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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, 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 men...

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Main Authors: Sievers, Philipp (Author) , Arora, Sonali (Author) , Hielscher, Thomas (Author) , Savran, Dilan (Author) , Schrimpf, Daniel (Author) , Banan, Rouzbeh (Author) , Vonhören, David (Author) , Pusch, Stefan (Author) , Sill, Martin (Author) , Appay, Romain (Author) , Wirsching, Hans-Georg (Author) , Hortobagyi, Tibor (Author) , Dohmen, Hildegard (Author) , Acker, Till (Author) , Kohlhof-Meinecke, Patricia (Author) , Schweizer, Leonille (Author) , Wefers, Annika K. (Author) , Harter, Patrick Nikolaus (Author) , Hartmann, Christian (Author) , Beschorner, Rudi (Author) , Schittenhelm, Jens Florian (Author) , Behling, Felix (Author) , Tabatabai, Ghazaleh (Author) , Mawrin, Christian (Author) , Snuderl, Matija (Author) , Maas, Sybren L. N. (Author) , Wesseling, Pieter (Author) , Brandner, Sebastian (Author) , Korshunov, Andrey (Author) , Ratliff, Miriam (Author) , Krieg, Sandro (Author) , Wick, Wolfgang (Author) , Jones, David T. W. (Author) , Pfister, Stefan (Author) , Holland, Eric C (Author) , Deimling, Andreas von (Author) , Szulzewsky, Frank (Author) , Sahm, Felix (Author)
Format: Article (Journal)
Language:English
Published: September 2025
In: Neuro-Oncology
Year: 2025, Volume: 27, Issue: 9, Pages: 2326-2340
ISSN:1523-5866
DOI:10.1093/neuonc/noaf105
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1093/neuonc/noaf105
Verlag, lizenzpflichtig, Volltext: https://academic.oup.com/neuro-oncology/article/27/9/2326/8116004
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Author Notes:Philipp Sievers, Sonali Arora, Thomas Hielscher, Dilan Savran, Daniel Schrimpf, Rouzbeh Banan, David Vonhören, Stefan Pusch, Martin Sill, Romain Appay, Hans-Georg Wirsching, Tibor Hortobagyi, Hildegard Dohmen, Till Acker, Patricia Kohlhof-Meinecke, Leonille Schweizer, Annika K Wefers, Patrick N Harter, Christian Hartmann, Rudi Beschorner, Jens Schittenhelm, Felix Behling, Ghazaleh Tabatabai, Christian Mawrin, Matija Snuderl, Sybren L N Maas, Pieter Wesseling, Sebastian Brandner, Andrey Korshunov, Miriam Ratliff, Sandro M Krieg, Wolfgang Wick, David T W Jones, Stefan M Pfister, Eric C Holland, Andreas von Deimling, Frank Szulzewsky, Felix Sahm
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Summary: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.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.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.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.”
Item Description:Online veröffentlicht: 18. April 2025
Gesehen am 22.10.2025
Physical Description:Online Resource
ISSN:1523-5866
DOI:10.1093/neuonc/noaf105

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