J Pathol Transl Med.  2018 Mar;52(2):71-78. 10.4132/jptm.2017.10.21.

Protein Phosphatase Magnesium-Dependent 1δ (PPM1D) Expression as a Prognostic Marker in Adult Supratentorial Diffuse Astrocytic and Oligodendroglial Tumors

• Jeong HJ
• Woo CG
• Lee B
• Khang SK
• Nam SJ
• Choi J

• KMID: 2408506
• DOI: http://doi.org/10.4132/jptm.2017.10.21

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.

Keyword

PPM1D; IDH1; Mutation; Diffuse astrocytic and oligodendroglial tumors; Supratentorial gliomas; Molecular marker

MeSH Terms

Adult*
Biomarkers
Brain Stem
Fluorescence
Gene Amplification
Glioma
Humans
Immunohistochemistry
In Situ Hybridization
Isocitrate Dehydrogenase
Multivariate Analysis
Prognosis
RNA, Messenger
Biomarkers
Isocitrate Dehydrogenase
RNA, Messenger

Figure

• 

  Fig. 1. A representative case of high-grade glioma. (A) Protein phosphatase magnesium-dependent 1δ (PPM1D) staining shows a high percentage of cells with positive protein expression in both the nucleus and cytoplasm in the anaplastic oligodendroglioma. (B) RNAscope in situ hybridization analysis shows positive expression of PPM1D shown as red dots. (C) Fluorescence in situ hybridization shows amplified PPM1D gene copies as red spots.

• 

  Fig. 2. Kaplan-Meier survival curves of patients with supratentorial diffuse astrocytic and oligodendroglial tumors. (A) Comparison of patients with protein phosphatase magnesium-dependent 1δ (PPM1D) expression and those without PPM1D expression. (B) Comparison of patients with isocitrate dehydrogenase 1 (IDH1) mutation versus those with wild-type IDH1. (C) Comparison of patients with PPM1D expression versus those without PPM1D expression with or without an additional IDH1 mutation. Log-rank tests for a, b, and c yielded p=.003, p<.001, and p< .001, respectively.

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