Probes for P53

We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically.

Abstract

BACKGROUND:

Protein phosphatase magnesium-dependent 1δ (PPM1D) is a p53-induced serine/threonine phosphatase, which is overexpressed in various human cancers. A recent study reported that the mutation in the PPM1D gene is associated with poor prognosis in brainstem gliomas. In this study, we evaluate the utility of PPM1D as a prognostic biomarker of adult supratentorial diffuse astrocytic and oligodenroglial tumors.

MATERIALS AND METHODS:

To investigate PPM1D protein expression, mRNA expression, and copy number changes, immunohistochemistry, RNAscope in situ hybridization, and fluorescence in situ hybridization in 84 adult supratentorial diffuse gliomas were performed, respectively. We further analyzed clinical characteristics and overall survival (OS) according to PPM1D protein expression, and examined its correlation with other glioma biomarkers such as isocitrate dehydrogenase (IDH) mutation, and p53 expression.

RESULTS:

Forty-six (54.8%) cases were PPM1D-positive. PPM1D expression levels were significantly correlated with PPM1D transcript levels (P=0.035), but marginally with PPM1D gene amplification (P=0.079). Patients with high-grade gliomas showed a higher frequency of PPM1D expression than those with low-grade gliomas (P<0.001). Multivariate analysis demonstrated that PPM1D expression (hazard ratio [HR] 2.58, P=0.032), age over 60 years (HR 2.55, P=0.018), and IDH1 mutation (HR 0.18, P=0.002) were significantly independent prognostic factors; p53 expression had no prognostic significance (P=0.986). The patients with tumor expressing PPM1D showed a shorter OS (P=0.003). Moreover, patients with tumor harboring wild-type IDH1 and PPM1D expression had the worst OS (P<0.001).

CONCLUSION:

Our data suggest that a subset of gliomas express PPM1D; PPM1D expression is a significant marker of poor prognosis in adult supratentorial diffuse astrocytic and oligodenroglial tumors.