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Ewing sarcoma

Nature Reviews Disease Primers volume 4, Article number: 5 (2018) Cite this article

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Abstract

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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Fig. 1: FET–ETS fusion oncogenes in Ewing sarcoma.
Fig. 2: Genetic predisposition to Ewing sarcoma.
Fig. 3: EWSR1–FLI1-mediated epigenetic remodelling of regulatory elements.
Fig. 4: Mechanisms of metastasis in Ewing sarcoma.
Fig. 5: Radiological presentation of Ewing sarcoma.
Fig. 6: Histomorphology of Ewing sarcoma.

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Acknowledgements

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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Authors and Affiliations

  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

Authors
  1. Thomas G. P. Grünewald
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Contributions

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.

Corresponding authors

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

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Related links

NCI Pediatric Preclinical Testing Consortium: http://www.ncipptc.org/

SARC Clinical trials: https://www.clinicaltrials.gov/

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Grünewald, T.G.P., Cidre-Aranaz, F., Surdez, D. et al. Ewing sarcoma. Nat Rev Dis Primers 4, 5 (2018). https://doi.org/10.1038/s41572-018-0003-x

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