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

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.