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Open Access 01-12-2019 | Ependymoma | Original Paper

MYCN amplification drives an aggressive form of spinal ependymoma

Authors: David R. Ghasemi, Martin Sill, Konstantin Okonechnikov, Andrey Korshunov, Stephen Yip, Peter W. Schutz, David Scheie, Anders Kruse, Patrick N. Harter, Marina Kastelan, Marlies Wagner, Christian Hartmann, Julia Benzel, Kendra K. Maass, Mustafa Khasraw, Ronald Sträter, Christian Thomas, Werner Paulus, Christian P. Kratz, Hendrik Witt, Daisuke Kawauchi, Christel Herold-Mende, Felix Sahm, Sebastian Brandner, Marcel Kool, David T. W. Jones, Andreas von Deimling, Stefan M. Pfister, David E. Reuss, Kristian W. Pajtler

Published in: Acta Neuropathologica | Issue 6/2019

Abstract

Spinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showed MYCN amplification as a characteristic genetic alteration in all cases of our cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization. The histological diagnosis was anaplastic ependymoma (WHO Grade III) in ten cases and classic ependymoma (WHO Grade II) in three cases. Histological re-evaluation in five primary tumors and seven relapses showed characteristic histological features of ependymoma, namely pseudorosettes, GFAP- and EMA positivity. Electron microscopy revealed cilia, complex intercellular junctions and intermediate filaments in a representative sample. Taking these findings into account, we suggest to designate this molecular subgroup spinal ependymoma with MYCN amplification, SP-EPN-MYCN. SP-EPN-MYCN tumors showed distinct growth patterns with intradural, extramedullary localization mostly within the thoracic and cervical spine, diffuse leptomeningeal spread throughout the whole CNS and infiltrative invasion of the spinal cord. Dissemination was observed in 100% of cases. Despite high-intensity treatment, SP-EPN-MYCN showed significantly worse median progression free survival (PFS) (17 months) and median overall survival (OS) (87 months) than all other previously described molecular spinal ependymoma subgroups. OS and PFS were similar to supratentorial ependymoma with RELA-fusion (ST-EPN-RELA) and posterior fossa ependymoma A (PF-EPN-A), further highlighting the aggressiveness of this distinct new subgroup. We, therefore, propose to establish SP-EPN-MYCN as a new molecular subgroup in ependymoma and advocate for testing newly diagnosed spinal ependymal tumors for MYCN amplification.

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Title: MYCN amplification drives an aggressive form of spinal ependymoma
Authors: David R. Ghasemi
Martin Sill
Konstantin Okonechnikov
Andrey Korshunov
Stephen Yip
Peter W. Schutz
David Scheie
Anders Kruse
Patrick N. Harter
Marina Kastelan
Marlies Wagner
Christian Hartmann
Julia Benzel
Kendra K. Maass
Mustafa Khasraw
Ronald Sträter
Christian Thomas
Werner Paulus
Christian P. Kratz
Hendrik Witt
Daisuke Kawauchi
Christel Herold-Mende
Felix Sahm
Sebastian Brandner
Marcel Kool
David T. W. Jones
Andreas von Deimling
Stefan M. Pfister
David E. Reuss
Kristian W. Pajtler
Publication date: 01-12-2019
Publisher: Springer Berlin Heidelberg
Keywords: Ependymoma
Fluorescence in Situ Hybridization
Ependymoma
Spinal Tumor
Ependymoma
Published in: Acta Neuropathologica / Issue 6/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02056-2

At a glance: The STEP trials

Springer Medicine

MYCN amplification drives an aggressive form of spinal ependymoma

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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