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Open Access 01-06-2024 | Ependymoma | Original Paper

Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation

Authors: Sina Neyazi, Erika Yamazawa, Karoline Hack, Shota Tanaka, Genta Nagae, Catena Kresbach, Takayoshi Umeda, Alicia Eckhardt, Kenji Tatsuno, Lara Pohl, Taijun Hana, Michael Bockmayr, Phyo Kim, Mario M. Dorostkar, Toshihiro Takami, Denise Obrecht, Keisuke Takai, Abigail K. Suwala, Takashi Komori, Shweta Godbole, Annika K. Wefers, Ryohei Otani, Julia E. Neumann, Fumi Higuchi, Leonille Schweizer, Yuta Nakanishi, Camelia-Maria Monoranu, Hirokazu Takami, Lara Engertsberger, Keisuke Yamada, Viktoria Ruf, Masashi Nomura, Theresa Mohme, Akitake Mukasa, Jochen Herms, Shunsaku Takayanagi, Martin Mynarek, Reiko Matsuura, Katrin Lamszus, Kazuhiko Ishii, Lan Kluwe, Hideaki Imai, Andreas von Deimling, Tsukasa Koike, Martin Benesch, Yoshihiro Kushihara, Matija Snuderl, Shohei Nambu, Stephan Frank, Takaki Omura, Christian Hagel, Kazuha Kugasawa, Viktor F. Mautner, Koichi Ichimura, Stefan Rutkowski, Hiroyuki Aburatani, Nobuhito Saito, Ulrich Schüller

Published in: Acta Neuropathologica | Issue 1/2024

Abstract

Ependymomas encompass multiple clinically relevant tumor types based on localization and molecular profiles. Tumors of the methylation class “spinal ependymoma” (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical relevance have been described in a large, epigenetically defined series. Transcriptomic (n = 72), epigenetic (n = 225), genetic (n = 134), and clinical data (n = 112) were integrated for a detailed molecular overview on SP-EPN. Additionally, we mapped SP-EPN transcriptomes to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. The integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord revealed that SP-EPN display the highest similarities to mature adult ependymal cells. Unsupervised hierarchical clustering of transcriptomic data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype A tumors primarily carried previously known germline or sporadic NF2 mutations together with 22q loss (bi-allelic NF2 loss), resulting in decreased NF2 expression. Furthermore, they more often presented as multilocular disease and demonstrated a significantly reduced progression-free survival as compared to SP-EP subtype B. In contrast, subtype B predominantly contained samples without NF2 mutation detected in sequencing together with 22q loss (monoallelic NF2 loss). These tumors showed regular NF2 expression but more extensive global copy number alterations. Based on integrated molecular profiling of a large multi-center cohort, we identified two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities.

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Title: Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation
Authors: Sina Neyazi
Erika Yamazawa
Karoline Hack
Shota Tanaka
Genta Nagae
Catena Kresbach
Takayoshi Umeda
Alicia Eckhardt
Kenji Tatsuno
Lara Pohl
Taijun Hana
Michael Bockmayr
Phyo Kim
Mario M. Dorostkar
Toshihiro Takami
Denise Obrecht
Keisuke Takai
Abigail K. Suwala
Takashi Komori
Shweta Godbole
Annika K. Wefers
Ryohei Otani
Julia E. Neumann
Fumi Higuchi
Leonille Schweizer
Yuta Nakanishi
Camelia-Maria Monoranu
Hirokazu Takami
Lara Engertsberger
Keisuke Yamada
Viktoria Ruf
Masashi Nomura
Theresa Mohme
Akitake Mukasa
Jochen Herms
Shunsaku Takayanagi
Martin Mynarek
Reiko Matsuura
Katrin Lamszus
Kazuhiko Ishii
Lan Kluwe
Hideaki Imai
Andreas von Deimling
Tsukasa Koike
Martin Benesch
Yoshihiro Kushihara
Matija Snuderl
Shohei Nambu
Stephan Frank
Takaki Omura
Christian Hagel
Kazuha Kugasawa
Viktor F. Mautner
Koichi Ichimura
Stefan Rutkowski
Hiroyuki Aburatani
Nobuhito Saito
Ulrich Schüller
Publication date: 01-06-2024
Publisher: Springer Berlin Heidelberg
Keywords: Ependymoma
Ependymoma
Ependymoma
Epigenetics
Published in: Acta Neuropathologica / Issue 1/2024
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-023-02668-9

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Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation

Abstract

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Abstract

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