Ewing sarcoma

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: FETETS 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.

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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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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.

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

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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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