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Germline PTPRD mutations in Ewing sarcoma: biologic and clinical implications.

Jiang Y, Janku F, Subbiah V, Angelo LS, Naing A, Anderson PM, Herzog CE, Fu S, Benjamin RS, Kurzrock R - Oncotarget (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

ABSTRACT
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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IGF-1R is one of the mediators of STAT3 activitySTAT3 is phosphorylated by JAK2, after being recruited to IGF-1R by RACK1. After STAT3's phosphorylation by JAK2, PTPRD normally dephosphorylates STAT3. In the presence of a truncated PTPRD, STAT3 would remain phosphorylated.
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Figure 1: IGF-1R is one of the mediators of STAT3 activitySTAT3 is phosphorylated by JAK2, after being recruited to IGF-1R by RACK1. After STAT3's phosphorylation by JAK2, PTPRD normally dephosphorylates STAT3. In the presence of a truncated PTPRD, STAT3 would remain phosphorylated.

Mentions: Of the eight patients with Ewing sarcoma, three (37.5%) had germline mutations in the PTPRD gene. Patient 1 (Table 1; age 24 at diagnosis) had mutational analysis of 182 cancer-related genomic alterations in formalin-fixed paraffin-embedded tumor tissue performed using a Clinical Laboratory Improvement Amendment approved Foundation One platform. Simultaneously, DNA extracted from tumor tissue and PBMCs from the same patient were analyzed independently with next-generation whole exome sequencing in the MD Anderson Core Laboratory using the SOLiD platform. A PTPRD mutation annotated as a W775stop germline mutation was found in both the patient's tumor and PBMCs (Figure 1). The PTPRD mutation was confirmed by polymerase chain reaction (PCR)-based Sanger sequencing in genomic DNA derived from tumor and PBMCs. The W775stop germline mutation is located in the extracellular fibronectin type III (FN3) region (Figure 1).[10] The mutation of tryptophan to a stop codon results in the truncation of all transmembrane and intracellular domains, which leads to partial loss of the dephosphorylation function of PTPRD. Because PTPRD functions as a STAT3 phosphorylation suppressor, it is plausible that partial loss of PTPRD can lead to increased STAT3 phosphorylation.[11] In addition, NGS revealed a V253I germline mutation located in the third immunoglobulin (Ig)-like domain of the receptor protein tyrosine phosphatase (RPTP)-F region, also known as LAR, within the extracellular domain (Figure 1) [10]. The impact of this mutation is, however, unclear. Patient 1 had durable CRs resulting from IGF-1R inhibitor-based therapies (Figure 2).[14, 17-20]


Germline PTPRD mutations in Ewing sarcoma: biologic and clinical implications.

Jiang Y, Janku F, Subbiah V, Angelo LS, Naing A, Anderson PM, Herzog CE, Fu S, Benjamin RS, Kurzrock R - Oncotarget (2013)

IGF-1R is one of the mediators of STAT3 activitySTAT3 is phosphorylated by JAK2, after being recruited to IGF-1R by RACK1. After STAT3's phosphorylation by JAK2, PTPRD normally dephosphorylates STAT3. In the presence of a truncated PTPRD, STAT3 would remain phosphorylated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757245&req=5

Figure 1: IGF-1R is one of the mediators of STAT3 activitySTAT3 is phosphorylated by JAK2, after being recruited to IGF-1R by RACK1. After STAT3's phosphorylation by JAK2, PTPRD normally dephosphorylates STAT3. In the presence of a truncated PTPRD, STAT3 would remain phosphorylated.
Mentions: Of the eight patients with Ewing sarcoma, three (37.5%) had germline mutations in the PTPRD gene. Patient 1 (Table 1; age 24 at diagnosis) had mutational analysis of 182 cancer-related genomic alterations in formalin-fixed paraffin-embedded tumor tissue performed using a Clinical Laboratory Improvement Amendment approved Foundation One platform. Simultaneously, DNA extracted from tumor tissue and PBMCs from the same patient were analyzed independently with next-generation whole exome sequencing in the MD Anderson Core Laboratory using the SOLiD platform. A PTPRD mutation annotated as a W775stop germline mutation was found in both the patient's tumor and PBMCs (Figure 1). The PTPRD mutation was confirmed by polymerase chain reaction (PCR)-based Sanger sequencing in genomic DNA derived from tumor and PBMCs. The W775stop germline mutation is located in the extracellular fibronectin type III (FN3) region (Figure 1).[10] The mutation of tryptophan to a stop codon results in the truncation of all transmembrane and intracellular domains, which leads to partial loss of the dephosphorylation function of PTPRD. Because PTPRD functions as a STAT3 phosphorylation suppressor, it is plausible that partial loss of PTPRD can lead to increased STAT3 phosphorylation.[11] In addition, NGS revealed a V253I germline mutation located in the third immunoglobulin (Ig)-like domain of the receptor protein tyrosine phosphatase (RPTP)-F region, also known as LAR, within the extracellular domain (Figure 1) [10]. The impact of this mutation is, however, unclear. Patient 1 had durable CRs resulting from IGF-1R inhibitor-based therapies (Figure 2).[14, 17-20]

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus