Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
received:
21
06
2021
accepted:
22
03
2022
pubmed:
10
5
2022
medline:
20
5
2022
entrez:
9
5
2022
Statut:
ppublish
Résumé
Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2/Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients.
Identifiants
pubmed: 35534562
doi: 10.1038/s41588-022-01061-8
pii: 10.1038/s41588-022-01061-8
pmc: PMC9374001
mid: NIHMS1826905
doi:
Substances chimiques
Neurofibromin 2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
649-659Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM007618
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA213944
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA246808
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA097257
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA209891
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA262311
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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