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Novel secondary somatic mutations in Ewing's sarcoma and desmoplastic small round cell tumors

Yunyun Jiang1, Vivek Subbiah2, Filip Janku1

  • 1Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

Plos One
|August 15, 2014
PubMed
Abstract

Insights

This study identified actionable mutations in advanced Ewing's sarcoma (ES) and desmoplastic small round cell tumors (DSRCT). These findings pave the way for targeted therapies in these rare cancers.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Ewing's sarcoma (ES) and desmoplastic small round cell tumors (DSRCT) are rare pediatric cancers.
  • These tumors are characterized by EWS translocations and have a paucity of known somatic mutations.
  • Previous research has identified very few mutations in ES and none in DSRCT, highlighting a gap in understanding their molecular drivers.

Purpose of the Study:

  • To investigate potential actionable somatic mutations in patients with advanced ES and DSRCT.
  • To identify novel molecular targets for therapeutic intervention in these rare tumor types.
  • To explore the genetic landscape of ES and DSRCT to inform personalized treatment strategies.

Main Methods:

  • Tumor tissue from 28 patients with ES or DSRCT was analyzed.
  • A combination of Next-generation exome sequencing, Multiplex PCR/Mass Spectroscopy, PCR-based single-gene mutation screening, Sanger sequencing, and Morphoproteomics was employed.
  • This technology-agnostic approach allowed for comprehensive mutation detection.

Main Results:

  • Six out of 28 patients (21.4%) with advanced ES or DSRCT harbored novel somatic mutations.
  • Identified mutations included KRAS, PTPRD, GRB10, MET, and PIK3CA.
  • Two patients with GRB10 mutations and one with PTPRD and GRB10 mutations achieved complete remission with an Insulin-like Growth Factor 1 Receptor (IGF1R) inhibitor.
  • A patient developing resistance to IGF1R inhibitor treatment showed a KRAS mutation, suggesting RAF/RAS/MEK pathway activation.

Conclusions:

  • This study reports several actionable mutations in advanced ES and DSRCT with direct implications for targeted therapy.
  • The findings provide an initial mutational roadmap for developing individualized combination therapies.
  • The identification of mutations like KRAS in resistant tumors highlights the potential for acquired resistance mechanisms and the need for adaptive treatment strategies.

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