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

Classification DNA methylation Ependymoma NF2-related schwannomatosis Transcriptomics

Journal

Acta neuropathologica

ISSN: 1432-0533

Titre abrégé: Acta Neuropathol

Pays: Germany

ID NLM: 0412041

Informations de publication

Date de publication:
24 Jan 2024

Historique:

received: 05 10 2023

accepted: 12 12 2023

revised: 28 11 2023

medline: 24 1 2024

pubmed: 24 1 2024

entrez: 24 1 2024

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1007/s00401-023-02668-9 PMID: 38265489

pubmed: 38265489

doi: 10.1007/s00401-023-02668-9

pii: 10.1007/s00401-023-02668-9

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

Informations de copyright

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