Protein Phosphatase Magnesium-Dependent 1δ (PPM1D) Expression as a Prognostic Marker in Adult Supratentorial Diffuse Astrocytic and Oligodendroglial Tumors
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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 a mutation in the PPM1D gene is associated with poor prognosis in brainstem gliomas. In this study, we evaluated the utility of PPM1D as a prognostic biomarker of adult supratentorial diffuse astrocytic and oligodendroglial tumors. Methods: To investigate PPM1D protein expression, mRNA expression, and copy number changes, immunohistochemistry, RNAscope in situ hybridization, and fluorescence in situ hybridization were performed in 84 adult supratentorial diffuse gliomas. 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 cases (54.8%) were PPM1D-positive. PPM1D expression levels were significantly correlated with PPM1D transcript levels (p = .035), but marginally with PPM1D gene amplification (p = .079). Patients with high-grade gliomas showed a higher frequency of PPM1D expression than those with low-grade gliomas (p < .001). Multivariate analysis demonstrated that PPM1D expression (hazard ratio [HR], 2.58; p = .032), age over 60 years (HR, 2.55; p = .018), and IDH1 mutation (HR, 0.18; p = .002) were significantly independent prognostic factors; p53 expression had no prognostic significance (p = .986). The patients with tumor expressing PPM1D showed a shorter OS (p = .003). Moreover, patients with tumor harboring wild-type IDH1 and PPM1D expression had the worst OS (p < .001). Conclusions: 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 oligodendroglial tumors.
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 a mutation in the PPM1D gene is associated with poor prognosis in brainstem gliomas. In this study, we evaluated the utility of PPM1D as a prognostic biomarker of adult supratentorial diffuse astrocytic and oligodendroglial tumors. Methods: To investigate PPM1D protein expression, mRNA expression, and copy number changes, immunohistochemistry, RNAscope in situ hybridization, and fluorescence in situ hybridization were performed in 84 adult supratentorial diffuse gliomas. 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 cases (54.8%) were PPM1D-positive. PPM1D expression levels were significantly correlated with PPM1D transcript levels (p = .035), but marginally with PPM1D gene amplification (p = .079). Patients with high-grade gliomas showed a higher frequency of PPM1D expression than those with low-grade gliomas (p < .001). Multivariate analysis demonstrated that PPM1D expression (hazard ratio [HR], 2.58; p = .032), age over 60 years (HR, 2.55; p = .018), and IDH1 mutation (HR, 0.18; p = .002) were significantly independent prognostic factors; p53 expression had no prognostic significance (p = .986). The patients with tumor expressing PPM1D showed a shorter OS (p = .003). Moreover, patients with tumor harboring wild-type IDH1 and PPM1D expression had the worst OS (p < .001). Conclusions: 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 oligodendroglial tumors.
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