Molecular signatures define BAP1-altered meningioma as a distinct CNS tumor with deregulation of Polycomb repressive complex target genes

Meningiomas are the most common primary intracranial neoplasms, exhibiting diverse patient outcomes. Despite most meningiomas being benign, a significant subset recurs postoperatively, posing substantial treatment challenges. Through an integrative analysis of DNA methylation data from over 10,000 meningioma samples, we identify BAP1-altered meningiomas as a molecularly distinct and biologically aggressive CNS tumor subtype, characterized by recurrent loss of chromosome 3p21 around the BAP1 locus and driven by diverse BAP1-inactivating alterations. While BAP1-altered meningiomas often exhibit rhabdoid morphology, this feature is not exclusive to them and should not serve as a definitive grading criterion. However, progression-free survival analysis indicates that patients with BAP1-driven meningiomas have a prognosis similar to WHO grade 3 meningiomas. Gene expression profiling reveals upregulation of PRC target genes and dysregulated Polycomb signaling, alongside elevated expression in various cellular and growth factor pathways. This molecular portrait of BAP1-altered meningiomas underscores potential pathway-specific therapeutic targets that should be prioritized for future investigation