Mutational Inactivation of PTPRD in Glioblastoma Multiforme and Malignant Melanoma

Solomon, David A.; Kim, Jung-Sik; Cronin, Julia C.; Sibenaller, Zita A.; Ryken, Timothy C.; Rosenberg, Steven A.; Ressom, Habtom W.; Jean, Walter C.; Bigner, Darell D.; Yan, Hai; Samuels, Yardena; Waldman, Todd

doi:10.1158/0008-5472.can-08-3272

Cited by 115 publications

(147 citation statements)

References 28 publications

(22 reference statements)

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“…Because GBM is a highly heterogeneous tumor, a challenge remains to determine which molecular alterations drive tumorigenesis and to understand the underlying mechanisms of action. Recent work by our group and others have identified inactivation of protein tyrosine phosphatase receptor-δ (PTPRD) as a frequent alteration in GBM and other tumors, and showed that PTPRD copy number loss correlates with poor prognosis (5)(6)(7)(8)(9)(10). Despite the high prevalence of PTPRD inactivation in human tumors, it is not known whether loss of PTPRD can promote tumorigenesis.…”

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confidence: 99%

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Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Ortiz

Fabius²,

Wu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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PTPRD, which encodes the protein tyrosine phosphatase receptor-δ, is one of the most frequently inactivated genes across human cancers, including glioblastoma multiforme (GBM). PTPRD undergoes both deletion and mutation in cancers, with copy number loss comprising the primary mode of inactivation in GBM. However, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo, and the mechanistic basis of PTPRD function in tumors is unclear. Here, using genomic analysis and a glioma mouse model, we demonstrate that loss of Ptprd accelerates tumor formation and define the oncogenic context in which Ptprd loss acts. Specifically, we show that in human GBMs, heterozygous loss of PTPRD is the predominant type of lesion and that loss of PTPRD and the CDKN2A/p16 INK4A tumor suppressor frequently co-occur. Accordingly, heterozygous loss of Ptprd cooperates with p16 deletion to drive gliomagenesis in mice. Moreover, loss of the Ptprd phosphatase resulted in phospho-Stat3 accumulation and constitutive activation of Stat3-driven genetic programs. Surprisingly, the consequences of Ptprd loss are maximal in the heterozygous state, demonstrating a tight dependence on gene dosage. Ptprd loss did not increase cell proliferation but rather altered pathways governing the macrophage response. In total, we reveal that PTPRD is a bona fide tumor suppressor, pinpoint PTPRD loss as a cause of aberrant STAT3 activation in gliomas, and establish PTPRD loss, in the setting of CDKN2A/p16 INK4A deletion, as a driver of glioma progression.G lioblastoma multiforme (GBM) is a devastating disease. It is the most common and aggressive type of glioma and outcomes remain poor despite current treatments (1). To increase our understanding of the genetic basis of this malignancy, several mutational survey studies examining GBM have been completed and provide a detailed view of the molecular changes underlying this cancer (2-4). Because GBM is a highly heterogeneous tumor, a challenge remains to determine which molecular alterations drive tumorigenesis and to understand the underlying mechanisms of action. Recent work by our group and others have identified inactivation of protein tyrosine phosphatase receptor-δ (PTPRD) as a frequent alteration in GBM and other tumors, and showed that PTPRD copy number loss correlates with poor prognosis (5-10). Despite the high prevalence of PTPRD inactivation in human tumors, it is not known whether loss of PTPRD can promote tumorigenesis. Furthermore, the mechanisms of action and the oncogenic context in which PTPRD acts remain obscure.PTPRD belongs to a family of protein-tyrosine phosphatases that collectively have been implicated in functions, including the regulation of receptor tyrosine kinases, growth, cell migration, and angiogenesis (11). Previously, we demonstrated that phosphorylated STAT3 (p-STAT3) is a substrate of PTPRD and that cancer-specific mutations in PTPRD abrogate the ability of the phosphatase to dephosphorylate STAT3 (5). Interestingly, accumulation of phosphorylated STAT3 and STAT3 hyper...

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confidence: 99%

“…The CDKN2A locus produces the p16 INK4A and p14/p19 ARF tumor suppressors by alternate splicing (15). We and others have shown that selective pressure exists for inactivation of both PTPRD and CDKN2A, on chromosome 9p, in many types of cancer (5,6,10,16). Both genes are frequently deleted or mutated.…”

mentioning

confidence: 99%

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Ortiz

Fabius²,

Wu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…17,[20][21][22] The overexpression of PTPRD in vitro causes transient growth arrest and an increase in apoptotic cells, with the converse demonstrated for the knockdown of PTPRD. 17,21,23 Furthermore, PTPRD has been shown to dephosphorylate the tyrosine 705 residue of pStat3 in vitro, which is the first putative target of its catalytic phosphatase activity. 21 Collectively, these studies suggest that PTPRD has growth-suppressive activities in human cancer cells.…”

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confidence: 99%

“…Homozygous deletion of PTPRD has been reported at a frequency of 8-20% in lung cancer, melanoma, neuroblastoma, glioblastoma multiforme, laryngeal SCC and lymphoma. [13][14][15][16][17][18][19] Mutations of the coding exons of PTPRD and methylation at the promoter region have also been reported in lung cancer, melanoma, glioblastoma, breast and colorectal cancers, indicating that multiple mechanisms of disruption affect this gene in cancer. 17,[20][21][22] The overexpression of PTPRD in vitro causes transient growth arrest and an increase in apoptotic cells, with the converse demonstrated for the knockdown of PTPRD.…”

mentioning

confidence: 99%

“…[13][14][15][16][17][18][19] Mutations of the coding exons of PTPRD and methylation at the promoter region have also been reported in lung cancer, melanoma, glioblastoma, breast and colorectal cancers, indicating that multiple mechanisms of disruption affect this gene in cancer. 17,[20][21][22] The overexpression of PTPRD in vitro causes transient growth arrest and an increase in apoptotic cells, with the converse demonstrated for the knockdown of PTPRD. 17,21,23 Furthermore, PTPRD has been shown to dephosphorylate the tyrosine 705 residue of pStat3 in vitro, which is the first putative target of its catalytic phosphatase activity.…”

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Metastatic cutaneous squamous cell carcinoma shows frequent deletion in the protein tyrosine phosphatase receptor Type D gene

Lambert

Harwood

Purdie

et al. 2011

Intl Journal of Cancer

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Cutaneous squamous cell carcinoma (cSCC) is the second most common form of nonmelanoma skin cancer (NMSC), and its incidence is increasing rapidly. Metastatic cSCC accounts for the majority of deaths associated with NMSC, but the genetic basis for cSCC progression remains poorly understood. A previous study identified small deletions (typically <1 Mb) in the protein tyrosine phosphatase receptor Type D (PTPRD) gene that segregated with more aggressive cSCC. To investigate the apparent association between deletion within PTPRD and cSCC metastasis, a series of 74 formalin-fixed paraffin-embedded tumors from 31 patients was analyzed using a custom Illumina 384 SNP microarray. Deletions were found in 37% of patients with metastatic cSCC and were strongly associated with metastatic tumors when compared to those that had not metastasized (p 5 0.007). Subsequent mutation analysis revealed a higher mutation rate for PTPRD than has been reported in any other cancer type, with 37% of tumors harboring a somatic mutation. Conversely, bisulfite sequencing showed that methylation was not a mechanism of PTPRD disruption in cSCC. This is the first report to observe an association between deletion within PTPRD and metastatic disease and highlights the potential use of these deletions as a diagnostic biomarker for tumor progression. Combined with the high mutation rate observed in our study, PTPRD is one of the most commonly altered genes in cSCC and warrants further investigation to determine its significance for metastasis in other tumor types.Nonmelanoma skin cancer (NMSC) has a predicted prevalence equal to that of all other cancers combined and its incidence is increasing.1 There are more than 81,500 new cases of NMSC diagnosed annually in the United Kingdom alone, placing a heavy burden on both patients and healthcare resources.2 Despite accounting for only 20% of total NMSC cases, cutaneous squamous cell carcinoma (cSCC) is responsible for the majority of NMSC deaths, largely as a result of metastatic disease. A subset of immunosuppressed individuals, such as organ transplant recipients on long-term immunosuppressive drugs, develop particularly aggressive tumors with an increased risk of metastasis.3 Risk factors for metastasis include poor differentiation of the tumor cells, large tumor size, tumor depth >5 mm, immunosuppression and localization on the ear and lip. [4][5][6][7] Metastatic cSCC is currently treated by surgical intervention and/or chemotherapy or radiotherapy and is associated with a poor outcome. 8Despite the well-established role of ultraviolet radiation (UVR) in the etiology of cSCC, the molecular events underlying its development remain largely undefined. Inactivation of the tumor suppressor genes TP53 and p16INK4A is a common and early event in cSCC pathogenesis and is characteristic of all histological grades of tumor. 9,10 Recently, genotyping of 60 cSCC identified high rates of loss of heterozygosity (LOH)

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D9S168 microsatellite alteration predicts a poor prognosis in patients with clear cell renal cell carcinoma and correlates with the down‐regulation of protein tyrosine phosphatase receptor delta

Li¹,

Tan²,

Ye³

et al. 2011

Cancer

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BACKGROUND:The role of microsatellite alterations in surgically excised tumors in predicting the prognosis of patients with clear cell renal cell carcinoma (ccRCC) remains largely unknown. METHODS: Specimens from 93 patients with sporadic ccRCC were used to screen microsatellite alterations using 12 markers on chromosomes 3p, 9p, and 14q according to disease stage. Survival was evaluated by using the Kaplan-Meier method and Cox regression analysis. The expression of targeted genes was examined using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. RESULTS: Of the markers that were screened, D9S168 (9p23-22) had the highest frequency (36.9%) of microsatellite alteration in the specimens. D9S168 alterations were frequent in high-stage tumors. Seventy-eight patients who had ccRCC without distant metastasis at the time of surgery were followed for a median of 31.7 months. Overall survival and disease-free survival were poorer for patients with D9S168 alteration than for those without alteration (P < .001 for each; log-rank test). Cox regression analysis indicated that D9S168 alteration was associated independently with cancer-related death (P ¼ .010). The D9S168 alteration, which was located at the 5 0 -untranslated region of a gene that encodes protein tyrosine phosphatase (PTP) receptor delta (PTPRD), was associated significantly with low expression of PTPRD at the messenger RNA level (P ¼ .001). Immunohistochemistry revealed that the expression of PTPRD was strong in normal kidney proximal tubular epithelial cells, from which ccRCC originated, and was greatly down-regulated in ccRCC (P < .001; Wilcoxon rank-sum test). CONCLUSIONS: D9S168 microsatellite alteration in tumors predicted a poor prognosis for patients with ccRCC after curative nephrectomy. The authors concluded that PTPRD is a putative tumor suppressor in ccRCC and has therapeutic potential.

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Mutational Inactivation of PTPRD in Glioblastoma Multiforme and Malignant Melanoma

Cited by 115 publications

References 28 publications

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Metastatic cutaneous squamous cell carcinoma shows frequent deletion in the protein tyrosine phosphatase receptor Type D gene

D9S168 microsatellite alteration predicts a poor prognosis in patients with clear cell renal cell carcinoma and correlates with the down‐regulation of protein tyrosine phosphatase receptor delta

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