Immunostaining of Increased Expression of Enhancer of Zeste Homolog 2 (EZH2) in Diffuse Midline Glioma H3K27M-Mutant Patients with Poor Survival

• Published in: Pathobiology (Basel) Vol. 86; no. 2-3; pp. 152 - 161
• Main Authors: Karlowee, Vega, Amatya, Vishwa Jeet, Takayasu, Takeshi, Takano, Motoki, Yonezawa, Ushio, Takeshima, Yukio, Sugiyama, Kazuhiko, Kurisu, Kaoru, Yamasaki, Fumiyuki
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland 01.01.2019
• Subjects: Adolescent; Adult; Brain Neoplasms - diagnosis; Brain Neoplasms - genetics; Child; Enhancer of Zeste Homolog 2 Protein - genetics; Female; Glioma - diagnosis; Glioma - genetics; Histones - genetics; Humans; Immunohistochemistry; Male; Middle Aged; Mutation; Original Paper; Polycomb Repressive Complex 2 - genetics; Prognosis; Staining and Labeling; Survival Analysis; Young Adult; H3K27M mutant; Immunohistochemical staining; Diffuse midline glioma; EZH2
• ISSN: 1015-2008; 1423-0291
• DOI: 10.1159/000496691

Introduction: The interaction of K27M mutation in histone H3 (H3K27M mutation) with polycomb repressive complex 2 (PRC2) is facilitated by the enhancer of zeste homolog 2 (EZH2). Subsequently, this interaction leads to the global reduction level of H3K27me3. We analyzed the EZH2 expression level in H3K27M mutation-positive tumors and revealed the association of high EZH2 expression with poor survival. Methods: Our study included 12 patients, with an age range of 6–56 years and treated between 2007 and 2016. All patients underwent MRI study for nonenhanced T1, T2, diffusion, gadolinium-enhanced T1-weighted imaging, and fluid-attenuated inversion recovery (FLAIR). Immunohistochemical staining was performed against H3K27M, H3K27me3, EZH2, EED, mutant isocitrate dehydrogenase 1 (IDH1), α-thalassemia X-linked intellectual disability (ATRX), p53, O6-methylguanine-DNA methyltransferase (MGMT), and Ki-67 antibodies. Results: All patients were negative for IDH1R132H and H3K27me3, but H3K27M-positive. Staining against EZH2 was negative in all histological features of grade II cases (3/12) and positive in grade III and IV cases; EZH2 positivity is associated with poor prognosis (p = 0.0082). EZH2 positivity was not associated with EED positivity. Retained ATRX staining was found mostly in grade III and IV cases (6/12). P53 was predominantly positive in cases of astrocytoma and glioblastoma (8/12). The labeling index of Ki-67 was 1.2–31.4% for grade II and III histological features and 11.2–24.8% for grade IV. Conclusion: We suggest that the expression of EZH2 is not associated with the PRC2 pathway and increases in patients with H3K27M-mutant diffuse midline glioma and a poor prognosis. Further studies are necessary to understand the mechanism involved.