The clinical heterogeneity of round cell sarcomas with EWSR1/FUS gene fusions: Impact of gene fusion type on clinical features and outcome

Genes Chromosomes Cancer. 2020 Sep;59(9):525-534. doi: 10.1002/gcc.22857. Epub 2020 May 28.


The genetic hallmark of classic Ewing sarcoma is a recurrent fusion between EWSR1 and FUS gene with a member of the ETS transcription factor family. In contrast, tumors with non-ETS gene partners have been designated until recently "Ewing-like sarcoma," as a provisional molecular entity, as their clinical and pathologic features were still evolving. However, this group was reclassified as "round cell sarcoma with EWSR1-non-ETS fusions" in the latest 2020 WHO classification. Moreover, round cell sarcomas with either CIC or BCOR gene abnormalities, initially classified under Ewing family of tumors, are now regarded as stand-alone pathologic entities based on their distinct features. In this study we investigated the clinical characteristics of 226 confirmed Ewing sarcoma patients (EWSR1-FLI1 [n = 176], EWSR1/FUS-ERG [n = 35], EWSR1/FUS-FEV [n = 12], and EWSR1-ETV1/4 [n = 3]) and 14 round cell sarcoma patients with EWSR1-non-ETS fusion (EWSR1/FUS-NFATC2 [n = 10], EWSR1-PATZ1 [n = 3], and EWSR1-VEZF1 [n = 1]). The impact on overall survival (OS) was assessed in 90 patients with available follow-up, treated between 2011 and 2018. Patients with fusions involving FEV and NFATC2 genes showed an older median age at diagnosis, compared to those with EWSR1-FLI1 (P = .005), while extraskeletal location was more common in tumors with noncanonical EWSR1-FLI1 fusions (P = .001). Axial and pelvic primary sites were more common in patients with EWSR1-FLI1 (72%), while tumors with NFATC2 fusions were more frequent in the limb (78%, P = .006). The 3-year OS in patients with EWSR1-FLI1 was 91%, compared to only 60% in patients with alternative fusions (P = .037); the latter group showing a higher rate of metastases at presentation. However, this OS difference was not significant in patients with localized tumor (P = .585). Our study demonstrates significant correlations between fusion subtype and age at presentation, primary tumor sites, and OS, in both conventional Ewing sarcoma and round cell sarcoma with EWSR1-non ETS fusions patients. Larger studies are needed to determine survival differences in localized tumors.

Keywords: EWSR1; FUS; Ewing sarcoma; Ewing-like sarcoma; gene fusions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Biomarkers, Tumor / genetics*
  • Bone Neoplasms / genetics*
  • Bone Neoplasms / pathology
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Oncogene Fusion*
  • Oncogene Proteins, Fusion / genetics*
  • RNA-Binding Protein EWS / genetics*
  • RNA-Binding Protein FUS / genetics*
  • Sarcoma, Ewing / genetics*
  • Sarcoma, Ewing / pathology
  • Survival Analysis


  • Biomarkers, Tumor
  • EWSR1 protein, human
  • FUS protein, human
  • Oncogene Proteins, Fusion
  • RNA-Binding Protein EWS
  • RNA-Binding Protein FUS