THE MENINGIOMA ENHANCER LANDSCAPE DELINEATES PROGNOSTIC SUBGROUPS AND DRIVES DRUGGABLE DEPENDENCIES

Meningiomas are the most common primary intracranial tumor with currentclassification offering limited therapeutic guidance. Here, we interrogatedmeningioma enhancer landscapes from 33 tumors to stratify patients based uponprognosis and identify novel meningioma-specific dependencies. Enhancersrobustlystratifiedmeningiomasintothreebiologicallydistinctgroups(adipogenesis/cholesterol, mesodermal and neural crest) distinguished bydistinct hormonal lineage transcriptional regulators. Meningioma landscapesclustered with intrinsic brain tumors and hormonally-responsive systemic cancerswith meningioma subgroups reflecting progesterone or androgen hormonalsignaling. Enhancer classification identified a subset of tumors with poorprognosis, irrespective of histological grading. Super enhancer signaturespredicted drug dependencies with superior in vitro efficacy to treatment basedupon the NF2 genomic profile. Inhibition of DUSP1, a novel and druggablemeningioma target, impaired tumor growth in vivo. Collectively, epigeneticlandscapes empower meningioma classification and identification of noveltherapies.