Novel secondary somatic mutations in Ewing's sarcoma and desmoplastic small round cell tumors. PLoS One 2014;9(8):e93676
Date
08/15/2014Pubmed ID
25119929Pubmed Central ID
PMC4131855DOI
10.1371/journal.pone.0093676Scopus ID
2-s2.0-84905915756 (requires institutional sign-in at Scopus site) 34 CitationsAbstract
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.
Author List
Jiang Y, Subbiah V, Janku F, Ludwig JA, Naing A, Benjamin RS, Brown RE, Anderson P, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Bone Neoplasms
Child
Desmoplastic Small Round Cell Tumor
GRB10 Adaptor Protein
Humans
Middle Aged
Mutation
Proto-Oncogene Proteins
Proto-Oncogene Proteins p21(ras)
Receptor, IGF Type 1
Sarcoma, Ewing
Young Adult
ras Proteins