Abstract 1132: PTPRD is a frequent tumor suppressor in malignant astrocytoma

Abstract

Abstract A slew of loss of heterozygosity studies for over more than a decade indicated existance of tumor suppressor/s other than p16 on 9p. With high resolution DNA microarray data, infrequent loss of a locus at 9p24 have been reported in neuroblastoma, esophageal, colon and lung cancers. Along with >30% loss of whole arm of 9p, we have observed occasional homo and heterozygous loss of a ∼2.6Mb locus, about 10Mb away from p16 gene on 9p in a few glioblastoma multiforme (GBM). Out of 14 genes located in this minimum deletion region, PTPRD expression was lost in ∼65-88% GBM (n=181) and more than 40% AA (n=48). The TCGA data showed similar frequency of loss of PTPRD expression, and mutation in ∼6% of GBM. Compared to nonneoplastic brain, the anaplastic astrocytoma (AA) and GBM had significant loss (p=0.0003 and 3.7 × 10-7, respectively) of PTPRD in our sample set; and TCGA GBM (p=2.7 × 10-14). Earlier we reported 3 genetic GBM subgroups: proneural, proliferative and mesenchymal where proneural GBM have relatively better survival than the others (Phillips et al, 2006). PTPRD expression loss were more significant in proliferative and mesenchymal GBM (P=3.7 × 10-8 and 2.6 × 10-7, respectively) than in proneural (p=0.0001) GBM, suggesting its expression level could be associated with survival. In a set of 306 TCGA GBM with survival data, PTPRD loss was associated with survival (log rank p<0.05). In a small set of GBM (n=11), PTPRD was lost at different degree and pattern in every tumor. Overexpression of PTPRD in U251 and U87 GBM cell lines with relatively little to no PTPRD expression lead to decreased growth rate (p<0.01) and survival (p<0.00001) in both the lines. PTPRD overexpression in these lines caused apoptosis (increased number of sub G0 cell population, and increased PARP cleavage). Downregulation of PTPRD in immortalized normal human astrocytes increased their growth rate and survival. Gene enrichment analysis identified 25 pathways connected to PTPRD expression level, many of them with key tyrosine kinase genes, and leads to survival or cell death phenotypes. PTPRD overexpression dephysphorylated phosphotyrosine/s of a ∼120Kd protein in U251 GBM cells. PTPRD loss has been reported to increase flank GBM xenograft growth rate (Solomon et al, 2008). PTPRD promoter hypermethylation in GBM, and loss mediated tumorigenecity in normal human astrocytes have also been reported recently (Veeriah et al, 2009). Together, this data suggest that PTPRD is a potent and frequent tumor suppressor in astrocytoma, and could be that elusive other tumor suppressor on 9p. This work was supported by the Arizona Biomedical Research Commission, Barrow Neurological Foundation, and Diane and Bruce Halle Fund. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1132.