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

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE287322 | GEO | 2025/04/14

REPOSITORIES: GEO

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

Project description:Background: Meningiomas are the most common primary intracranial neoplasms, with highly variable patient outcomes. While most meningiomas are benign, a significant subset recurs postoperatively, presenting substantial treatment challenges. BAP1 gene inactivation has been suggested as a marker for aggressive meningiomas, although its precise molecular and clinical roles remain poorly understood. Methods: To comprehensively investigate BAP1-altered meningiomas, we used six meningiomas with known BAP1 alterations as a discovery set. Genome-wide DNA methylation profiling of these samples, along 11,151 reference meningiomas, identified a distinct molecular cluster (n = 42) using unsupervised visualization approaches. These tumors were further characterized by DNA/RNA sequencing, histopathological examination, and a retrospective review of clinical data, compared to reference meningioma cohorts, providing a thorough characterization of this rare tumor subtype. Results: Our integrative analysis revealed BAP1-altered meningiomas as a distinct CNS tumor subtype, characterized by recurrent loss of chromosome 3p21 and driven by various BAP1-inactivating alterations. Although rhabdoid morphology is present in some cases, it is not exclusive and should not be used as a grading criterion. Progression-free survival analysis showed a median of 21 months (95% CI: 12-NA), with a 2-year overall survival rate of 79% (95% CI: 60%-100%), highlighting the aggressive nature of these tumors. Gene expression profiling revealed upregulation of PRC target genes, dysregulated Polycomb signaling, and elevated expression in several cellular and growth factor pathways. Conclusions: BAP1-altered meningiomas represent a distinct and aggressive CNS tumor subtype associated with PRC dysregulation and recurrent 3p chromosome loss. These findings support the designation "meningioma, BAP1-altered."

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Project description:Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset is of higher grade, recurs even after multiple surgeries, and frequently fatal. Around half of meningiomas harbor inactivating mutations in NF2. While low-grade NF2 mutant meningiomas harbor few additional mutations in addition to NF2 inactivation, high-grade NF2 mutant tumors frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as an oncogene in NF2 mutant meningiomas. Here, we show that high-grade NF2 mutant meningiomas downregulate YAP1 signaling, in part through upregulating the expression of the YAP1 competitor VGLL4 and the YAP1 upstream regulators FAT3/4. Overexpression of VGLL4 resulted in the downregulation of YAP activity and the growth inhibition of low-grade NF2 mutant meningioma cells. Our results have important implications for the efficacy of therapies targeting oncogenic YAP1 in high-grade NF2 mutant meningiomas.

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"Immunogenic subtype" characterised by macrophages infiltration predominantly comprise meningiomas in neurofibromatosis type 2 patients

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Homo sapiens

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