additional larger series with integrated genomic and epigenetic datasets are needed for better subclassification, as the resulting oncogenic kinase activation underscores the potential for targeted therapy.<\/jats:p>","DOI":"10.1002\/gcc.23232","type":"journal-article","created":{"date-parts":[[2024,4,12]],"date-time":"2024-04-12T13:30:14Z","timestamp":1712928614000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["<i>FGFR1<\/i> fusions as a novel molecular driver in rhabdomyosarcoma"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0615-8982","authenticated-orcid":false,"given":"Henry","family":"de Traux De Wardin","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Memorial Sloan Kettering Cancer Center  New York New York USA"},{"name":"Department of Pediatrics Brussels University Hospital, Academic Children's Hospital Queen Fabiola, Universit\u00e9 Libre de Bruxelles  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Cyrta","sequence":"additional","affiliation":[{"name":"Department of Pathology Institut Curie, PSL University  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josephine K.","family":"Dermawan","sequence":"additional","affiliation":[{"name":"Robert J. 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