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

TY - JOUR

T1 - Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation

AU - Neyazi, Sina

AU - Yamazawa, Erika

AU - Hack, Karoline

AU - Tanaka, Shota

AU - Nagae, Genta

AU - Kresbach, Catena

AU - Umeda, Takayoshi

AU - Eckhardt, Alicia

AU - Tatsuno, Kenji

AU - Pohl, Lara

AU - Hana, Taijun

AU - Bockmayr, Michael

AU - Kim, Phyo

AU - Dorostkar, Mario M

AU - Takami, Toshihiro

AU - Obrecht, Denise

AU - Takai, Keisuke

AU - Suwala, Abigail K

AU - Komori, Takashi

AU - Godbole, Shweta

AU - Wefers, Annika K

AU - Otani, Ryohei

AU - Neumann, Julia E

AU - Higuchi, Fumi

AU - Schweizer, Leonille

AU - Nakanishi, Yuta

AU - Monoranu, Camelia-Maria

AU - Takami, Hirokazu

AU - Engertsberger, Lara

AU - Yamada, Keisuke

AU - Ruf, Viktoria

AU - Nomura, Masashi

AU - Mohme, Theresa

AU - Mukasa, Akitake

AU - Herms, Jochen

AU - Takayanagi, Shunsaku

AU - Mynarek, Martin

AU - Matsuura, Reiko

AU - Lamszus, Katrin

AU - Ishii, Kazuhiko

AU - Kluwe, Lan

AU - Imai, Hideaki

AU - von Deimling, Andreas

AU - Koike, Tsukasa

AU - Benesch, Martin

AU - Kushihara, Yoshihiro

AU - Snuderl, Matija

AU - Nambu, Shohei

AU - Frank, Stephan

AU - Omura, Takaki

AU - Hagel, Christian

AU - Kugasawa, Kazuha

AU - Mautner, Viktor F

AU - Ichimura, Koichi

AU - Rutkowski, Stefan

AU - Aburatani, Hiroyuki

AU - Saito, Nobuhito

AU - Schüller, Ulrich

N1 - © 2024. The Author(s).

PY - 2024/1/24

Y1 - 2024/1/24

N2 - 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.

AB - 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.

KW - Adult

KW - Child

KW - Humans

KW - Transcriptome

KW - Gene Expression Profiling

KW - Ependymoma

KW - Spinal Cord Neoplasms

KW - Mutation

KW - Epigenesis, Genetic

U2 - 10.1007/s00401-023-02668-9

DO - 10.1007/s00401-023-02668-9

M3 - SCORING: Journal article

C2 - 38265489

VL - 147

SP - 22

JO - ACTA NEUROPATHOL

JF - ACTA NEUROPATHOL

SN - 0001-6322

IS - 1

ER -