@article{e76a663d3fb14aacb0f4975c043213c8,
title = "Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities",
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.",
author = "Abrar Choudhury and Magill, {Stephen T.} and Eaton, {Charlotte D.} and Prager, {Briana C.} and Chen, {William C.} and Cady, {Martha A.} and Kyounghee Seo and Lucas, {Calixto Hope G.} and Casey-Clyde, {Tim J.} and Vasudevan, {Harish N.} and Liu, {S. John} and Villanueva-Meyer, {Javier E.} and Lam, {Tai Chung} and Pu, {Jenny Kan Suen} and Li, {Lai Fung} and Leung, {Gilberto Ka Kit} and Swaney, {Danielle L.} and Zhang, {Michael Y.} and Chan, {Jason W.} and Zhixin Qiu and Martin, {Michael V.} and Susko, {Matthew S.} and Braunstein, {Steve E.} and Bush, {Nancy Ann Oberheim} and Schulte, {Jessica D.} and Nicholas Butowski and Sneed, {Penny K.} and Berger, {Mitchel S.} and Krogan, {Nevan J.} and Arie Perry and Phillips, {Joanna J.} and Solomon, {David A.} and Costello, {Joseph F.} and McDermott, {Michael W.} and Rich, {Jeremy N.} and Raleigh, {David R.}",
note = "Funding Information: We thank A. Abate, A. Bhaduri, A. Tward and B. Tomlin for comments and reagents; K. Probst and N. Sirivansanti for illustrations; A. Shai and the staff of the UCSF Brain Tumor Center Biorepository and Pathology Core; T. Ozawa and the staff of the UCSF Brain Tumor Center Preclinical Therapeutics Core; and E. Chow and the staff of the UCSF Center for Advanced Technology. This study was supported by the UCSF Wolfe Meningioma Program Project and National Institutes of Health (NIH) grants F30 CA246808 and T32 GM007618 to A.C.; NIH grant P50 CA097257 to J.J.P.; the UCSF Wolfe Meningioma Program Project, NIH grant F32 CA213944, and the Northwestern Medicine Malnati Brain Institute of the Lurie Cancer Center to S.T.M.; the UCSF Wolfe Meningioma Program Project (C.D.E., J.E.V-M., H.N.V., S.E.B., N.A.O.B., J.S. and N.B.); NIH grant U54 CA209891 to N.J.K; and the UCSF Physician Scientist Scholar Program, the UCSF Wolfe Meningioma Program Project and NIH grant R01 CA262311 to D.R.R. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = may,
doi = "10.1038/s41588-022-01061-8",
language = "English (US)",
volume = "54",
pages = "649--659",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "5",
}