Germline PTPRD mutations in Ewing sarcoma: biologic and clinical implications. Oncotarget 2013 Jun;4(6):884-9
Date
06/27/2013Pubmed ID
23800680Pubmed Central ID
PMC3757245DOI
10.18632/oncotarget.1021Scopus ID
2-s2.0-84880823765 (requires institutional sign-in at Scopus site) 28 CitationsAbstract
Ewing sarcoma occurs in children, adolescents and young adults. High STAT3 levels have been reported in approximately 50% of patients with Ewing sarcoma, and may be important in tumorigenesis. Protein tyrosine phosphatase delta (PTPRD) is a tumor suppressor that inhibits STAT3 activation. To date, while somatic mutations in PTPRD have been reported in diverse tumors, germline mutations of PTPRD have not been investigated in Ewing sarcoma or other cancers. We identified a novel germline mutation in the PTPRD gene in three of eight patients (37.5%) with metastatic Ewing sarcoma. Although the functional impact in two of the patients is unclear, in one of them the aberration was annotated as a W775stop germline mutation, and would be expected to lead to gene truncation and, hence, loss of the STAT3 dephosphorylation function of PTPRD. Since STAT3 is phosphorylated after being recruited to the insulin growth factor receptor (IGF-1R), suppression of IGF-1R could attenuate the enhanced STAT3 activation expected in the presence of PTPRD mutations. Of interest, two of three patients with germline PTPRD mutations achieved durable complete responses following treatment with IGF-1R monoclonal antibody-based therapies. Our pilot data suggest that PTPRD germline mutations may play a role in the development of Ewing sarcoma, a disease of young people, and their presence may have implications for therapy.
Author List
Jiang Y, Janku F, Subbiah V, Angelo LS, Naing A, Anderson PM, Herzog CE, Fu S, Benjamin RS, 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
Antibodies, Monoclonal
Bone Neoplasms
Cell Line, Tumor
Clinical Trials as Topic
Female
Germ-Line Mutation
Humans
Male
Phosphorylation
Receptor, IGF Type 1
Receptor-Like Protein Tyrosine Phosphatases, Class 2
STAT3 Transcription Factor
Sarcoma, Ewing
Young Adult
