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

• Published in: PloS one 2014-08, Vol.9 (8), p.e93676-e93676
• Main Authors: Jiang, Yunyun, Subbiah, Vivek, Janku, Filip, Ludwig, Joseph A, Naing, Aung, Benjamin, Robert S, Brown, Robert E, Anderson, Pete, Kurzrock, Razelle
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Analysis; Biology and Life Sciences; Biopsy; Bone Neoplasms - genetics; Cancer therapies; Chemotherapy; Child; Clinical trials; Colorectal cancer; Cytotoxicity; Desmoplastic Small Round Cell Tumor - genetics; DNA sequencing; Ewing's sarcoma; Ewings sarcoma; EWS protein; Gene mutation; Gene sequencing; Genes; Genetic aspects; GRB10 Adaptor Protein - genetics; Hematology; Humans; Inhibitors; Insulin; Insulin-like growth factors; Kinases; Laboratories; Lung cancer; Mass spectroscopy; Medical prognosis; Medicine; Medicine and Health Sciences; Metastasis; Middle Aged; Mutation; Oncology; Pathology; Patients; Pediatrics; Phosphatase; Point mutation; Polymerase chain reaction; Pretreatment; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); Raf protein; ras Proteins - genetics; Receptor, IGF Type 1 - antagonists & inhibitors; Remission; Sarcoma; Sarcoma, Ewing - genetics; Spectroscopy; Therapy; Translocation; Tumors; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0093676

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. 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. 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. 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.