title: Novel secondary somatic mutations in Ewing's sarcoma and desmoplastic small round cell tumors.
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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
authors.affiliation: 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.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: 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.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ludwig
authors.affiliation: 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.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.affiliation: Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Benjamin
authors.affiliation: From the Department of Pathology, UT Health-Department of Pathology and Laboratory medicine, Houston, Texas, United States of America.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Brown
authors.affiliation: 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.
authors.forename: Pete
authors.initials: P
authors.lastname: Anderson
authors.affiliation: 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.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000293:Adolescent; D000328:Adult; D001859:Bone Neoplasms / Q000235:genetics*; D002648:Child; D058405:Desmoplastic Small Round Cell Tumor / Q000235:genetics*; D051383:GRB10 Adaptor Protein / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D012512:Sarcoma, Ewing / Q000235:genetics*; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D051383:GRB10 Adaptor Protein; D017526:Receptor, IGF Type 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins