Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Brain Tumor Pathology
Published in: Brain Tumor Pathology 1/2021

01-01-2021 | Ependymoma | Original Article

EZH2 inhibitory protein (EZHIP/Cxorf67) expression correlates strongly with H3K27me3 loss in posterior fossa ependymomas and is mutually exclusive with H3K27M mutations

Authors: Aruna Nambirajan, Agrima Sharma, Madhu Rajeshwari, Meher Tej Boorgula, Ramesh Doddamani, Ajay Garg, Vaishali Suri, Chitra Sarkar, Mehar Chand Sharma

Published in: Brain Tumor Pathology | Issue 1/2021

Login to get access

Abstract

The PFA molecular subgroup of posterior fossa ependymomas (PF-EPNs) shows poor outcome. H3K27me3 (me3) loss by immunohistochemistry (IHC) is a surrogate marker for PFA wherein its loss is attributed to overexpression of Cxorf67/EZH2 inhibitory protein (EZHIP), C17orf96, and ATRX loss. We aimed to subgroup PF-EPNs using me3 IHC and study correlations of the molecular subgroups with other histone related proteins, 1q gain, Tenascin C and outcome. IHC for me3, acetyl-H3K27, H3K27M, ATRX, EZH2, EZHIP, C17orf96, Tenascin-C, and fluorescence in-situ hybridisation for chromosome 1q25 locus were performed on an ambispective PF-EPN cohort (2003–2019). H3K27M-mutant gliomas were included for comparison. Among 69 patients, PFA (me3 loss) constituted 64%. EZHIP overexpression and 1q gain were exclusive to PFA seen in 72% and 19%, respectively. Tenascin C was more frequently positive in PFA (p = 0.02). H3K27M expression and ATRX loss were noted in one case of PFA–EPN each. All H3K27M-mutant gliomas (n = 8) and PFA-EPN (n = 1) were EZHIP negative. C17orf96 and acetyl-H3K27 expression did not correlate with me3 loss. H3K27me3 is a robust surrogate for PF-EPN molecular subgrouping. EZHIP overexpression was exclusive to PFA EPNs and was characteristically absent in midline gliomas and the rare PFA harbouring H3K27M mutations representing mutually exclusive pathways leading to me3 loss.
Appendix
Available only for authorised users
Literature
1.
Ellison DW, McLendon R, Wiestler OD et al (2016) Ependymoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) WHO classification of tumours of the central nervous system, revised, 4th edn. IARC, Lyon, pp 106–112
2.
Dyer S, Prebble E, Davison V et al (2002) Genomic imbalances in pediatric intracranial ependymomas define clinically relevant groups. Am J Pathol 161:2133–2141CrossRefPubMedPubMedCentral
3.
Pajtler KW, Mack SC, Ramaswamy V et al (2017) The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 133:5–12CrossRefPubMed
4.
Korshunov A, Witt H, Hielscher T et al (2010) Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 28:3182–3190CrossRefPubMed
5.
Witt H, Mack SC, Ryzhova M et al (2011) Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20:143–157CrossRefPubMedPubMedCentral
6.
7.
Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stütz AM et al (2014) Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506:445–450CrossRefPubMedPubMedCentral
8.
Bayliss J, Mukherjee P, Lu C et al (2016) Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas. Sci Transl Med. 8:366ra161CrossRefPubMedPubMedCentral
9.
Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F et al (2015) Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27:728–743CrossRefPubMedPubMedCentral
10.
Pajtler KW, Wen J, Sill M et al (2018) Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol 136(2):211–226CrossRefPubMedPubMedCentral
11.
Ramaswamy V, Hielscher T, Mack SC et al (2016) Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis. J Clin Oncol 34:2468–2477CrossRefPubMedPubMedCentral
12.
13.
Zapotocky M, Beera K, Adamski J et al (2019) Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: cure at a cost. Cancer 125:1867–1876CrossRefPubMed
14.
Nambirajan A, Malgulwar PB, Sharma A et al (2019) Clinicopathological evaluation of PD-L1 expression and cytotoxic T-lymphocyte infiltrates across intracranial molecular subgroups of ependymomas: are these tumors potential candidates for immune check-point blockade? Brain Tumor Pathol 36:152–161CrossRefPubMed
15.
Michealraj KA, Kumar SA, Kim LJY et al (2020) Metabolic regulation of the epigenome drives lethal infantile ependymoma. Cell 181:1329–1345CrossRefPubMed
16.
Hübner JM, Müller T, Papageorgiou DN et al (2019) EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma. Neuro Oncol 21:878–889CrossRefPubMedPubMedCentral
17.
Jain SU, Do TJ, Lund PJ et al (2019) PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism. Nat Commun 10:2146CrossRefPubMedPubMedCentral
18.
Beringer M, Pisano P, Di Carlo V et al (2016) EPOP functionally links elongin and polycomb in pluripotent stem cells. Mol Cell 64:645–658CrossRefPubMed
19.
Castel D, Philippe C, Calmon R et al (2015) Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol 130:815–827CrossRefPubMedPubMedCentral
20.
Panwalkar P, Clark J, Ramaswamy V, Hawes D, Yang F, Dunham C et al (2017) Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. Acta Neuropathol 134:705–714CrossRefPubMedPubMedCentral
21.
Fukuoka K, Kanemura Y, Shofuda T et al (2018) Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors. Acta Neuropathol Commun 6:134CrossRefPubMedPubMedCentral
22.
Tanrıkulu B, Danyeli AE, Özek MM (2020) Is H3K27me3 status really a strong prognostic indicator for pediatric posterior fossa ependymomas? A single surgeon, single center experience. Childs Nerv Syst 36:941–949CrossRefPubMed
23.
Ellison DW, Kocak M, Figarella-Branger D et al (2011) Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. J Negat Results Biomed 10:7CrossRefPubMedPubMedCentral
24.
Rajeshwari M, Sharma MC, Kakkar A et al (2016) Evaluation of chromosome 1q gain in intracranial ependymomas. J Neurooncol 127:271–278CrossRefPubMed
25.
Jha P, Manjunath N, Singh J et al (2019) Analysis of PD-L1 expression and T cell infiltration in different molecular subgroups of diffuse midline gliomas. Neuropathology 39:413–424CrossRefPubMed
26.
Andreiuolo F, Le Teuff G, Bayar MA et al (2017) Integrating Tenascin-C protein expression and 1q25 copy number status in pediatric intracranial ependymoma prognostication: a new model for risk stratification. PLoS ONE 12:e0178351CrossRefPubMedPubMedCentral
27.
Upadhyaya SA, Robinson GW, Onar-Thomas A et al (2019) Molecular grouping and outcomes of young children with newly diagnosed ependymoma treated on the multi-institutional SJYC07 trial. Neuro Oncol 21:1319–1330CrossRefPubMedPubMedCentral
28.
Gessi M, Capper D, Sahm F et al (2016) Evidence of H3 K27M mutations in posterior fossa ependymomas. Acta Neuropathol 132:635–637CrossRefPubMed
29.
Ryall S, Guzman M, Elbabaa SK et al (2017) H3 K27M mutations are extremely rare in posterior fossa group A ependymoma. Childs Nerv Syst 33:1047–1051CrossRefPubMed
30.
31.
Rogers HA, Chapman R, Kings H et al (2018) Limitations of current in vitro models for testing the clinical potential of epigenetic inhibitors for treatment of pediatric ependymoma. Oncotarget 9:36530–36541CrossRefPubMedPubMedCentral
32.
Li AM, Dunham C, Tabori U et al (2015) EZH2 expression is a prognostic factor in childhood intracranial ependymoma: a Canadian Pediatric Brain Tumor Consortium study. Cancer 121:1499–1507CrossRefPubMed
33.
Venneti S, Garimella MT, Sullivan LM et al (2013) Evaluation of histone 3 lysine 27 trimethylation (H3K27me3) and enhancer of Zest 2 (EZH2) in pediatric glial and glioneuronal tumors shows decreased H3K27me3 in H3F3A K27M mutant glioblastomas. Brain Pathol 23:558–564CrossRefPubMedPubMedCentral
Metadata
Title
EZH2 inhibitory protein (EZHIP/Cxorf67) expression correlates strongly with H3K27me3 loss in posterior fossa ependymomas and is mutually exclusive with H3K27M mutations
Authors
Aruna Nambirajan
Agrima Sharma
Madhu Rajeshwari
Meher Tej Boorgula
Ramesh Doddamani
Ajay Garg
Vaishali Suri
Chitra Sarkar
Mehar Chand Sharma
Publication date
01-01-2021
Publisher
Springer Singapore
Published in
Brain Tumor Pathology / Issue 1/2021
Print ISSN: 1433-7398
Electronic ISSN: 1861-387X
DOI
https://doi.org/10.1007/s10014-020-00385-9

Other articles of this Issue 1/2021

Brain Tumor Pathology 1/2021 Go to the issue

Original Article

Central nervous system high grade neuroepithelial tumor with BCOR immunopositivity: Is there a molecular heterogeneity?

Editorial

The molecular framework of pediatric-type diffuse gliomas: shifting toward the revision of the WHO classification of tumors of the central nervous system

Original Article

Clinicopathologic significance of MYD88 L265P mutation and expression of TLR4 and P-STAT3 in primary central nervous system diffuse large B-cell lymphomas

Case Report

Ependymoma with C11orf95-MAML2 fusion: presenting with granular cell and ganglion cell features

Case Report

Genetic characterization of an aggressive optic nerve pilocytic glioma

Original Article

H3 G34-mutant high-grade glioma