Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities

Abrar Choudhury, Stephen T. Magill, Charlotte D. Eaton, Briana C. Prager, William C. Chen, Martha A. Cady, Kyounghee Seo, Calixto Hope G. Lucas, Tim J. Casey-Clyde, Harish N. Vasudevan, S. John Liu, Javier E. Villanueva-Meyer, Tai Chung Lam, Jenny Kan Suen Pu, Lai Fung Li, Gilberto Ka Kit Leung, Danielle L. Swaney, Michael Y. Zhang, Jason W. Chan, Zhixin QiuMichael V. Martin, Matthew S. Susko, Steve E. Braunstein, Nancy Ann Oberheim Bush, Jessica D. Schulte, Nicholas Butowski, Penny K. Sneed, Mitchel S. Berger, Nevan J. Krogan, Arie Perry, Joanna J. Phillips, David A. Solomon, Joseph F. Costello, Michael W. McDermott, Jeremy N. Rich, David R. Raleigh

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)649-659
Number of pages11
JournalNature Genetics
Volume54
Issue number5
DOIs
StatePublished - May 2022
Externally publishedYes

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