A NEW TUMOR SUPPRESSOR GENE

PTPRD a Strong Candidate for New Human Tumor Suppressor Gene

December 16, 2008 — A study of genes that contribute to glioblastoma multiforme (GBM) has found deletions in protein tyrosine phosphatase, receptor type D (PTPRD), in 14% of the GBM tumor samples. PTPRD mutations were also demonstrated in 12% of melanoma tumor samples. Published online December 15 in Cancer Research, the findings suggest that PTPRD fits the criteria for a tumor suppressor gene whose inactivation underlies many human cancers.

Cyclin-dependent kinase inhibitor 2A (CDKN2A) has been recognized as a tumor suppressor gene for more than a decade. However, although loss of heterozygosity on chromosome 9p has been reported in about 60% of melanomas, fewer than 10% of these demonstrated CDKN2A mutations. This raised the possibility that another tumor suppressor gene is also located on chromosome 9p. The present study found frequent PTPRD mutations or deletions in GBM tumor samples, making PTPRD a likely candidate for the "other" 9p tumor suppressor gene.

Senior author Todd Waldman, MD, PhD, associate professor of oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, told Medscape Pathology & Lab Medicine in an email: "[W]e didn't start out looking for the 'other' tumor suppressor gene telomeric to CDKN2A/B. Rather, we started out looking for new tumor suppressors in GBM and found this one, which fits the criteria for the 'other' 9p tumor suppressor gene."

Using a panel of 58 GBM tumor samples, the investigators screened for alterations in gene copy numbers. Focal deletions (<10>CDKN2A/B (78% of samples) and CDKN2C (16% of samples) and were next most prevalent in PTPRD (14% of samples). Large-scale chromosomal loss (>10 Mb) of PTPRD occurred in 33% of the GBM tumor samples, second only to large-scale loss of PTEN in 55% of samples.

Because the "other" tumor suppressor gene on chromosome 9p had been proposed in studies of malignant melanoma, the investigators extended their study of PTPRD to melanoma tumor samples. Among 47 tumor samples, 7 samples showed PTPRD mutations (8 somatic missense mutations and 2 somatic nonsense mutations). The 12% mutation frequency for PTPRD is one of the higher rates reported for specific genes in melanoma. In addition, PTPRD mutations have recently been reported in lung and colon cancers.

For a functional assessment, viral vectors were used to restore expression of PTPRD protein in cultures of GBM and melanoma cells that had PTPRD mutations or deletions. Restoration of PTPRD expression resulted in lowered viability and growth inhibition in the tumor cells. The authors point out: "These are the first reported data indicating that PTPRD has growth-suppressive properties when expressed in human cancer cells, supporting the hypothesis that PTPRD is a bona fide human tumor suppressor gene."

Asked whether a similar restoration of function could work in a clinical setting, Dr. Waldman replied: "One of the major challenges in cancer biology is how to 'target' a loss of function event like mutation of PTPRD with new drugs, since most pharmacology is focused on designing inhibitors."

He continued, "Probably the most fruitful future strategy will be to identify a downstream 'gain of function' in the PTPRD pathway that we can then use for drug development efforts for the design of novel inhibitors. In an effort to identify such targets, we are now actively looking for the substrates of the PTPRD tyrosine phosphatase activity."

Victor Velculescu, MD, PhD, associate professor of oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, also talked with Medscape Pathology & Lab Medicine by telephone about therapeutic approaches.

"PTPRD is a phosphatase," said Dr. Velculescu. "For every phosphatase, there has to be a complementary kinase — a kinase has to put a phosphate on a particular target molecule, and the phosphatase removes that phosphate. And so if the tyrosine phosphatase is being inactivated, that means that the phosphate remains on that molecule and the pathway is perhaps active more often."

Dr. Velculescu added, "You can imagine inhibiting the kinase because that must have an activating effect, as opposed to the inactivating effect of the phosphatase. So that could be a therapeutic modality which could result in the same effect that you saw with respect to reintroduction of PTPRD [in the cell cultures]. But it would be through the kinase," he said.