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,T. Casey-Clyde,Harish N. Vasudevan,S. John Liu,Javier Villanueva-Meyer,Tai Chung Lam,Jenny Kan-suen Pu,Lai-Fung Li,Gilberto K.K. Leung,Danielle L. Swaney,Michael Zhang,Jason Chan,Zhixin Qiu,Michael Martin,Matthew S. Susko,Steve Braunstein,Nancy Ann Oberheim Bush,Jessica Schulte,Nicholas Butowski,Penny K. Sneed,Mitchel S. Berger,Nevan J. Krogan,Arie Perry,T. J. Phillips,David A. Solomon,Joseph F. Costello,Michael P. McDermott,Jeremy N. Rich,David R. Raleigh +35 more
TLDR
In this paper , DNA methylation profiling of 565 meningiomas highlights three groups associated with distinct molecular, clinical and therapeutic features: immune-enriched, hypermitotic and Merlin-intact meningus.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. DNA methylation profiling of 565 meningiomas highlights three groups associated with distinct molecular, clinical and therapeutic features. read more
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Clinical implications of the 2021 edition of the WHO classification of central nervous system tumours
TL;DR: The main changes in the classification of diffuse and circumscribed gliomas, ependymomas, embryonal tumours and meningiomas are summarized and how each change will influence post-surgical treatment, clinical trial enrolment and cooperative studies are discussed.
Journal ArticleDOI
Brain borders at the central stage of neuroimmunology.
Journal ArticleDOI
Hypermitotic meningiomas harbor DNA methylation subgroups with distinct biological and clinical features.
Abrar Choudhury,William C. Chen,Calixto-Hope G Lucas,James Bayley,Akdes Serin Harmanci,Sybren L. N. Maas,Sandro Santagata,Tiemo J. Klisch,Arie Perry,Wenya Linda Bi,Felix Sahm,Akash J. Patel,Stephen T. Magill,David R. Raleigh +13 more
TL;DR: These data suggest meningioma DNA methylation groups may harbor subgroups unifying contrasting theories of mening ioma biology, which are previously reported alongside Merlin-intact and Immune-enriched tumors using an integrated molecular model.
Journal ArticleDOI
Clinical implementation of integrated molecular‐morphologic risk prediction for meningioma
Thomas Hielscher,Martin Sill,Philipp Sievers,Damian Stichel,Sebastian Brandner,David T. Jones,Andreas von Deimling,Felix Sahm,Sybren L. N. Maas +8 more
TL;DR: In this paper , the integrated molecular morphologic meningioma integrated score (IntS) was proposed for risk prediction of brain tumor classifier and showed that any loss over 5% of the chromosomal arm suffices for the calling of a CNV, and that input from the v12.5 classifier is as good or better than the dedicated menioma classifier (v2.4) and that there is most likely no need for additional testing for TERT−promoter mutations and/or homozygous losses of CDKN2A/B when defining the IntS for an individual patient.
Journal ArticleDOI
CDK 4/6 inhibitors for the treatment of meningioma
Jacob S. Young,Reilly L. Kidwell,Allison C. Zheng,Alexander F Haddad,Manish K. Aghi,David R. Raleigh,Jessica Schulte,Nicholas Butowski +7 more
TL;DR: In this paper , the authors describe the preclinical evidence for CDK4/6 inhibitors as a treatment for high-grade meningiomas and summarize evolving clinical experience with these agents.
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