Ewing Sarcoma (ES)

Overview

Ewing sarcoma is an aggressive small-round-cell sarcoma of bone and soft tissue, typically driven by EWSR1::FLI1 (or related ETS-family) gene fusions. Most cases occur in children and young adults.

Cohorts in the corpus

  • sarcoma_ucla_2024 — UCLA pediatric/adult sarcoma patient-derived tumor organoid (PDTO) biobank includes Ewing sarcoma specimens for organoid drug screening. PMID:39305899

Recurrent alterations

  • ES is characterized by recurrent EWSR1-rearrangements (canonical EWSR1::FLI1 t(11;22)); secondary alterations involve TP53, CDKN2A, and STAG2.
  • CCLE pharmacogenomic profiling included Ewing sarcoma cell lines among 947 lines tested across 24 drugs, enabling genotype-response correlation analyses PMID:22460905
  • EWS::FLI1 expression in human embryonic mesenchymal stem cells (heMSCs) alone is sufficient to impose an ES-like transcriptome, directly upregulate BRCA1 while impairing ATM/ATR-mediated DNA damage response, and generate metastatic Ewing-like tumors in NOD/SCID mice (40% penetrance), supporting heMSCs as the cell of origin. PMID:25186949
  • WGS of 112 Ewing sarcoma tumors (extended to 299 patients) identified STAG2 (17%), CDKN2A deletion (12%), TP53 (7%), and epigenetic regulators EZH2/BCOR/ZMYM3 (2.7% each) as recurrently mutated; STAG2+TP53 co-mutation defined a high-risk subtype with markedly inferior survival PMID:25223734
  • One odontogenic tumor harboring an EWSR1-FLI1 fusion in the MSK-IMPACT cohort (Morris et al.) was reclassified from ‘ameloblastic carcinoma’ to Ewing sarcoma with epithelial differentiation, illustrating that EWSR1-FLI1 fusions can occur in unusual anatomic sites and require histologic re-evaluation PMID:27442865.
  • PIPseq cohort identified EWSR1-FLI1 fusion as diagnostic in two Ewing sarcoma patients; one patient additionally showed low PAX8/FHIT/CASP10/CHD2 expression and high CHD11/FUS/MTA1 expression as a poor-prognosis transcriptomic signature; APC V1822D VOUS also returned in one ES patient PMID:28007021
  • EWSR1::BEND2 in-frame fusion sarcoma of the bladder initially diagnosed as extraskeletal Ewing sarcoma based on CD99 positivity and EWSR1 FISH; RNA-seq identified BEND2 (not an ETS family gene) as partner — reclassifying to EWSR1-non-ETS undifferentiated sarcoma per WHO 2020 PMID:28199314
  • In the MSK-IMPACT pan-cancer cohort, EWSR1-FLI1 was detected in 25 Ewing sarcoma (ES) cases — the 4th most common rearrangement overall (after TMPRSS2-ERG n=151, EGFRvIII n=65, EML4-ALK n=38); ES was included among 62 principal tumor types in msk_impact_2017. PMID:28481359

Subtypes

  • Conventional Ewing sarcoma (EWSR1::FLI1 / EWSR1::ERG fusions) is the dominant subtype; CIC-rearranged and BCOR-rearranged round-cell sarcomas are histologic mimics with distinct molecular drivers and are tracked separately under the round-cell-sarcoma family.

Therapeutic landscape

Sources

  • PMID:39305899 — UCLA sarcoma PDTO biobank with pharmacotyping across sarcoma subtypes including ES.

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