Meningioma epigenetic grouping reveals biologic drivers and therapeutic vulnerabilities

• DOI: 10.1101/2020.11.23.20237495
• Publication Date: 2020-11-27T22:50:13Z
• Authors: Abrar Choudhury; Stephen T. Magill; Charlotte D. Eaton; Briana C. Prager; William C. Chen; Kyounghee Seo; Calixto-Hope G. L...; Javier E. Villanu...; Tai-Chung Lam; Jenny Kan-Suen Pu; Lai-Fung Li; Gilberto Ka-Kit L...; Harish N. Vasudevan; S. John Liu; Jason W. Chan; Zhixin Qiu; Michael Y. Zhang; Michael V. Martin; Matthew S. Susko; Steve E. Braunstein; Nancy Ann Oberhei...; Jessica Schulte; Nicholas Butowski; Penny K. Sneed; Mitchel S. Berger; Arie Perry; Joanna J. Phillips; David A. Solomon; Joseph F. Costello; Michael W. McDermott; Jeremy N. Rich; David R. Raleigh
• Keywords: 0301 basic medicine; 03 medical and health sciences; 3. Good health

SUMMARY Meningiomas arising from the meningothelial central nervous system lining are most common primary intracranial tumors, and a significant cause of neurologic morbidity mortality 1 . There no effective medical therapies for meningioma patients 2,3 , new treatments have been encumbered by limited understanding biology. DNA methylation profiling provides robust classification tumors 4 can elucidate targets molecular therapy 5 Here we use on 565 meningiomas integrated with genetic, transcriptomic, biochemical, single-cell approaches to show comprised 3 epigenetic groups distinct clinical outcomes biological features informing patients. Merlin-intact (group A, 34%) best distinguished novel apoptotic tumor suppressor function NF2 /Merlin. Immune-enriched B, 38%) intermediate immune cell infiltration, HLA expression, lymphatic vessels. Hypermitotic C, 28%) worst convergent genetic mechanisms misactivating cycle. Consistently, find cycle inhibitors block growth in culture, organoids, xenografts, Our results establish framework biology, provide preclinical rationale treat