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PLoS One. 2014 Aug 13;9(8):e93676. doi: 10.1371/journal.pone.0093676. eCollection 2014.

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

Author information

1
Department 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.
2
Department 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; Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
3
Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
4
From the Department of Pathology, UT Health-Department of Pathology and Laboratory medicine, Houston, Texas, United States of America.
5
Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Pediatric Hematology/Oncology/BMT, Levine Children's Hospital/Levine Cancer Institute, Charlotte, North Carolina, United States of America.
6
Department 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; Center for Personalized Cancer Therapy and Division of Hematology & Oncology, University of California San Diego - Moores Cancer Center, La Jolla, California, United States of America.

Abstract

BACKGROUND:

Ewing's sarcoma (ES) and desmoplastic small round cell tumors (DSRCT) are small round blue cell tumors driven by an N-terminal containing EWS translocation. Very few somatic mutations have been reported in ES, and none have been identified in DSRCT. The aim of this study is to explore potential actionable mutations in ES and DSRCT.

METHODOLOGY:

Twenty eight patients with ES or DSRCT had tumor tissue available that could be analyzed by one of the following methods: 1) Next-generation exome sequencing platform; 2) Multiplex PCR/Mass Spectroscopy; 3) Polymerase chain reaction (PCR)-based single- gene mutation screening; 4) Sanger sequencing; 5) Morphoproteomics.

PRINCIPAL FINDINGS:

Novel somatic mutations were identified in four out of 18 patients with advanced ES and two of 10 patients with advanced DSRCT (six out of 28 (21.4%));KRAS (n = 1), PTPRD (n = 1), GRB10 (n = 2), MET (n = 2) and PIK3CA (n = 1). One patient with both PTPRD and GRB10 mutations and one with a GRB10 mutation achieved a complete remission (CR) on an Insulin like growth factor 1 receptor (IGF1R) inhibitor based treatment. One patient, who achieved a partial remission (PR) with IGF1R inhibitor treatment, but later developed resistance, demonstrated a KRAS mutation in the post-treatment resistant tumor, but not in the pre-treatment tumor suggesting that the RAF/RAS/MEK pathway was activated with progression.

CONCLUSIONS:

We have reported several different mutations in advanced ES and DSRCT that have direct implications for molecularly-directed targeted therapy. Our technology agnostic approach provides an initial mutational roadmap used in the path towards individualized combination therapy.

PMID:
25119929
PMCID:
PMC4131855
DOI:
10.1371/journal.pone.0093676
[Indexed for MEDLINE]
Free PMC Article

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