EZH2 inhibitory protein (EZHIP/Cxorf67) expression correlates strongly with H3K27me3 loss in posterior fossa ependymomas
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ORIGINAL ARTICLE
EZH2 inhibitory protein (EZHIP/Cxorf67) expression correlates strongly with H3K27me3 loss in posterior fossa ependymomas and is mutually exclusive with H3K27M mutations Aruna Nambirajan1 · Agrima Sharma1 · Madhu Rajeshwari1 · Meher Tej Boorgula2 · Ramesh Doddamani2 · Ajay Garg3 · Vaishali Suri1 · Chitra Sarkar1 · Mehar Sharma1 Received: 28 May 2020 / Accepted: 6 October 2020 © The Japan Society of Brain Tumor Pathology 2020
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. Keywords H3K27me3 · EZHIP · Cxorf67 · H3K27M · 1q
Introduction
Part of this study has been presented at the 47th Annual meeting of the International Society of Paediatric Neurosurgery (ISPN) held at Birmingham, United Kingdom in October, 2019 and published as an abstract. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10014-020-00385-9) contains supplementary material, which is available to authorized users. * Mehar Sharma [email protected] 1
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
2
Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India
3
Department of Neuroradiology, All India Institute of Medical Sciences, New Delhi, India
Ependymomas (EPN) are relatively rare gliomas that recapitulate the ependymal cells lining the ventricles and spinal canal [1]. They occur across the three major anatomical compartments of the central nervous system (CNS): supratentorium, posterior fossa (PF) and spinal cord. EPNs represent the third most common intracranial tumours in children, of which majority occur in the PF [2]. They are primarily treated b
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