The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers

Abstract

Tyrosine phosphorylation plays a critical role in regulating cellular function and is a central feature in signaling cascades involved in oncogenesis. The regulation of tyrosine phosphorylation is coordinately controlled by kinases and phosphatases (PTPs). Whereas activation of tyrosine kinases has been shown to play vital roles in tumor development, the role of PTPs is much less well defined. Here, we show that the receptor protein tyrosine phosphatase delta (PTPRD) is frequently inactivated in glioblastoma multiforme (GBM), a deadly primary neoplasm of the brain. PTPRD is a target of deletion in GBM, often via focal intragenic loss. In GBM tumors that do not possess deletions in PTPRD, the gene is frequently subject to cancer-specific epigenetic silencing via promoter CpG island hypermethylation (37%). Sequencing of the PTPRD gene in GBM and other primary human tumors revealed that the gene is mutated in 6% of GBMs, 13% of head and neck squamous cell carcinomas, and in 9% of lung cancers. These mutations were deleterious. In total, PTPRD inactivation occurs in >50% of GBM tumors, and loss of expression predicts for poor prognosis in glioma patients. Wild-type PTPRD inhibits the growth of GBM and other tumor cells, an effect not observed with PTPRD alleles harboring cancer-specific mutations. Human astrocytes lacking PTPRD exhibited increased growth. PTPRD was found to dephosphorylate the oncoprotein STAT3. These results implicate PTPRD as a tumor suppressor on chromosome 9p that is involved in the development of GBMs and multiple human cancers. glioblastoma multiforme ͉ methylation ͉ mutation L oss of tumor suppressor function leads to the initiation and progression of cancer (1, 2). Inactivation of tumor suppressor genes can result from both genetic mechanisms such as mutation and deletion or epigenetic mechanisms such as DNA hypermethylation (3, 4). Identification of these genes has provided insight into the biological processes underlying oncogenesis, but the key tumor suppressors in many cancers, such as glioblastoma multiforme (GBM), remain poorly defined.We previously identified the receptor protein tyrosine phosphatase delta (PTPRD) as a gene that predicts for poor prognosis in breast and colon cancer (4). PTPRD is a member of the highly conserved family of receptor protein tyrosine phosphatases (PTPs), several members of which have been implicated in tumorigenesis (5). The gene encodes a transmembrane protein with a cytoplasmic tyrosine phosphatase domain. The PTPRD gene is located within an area of the genome, chromosome 9p, found to be frequently lost in neuroblastoma, gliomas, lung cancer, and other malignancies (6-9). Some deletions of PTPRD have been noted in several of these studies. However, its close proximity to CDKN2A on chromosome 9p has complicated interpretations. In addition, in independent work during the course of our investigations, PTPRD mutations have been detected in a lung cancer genome study, although no functional validation of the alterations is noted (10-12). Together with thes...

Classical pathology and mutational load of breast cancer – integration of two worlds

“…Pointing towards a similar direction, the mutant variant of PTPRD (genetic aberrations in ∼7% of breast cancers 2) encoding the protein tyrosine phosphatase receptor type delta was also strongly associated with high numbers of mutated genes in breast cancer. PTPRD has been shown to act as tumour suppressor 49 and impairs function of Aurora A 50, a protein that has been shown to modulate genomic stability 51. Last but not least, the mutated variant of the putative breast cancer oncogene NF1 (genetic alterations in ∼5% of breast cancers 2) correlated with a high abundance of mutated genes in our study.…”

Clear-cell papillary renal cell carcinoma: molecular and immunohistochemical analysis with emphasis on the von Hippel–Lindau gene and hypoxia-inducible factor pathway-related proteins

“…Genomic DNA was extracted from two 10-mm frozen slices using the Genfind kit (Agencourt, Beverly, MA, USA), in a 96-well format, following the manufacturer's instructions, in a semiautomated manner as described previously. 25 The average yield was 2 mg of dsDNA. A total of 100 ng of DNA were used for whole genome amplification using the Repli-G Midi kit (Qiagen, Valencia, CA, USA).…”

“…Mutations were detected using an automated detection pipeline at the MSKCC Bioinformatics Core as described previously. 25 All putative mutations were confirmed by a second PCR and sequencing reaction, in parallel with amplification and sequencing of matched normal tissue DNA.…”

Genomics of Squamous Cell Lung Cancer

“…Inactivation of CDKN2A by methylation, inactivating mutations, exon 1␤ skipping, or homozygous deletions was observed in 72% of the 178 SQCC samples analyzed by TCGA [8]. PTPRD is a protein tyrosine phosphatase that plays a crucial role in STAT3 signaling and is considered to be a frequent target of inactivation in several cancers, including glioblastomas, SQCC of the head and neck and lung cancer [26].…”