Ewing sarcoma is the second most frequent bone tumour of childhood and adolescence that can also arise in soft tissue. Ewing sarcoma is a highly aggressive cancer, with a survival of 70–80% for patients with standard-risk and localized disease and ~30% for those with metastatic disease. Treatment comprises local surgery, radiotherapy and polychemotherapy, which are associated with acute and chronic adverse effects that may compromise quality of life in survivors. Histologically, Ewing sarcomas are composed of small round cells expressing high levels of CD99. Genetically, they are characterized by balanced chromosomal translocations in which a member of the FET gene family is fused with an ETS transcription factor, with the most common fusion being EWSR1–FLI1 (85% of cases). Ewing sarcoma breakpoint region 1 protein (EWSR1)–Friend leukaemia integration 1 transcription factor (FLI1) is a tumour-specific chimeric transcription factor (EWSR1–FLI1) with neomorphic effects that massively rewires the transcriptome. Additionally, EWSR1–FLI1 reprogrammes the epigenome by inducing de novo enhancers at GGAA microsatellites and by altering the state of gene regulatory elements, creating a unique epigenetic signature. Additional mutations at diagnosis are rare and mainly involve STAG2, TP53 and CDKN2A deletions. Emerging studies on the molecular mechanisms of Ewing sarcoma hold promise for improvements in early detection, disease monitoring, lower treatment-related toxicity, overall survival and quality of life.

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T.G.P.G. is supported by grants from the Wilhelm Sander Foundation (2016.167.1), German Cancer Aid (DKH-111886 and DKH-70112257) and the Deutsche Forschungsgemeinschaft (DFG 391665916). F.C.-A. is supported by a grant from the Barbara and Hubertus Trettner Foundation. E.M.T. is supported by a fellowship from the Austrian Science Fund (FWF; Elise Richter Fellowship V506-B28). E.d.A. is supported by grants from the Spanish Ministry of Economy-FEDER (PI17/00464, CB16/12/00361), the Asociación Pablo Ugarte and the María García-Estrada Foundation. U.D. is supported by grants from the German Cancer Aid (DKH108128 and DKH 70112018); ERA-Net-TRANSCAN (01KT1310), EEC, EU-FP7 602856, Trettner Foundation and Stiftung für krebskranke Kinder in Essen. The authors express their apologies to all authors whose valuable work could not be cited owing to restrictions in the number of references.

Reviewer information

Nature Reviews Disease Primers thanks S. DuBois, A. Llombart-Bosch, K. Scotlandi and other anonymous referee(s) for their contribution to the peer review of this work.

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  1. Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany

    • Thomas G. P. Grünewald
    •  & Florencia Cidre-Aranaz
  2. Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany

    • Thomas G. P. Grünewald
    •  & Florencia Cidre-Aranaz
  3. German Cancer Consortium, partner site Munich, Munich, Germany

    • Thomas G. P. Grünewald
    •  & Florencia Cidre-Aranaz
  4. German Cancer Research Center, Heidelberg, Germany

    • Thomas G. P. Grünewald
    • , Florencia Cidre-Aranaz
    •  & Uta Dirksen
  5. INSERM U830, Équipe Labellisé LNCC, PSL Université, SIREDO Oncology Centre, Institut Curie, Paris, France

    • Didier Surdez
    •  & Olivier Delattre
  6. Children’s Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria

    • Eleni M. Tomazou
    •  & Heinrich Kovar
  7. Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville/CIBERONC, Seville, Spain

    • Enrique de Álava
  8. Department of Pediatrics, Medical University Vienna, Vienna, Austria

    • Heinrich Kovar
  9. British Columbia Cancer Research Centre and University of British Columbia, Vancouver, Canada

    • Poul H. Sorensen
  10. Cooperative Ewing Sarcoma Study group, Essen University Hospital, Essen, Germany

    • Uta Dirksen
  11. German Cancer Consortium, partner site Essen, Essen, Germany

    • Uta Dirksen


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Introduction (T.G.P.G. and F.C.-A.); Epidemiology (T.G.P.G., F.C.-A. and O.D.); Mechanisms/pathophysiology (T.G.P.G., F.C.-A., D.S., E.M.T., E.d.A., H.K., O.D. and P.H.S.); Diagnosis, screening and prevention (T.G.P.G., F.C.-A., E.d.A., P.H.S. and U.D.); Management (T.G.P.G., F.C.-A. and U.D.); Quality of life (T.G.P.G., F.C.-A. and U.D.); Outlook (T.G.P.G., F.C.-A., D.S., E.M.T. and U.D.); Overview of the Primer (T.G.P.G. and F.C.-A.). T.G.P.G. and F.C.-A. contributed equally to this work.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Thomas G. P. Grünewald or Florencia Cidre-Aranaz.

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