EZH2 expression in gliomas: Correlation with CDKN2A gene deletion/ p16 loss and MIB‐1 proliferation index

Abstract

Enhancer of zeste homolog 2 (EZH2) mediated down-regulation of CDKN2A/p16 has been observed in cell lines as well as in a few carcinomas. However, there is no study correlating EZH2 expression with CDKN2A/p16 status in gliomas. Hence, the present study was conducted to evaluate EZH2 expression in astrocytic and oligodendroglial tumors and correlate with CDKN2A/p16 status as well as MIB-1 labeling index (LI). Gliomas of all grades (n = 118) were studied using immunohistochemistry to assess EZH2, p16 and MIB-1 LI and fluorescence in situ hybrization to evaluate CDKN2A gene status. EZH2 expression and CDKN2A homozygous deletion (HD) were both significantly more frequent in high-grade gliomas (HGG). Further, strong EZH2 expression (LI ≥ 25%) was significantly more common in HGGs without CDKN2A HD (48.7%; 19/39) as compared to cases with deletion (15.8%; 3/19). Loss of p16 expression was noted in 100% and 51.3% of CDKN2A deleted and non-deleted tumors, respectively. Notably, 80% (16/20) of the CDKN2A non-deleted HGGs with p16 loss had strong EZH2 expression, in contrast to only 15.8% (3/19) in the deleted group. Loss of p16 expression significantly correlated with MIB-1 LI, irrespective of EZH2 status. Thus, this study shows that EZH2 expression correlates with tumor grade in both astrocytic and oligodendroglial tumors and hence can be used as a diagnostic marker to differentiate between low and HGGs. Further, this is the first report demonstrating an inverse correlation of strong EZH2 expression with CDKN2A HD in HGGs. Loss of p16 protein expression is mostly attributable to CDKN2A HD and correlates significantly with MIB-1 LI. Notably, our study for the first time suggests a possible epigenetic mechanism of p16 loss in CDKN2A non-deleted HGGs mediated by strong EZH2 expression. A hypothetical model for control of proliferative activity in low versus HGGs is therefore proposed.

Midline Glioma in Adults: Clinicopathological, Genetic, and Epigenetic Analysis

“…11) Previous reports have shown that the expression of EZH2 is elevated in 80% of the high-grade gliomas with loss of p16 protein expression and conserved CDKN2A. 5) In our study, p16 and MTAP had no significant correlation with histological grade, EZH2, and H3K27me3. It is unclear whether this lack of correlation observed for p16 and MTAP is unique to midline gliomas or does it apply to gliomas in other regions as well.…”

“…Previous reports examining gliomas not restricted to the midline region showed correlation between EZH2 and histologically high-grade gliomas, and our study supports those observations. 5) Indeed, correlation of EZH2 with prognosis and histological grade is also applicable to glioma in the midline region. In H3K27M-mutant cases, H3K27M acts on the SET point of EZH2 to suppress its methylation activity.…”

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

“…Our finding, which is in line with a recent report by Eilers and colleagues (45), indicates that p16 loss might identify a subset of DFSP/FS-DFSP with poor prognosis. Noteworthy, an epigenetic link between p16 loss and EZH2 expression has been recently suggested (46). The evaluation of p16 gene copy number in the primary tumor of FS-DFSP patients included in the surgical series is ongoing to investigate to what extent this alteration is present at disease onset and correlates with the development of distant metastasis.…”

Genetic and epigenetic contribution to astrocytic gliomas pathogenesis

“…It has been observed that deregulation of each of these proteins are associated with primary human GBM or in GBM cell lines (Purkait et al . ). In a study, Miettinen et al .…”

“…P16 is an important regulator which is able to control a cell cycle cascade and includes cyclin-dependent kinase 4 (cdk4), cyclin D1, and pRb. It has been observed that deregulation of each of these proteins are associated with primary human GBM or in GBM cell lines (Purkait et al 2015). In a study, Miettinen et al (1999), assessed the association of CDKN2/p16 expression and cell proliferation activity and survival rate of patient with oligodendrogliomas and astrocytomas.…”