Enhancer landscape of meningioma

Meningiomas are the most common primary intracranial tumor. However, surgical resection and radiation frequently fail to eliminate high grade tumors, leading to significant morbidity and mortality. Predicting which tumors will recur rapidly is critical to effective treatment strategies. To address the prognostic challenges and dearth of therapeutic targets, we interrogated the enhancer landscape of a diverse cohort of meningiomas. Enhancers robustly stratified meningiomas into three biologically distinct groups and identified a subset of tumors with a poor prognosis, independent of histological grading. Integrating enhancer networks with transcriptional profiles revealed unique lineage transcriptional regulators associated with each subgroup. A strong hormonal epidemiologic association is well-characterized in meningiomas, but mechanistic insight remains lacking. We identified differential hormonal regulators that stratified between subgroups, and implicated progesterone receptor in maintaining the super enhancer network of a subset of tumors. Super enhancers marked critical and druggable dependencies across a panel of meningioma models.