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 Qiu; Michael 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

doi:10.1038/s41588-022-01061-8

Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities

Nat Genet. 2022 May;54(5):649-659. doi: 10.1038/s41588-022-01061-8. Epub 2022 May 9.

Authors

Abrar Choudhury^{1

2

3

4}, Stephen T Magill^#⁵, Charlotte D Eaton^#^{1

2}, Briana C Prager⁶, William C Chen^{1

2}, Martha A Cady^{1

2}, Kyounghee Seo^{1

2}, Calixto-Hope G Lucas^{1

2

7}, Tim J Casey-Clyde^{1

2}, Harish N Vasudevan^{1

2}, S John Liu^{1

2}, Javier E Villanueva-Meyer^{2

8}, Tai-Chung Lam⁹, Jenny Kan-Suen Pu¹⁰, Lai-Fung Li¹⁰, Gilberto Ka-Kit Leung¹⁰, Danielle L Swaney^{11

12

13}, Michael Y Zhang^{1

2}, Jason W Chan¹, Zhixin Qiu⁶, Michael V Martin², Matthew S Susko¹, Steve E Braunstein¹, Nancy Ann Oberheim Bush^{2

14}, Jessica D Schulte¹⁵, Nicholas Butowski², Penny K Sneed¹, Mitchel S Berger², Nevan J Krogan^{11

12

13}, Arie Perry^{2

7}, Joanna J Phillips^{2

7}, David A Solomon⁷, Joseph F Costello², Michael W McDermott^{2

16}, Jeremy N Rich¹⁷, David R Raleigh^{18

19}

Affiliations

¹ Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA.
² Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
³ Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA, USA.
⁴ Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Neurological Surgery, Northwestern University, Chicago, IL, USA. stephen.magill@northwestern.edu.
⁶ Department of Medicine, University of California, San Diego, San Diego, CA, USA.
⁷ Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
⁸ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.
⁹ Department of Clinical Oncology, The University of Hong Kong, Pokfulam, Hong Kong.
¹⁰ Division of Neurosurgery, Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
¹¹ J. David Gladstone Institutes, California Institute for Quantitative Biosciences, San Francisco, CA, USA.
¹² California Institute for Quantitative Biosciences, San Francisco, CA, USA.
¹³ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
¹⁴ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Department of Neurosciences, University of California, San Diego, San Diego, CA, USA.
¹⁶ Miami Neuroscience Institute, Baptist Health, Miami, FL, USA.
¹⁷ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA. drjeremyrich@gmail.com.
¹⁸ Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA. david.raleigh@ucsf.edu.
¹⁹ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. david.raleigh@ucsf.edu.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

DNA Methylation / genetics
Humans
Meningeal Neoplasms* / genetics
Meningioma* / genetics
Neurofibromin 2 / genetics
Proteomics

Substances

Neurofibromin 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding