Rhabdomyosarcoma with EWSR1::NF2 gene fusion: A case report potentially expanding its genetic spectrum Journal Article
| Authors: | Saoud, C.; Gundem, G.; Domenico, D.; Arango-Ossa, J. E.; Reed, D.; Vaynrub, M.; Papaemmanouil, E.; Bale, T. A.; Linos, K. |
| Article Title: | Rhabdomyosarcoma with EWSR1::NF2 gene fusion: A case report potentially expanding its genetic spectrum |
| Abstract: | Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, presenting with heterogeneous clinical and molecular subtypes. While gene fusions are predominantly associated with alveolar RMS, spindle cell RMS, especially congenital and intraosseous variants, are also linked to specific gene fusions. Furthermore, recently, FGFR1 kinase-driven RMSs were published. Here, we describe a case of RMS harboring an EWSR1::NF2 gene fusion, a deletion-driven genetic alteration that has not been previously documented in RMS or other soft tissue tumors. The patient was a 29-year-old female who presented with a lobulated ankle mass. Histologic examination revealed a malignant round cell tumor extensively infiltrating large nerve bundles. Immunohistochemical analysis demonstrated rhabdomyoblastic differentiation, consistent with rhabdomyosarcoma. While some areas showed features resembling the sclerosing and others the embryonal subtypes, the overall findings were considered unclassifiable. Targeted RNA sequencing revealed EWSR1(exon 9):: NF2(exon 7) gene fusion, which was confirmed on whole genome and targeted DNA sequencing. The latter did not yield specific diagnostic insights but revealed mutations in TSC2 (p.T1330M), ZFHX3 (p.A301T), and a NOTCH3 rearrangement, all of unknown oncogenic significance. MYC gene amplification was detected, but there was no evidence of chromosome 8 amplification or chromosome 11p15 loss of heterozygosity. Whole genome sequencing revealed a low tumor mutation burden (2.69/Mb) and showed no other significant potentially oncogenic events. DNA methylation studies using dimensionality reduction and unsupervised clustering placed the case within the embryonal RMS subtype. Although the absence of other oncogenic driver alterations suggests that the fusion may have played a pivotal role in pathogenesis, we cannot exclude the possibility that it represents a passenger alteration rather than a true driver mutation. If the former is true, further studies will be required to determine whether this fusion represents a novel RMS subtype or a rare driver in existing subtypes of RMS. © 2025 Wiley Periodicals LLC. |
| Keywords: | immunohistochemistry; adult; clinical article; human tissue; gene mutation; genetics; clinical feature; histopathology; pathogenesis; case report; nuclear magnetic resonance imaging; gene amplification; pathology; dna methylation; oncogene; fluorescence in situ hybridization; gene rearrangement; gene fusion; oncogene proteins, fusion; heterozygosity loss; rhabdomyosarcoma; chromosome 8; rna binding protein ews; ewsr1 protein, human; merlin; oncogene myc; nf2 gene; neurofibromin 2; fusion; rna-binding protein ews; nf2; ewsr1 gene; tsc2 gene; ewsr1; dna sequencing; humans; human; female; article; whole genome sequencing; rna sequencing; zfhx3 gene; tumor mutational burden; notch3 gene; oncogene fusion protein; nf2 protein, human; ankle disease; lobulated ankle mass |
| Journal Title: | Genes Chromosomes and Cancer |
| Volume: | 64 |
| Issue: | 1 |
| ISSN: | 1045-2257 |
| Publisher: | Wiley Periodicals, Inc |
| Date Published: | 2025-01-01 |
| Start Page: | e70025 |
| Language: | English |
| DOI: | 10.1002/gcc.70025 |
| PUBMED: | 39873201 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Konstantinos Linos -- Source: Scopus |
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MSK Authors
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55Linos -
212Papaemmanuil -
57Gundem -
122Bale -
50Arango Ossa -
36Vaynrub -
17Domenico -
22Saoud -
11Reed
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