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Multiscale-omic assessment of EWSR1-NFATc2 fusion positive sarcomas identifies the mTOR pathway as a potential

Nathan D Seligson1,2,3, Richard D Maradiaga4, Colin M Stets4

  • 1Department of Pharmacotherapy and Translational Research, The University of Florida, Jacksonville, FL, USA.

NPJ Precision Oncology
|May 22, 2021
PubMed

Insights

EWSR1-NFATc2 fusion positive sarcomas are distinct from Ewing sarcoma, showing unique genomic profiles and mTOR pathway activation. These findings support targeted therapies for this rare sarcoma subtype.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Sarcomas with EWSR1-NFATc2 fusions were historically classified with Ewing sarcoma.
  • Recent findings suggest distinct molecular features and treatment responses in EWSR1-NFATc2 fusion positive sarcomas.

Purpose of the Study:

  • To investigate the genomic and molecular characteristics of EWSR1-NFATc2 fusion positive sarcomas.
  • To compare these tumors with traditional Ewing sarcoma.
  • To explore potential therapeutic targets.

Main Methods:

  • Analysis of comprehensive genomic profiles from 1024 EWSR1 fusion positive sarcomas, including 14 EWSR1-NFATc2 fusions, from the FoundationCore® database.
  • Integration of data from Gene Expression Omnibus, Genomics of Drug Sensitivity in Cancer, and The Cancer Genome Atlas.
  • Case study of a patient with metastatic EWSR1-NFATc2 fusion positive sarcoma treated with mTOR and VEGF inhibition.

Main Results:

  • EWSR1-NFATc2 fusion positive sarcomas exhibit distinct genomic profiles compared to Ewing sarcoma.
  • Upregulation of the mTOR pathway was observed in EWSR1-NFATc2 fusion positive sarcomas.
  • A patient with metastatic disease achieved 47 months of stabilization with combination mTOR and VEGF inhibition.

Conclusions:

  • EWSR1-NFATc2 fusion positive sarcomas represent a distinct molecular entity.
  • Overactive mTOR signaling suggests potential therapeutic targeting.
  • Findings support the application of precision medicine strategies for Ewing family tumors.

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