Meningiomas are the most common primary intracranial
tumor with current classification offering limited therapeutic guidance. Here, we interrogated
meningioma enhancer landscapes from 33
tumors to stratify patients based upon prognosis and identify novel
meningioma-specific dependencies. Enhancers robustly stratified
meningiomas into three biologically distinct groups (adipogenesis/
cholesterol, mesodermal, and neural crest) distinguished by distinct hormonal lineage transcriptional regulators.
Meningioma landscapes clustered with intrinsic
brain tumors and hormonally responsive systemic
cancers with
meningioma subgroups, reflecting
progesterone or
androgen hormonal signaling. Enhancer classification identified a subset of
tumors with poor prognosis, irrespective of histologic grading. Superenhancer signatures predicted drug dependencies with superior in vitro efficacy to treatment based upon the NF2 genomic profile. Inhibition of DUSP1, a novel and druggable
meningioma target, impaired
tumor growth in vivo. Collectively, epigenetic landscapes empower
meningioma classification and identification of novel
therapies. SIGNIFICANCE: Enhancer landscapes inform prognostic classification of aggressive
meningiomas, identifying
tumors at high risk of recurrence, and reveal previously unknown therapeutic targets. Druggable dependencies discovered through epigenetic profiling potentially guide treatment of intractable
meningiomas.This article is highlighted in the In This Issue feature, p. 1611.