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

• Published in: Neuropathology 2015-10, Vol.35 (5), p.421-431
• Main Authors: Purkait, Suvendu, Sharma, Vikas, Jha, Prerana, Sharma, Mehar Chand, Suri, Vaishali, Suri, Ashish, Sharma, BS, Sarkar, Chitra
• Format: Article
• Language: English
• Subjects: Adult; Aged; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; CDKN2A; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Enhancer of Zeste Homolog 2 Protein; EZH2; Female; Gene Deletion; Genes, p16; Glioma - genetics; Glioma - metabolism; Glioma - pathology; gliomas; Humans; Ki-67 Antigen - metabolism; Male; Middle Aged; p16; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Retrospective Studies; Tumors; Young Adult
• ISSN: 0919-6544; 1440-1789
• DOI: 10.1111/neup.12201

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.