Germline PTPRD Mutations in Ewing Sarcoma: Biologic and Clinical Implications
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Yunyun Jiang1,*, Filip Janku1,*, Vivek Subbiah1, Laura S. Angelo1, Aung Naing1, Peter M. Anderson2, Cynthia E. Herzog2, Siqing Fu1, Robert S. Benjamin3, Razelle Kurzrock4
1 Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2 Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3 Department of Sarcoma Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
4 Moores Cancer Center, The University of California San Diego, La Jolla, California, USA
* These authors contributed equally to the work
Filip Janku, email:
Keywords: Ewing sarcoma, PTPRD, mutation, germline
Received: May 7, 2013 Accepted: June 3, 2013 Published: June 5, 2013
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.
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