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. 2025 Apr 18:noaf105.
doi: 10.1093/neuonc/noaf105. Online ahead of print.

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

Philipp Sievers  1   2 , Sonali Arora  3 , Thomas Hielscher  4 , Dilan Savran  1   2 , Daniel Schrimpf  1   2 , Rouzbeh Banan  1   2 , David Vonhören  2 , Stefan Pusch  1   2 , Martin Sill  5   6 , Romain Appay  7   8 , Hans-Georg Wirsching  9 , Tibor Hortobagyi  10 , Hildegard Dohmen  11 , Till Acker  11 , Patricia Kohlhof-Meinecke  12 , Leonille Schweizer  13   14   15 , Annika K Wefers  16   17 , Patrick N Harter  18   19   20 , Christian Hartmann  21 , Rudi Beschorner  22   23 , Jens Schittenhelm  22   23 , Felix Behling  23   24   25 , Ghazaleh Tabatabai  23   25 , Christian Mawrin  26 , Matija Snuderl  27 , Sybren L N Maas  28   29 , Pieter Wesseling  30   31 , Sebastian Brandner  32   33 , Andrey Korshunov  1   2 , Miriam Ratliff  34   35 , Sandro M Krieg  36 , Wolfgang Wick  35   37 , David T W Jones  5   38   39 , Stefan M Pfister  5   6   39   40 , Eric C Holland  3 , Andreas von Deimling  1   2 , Frank Szulzewsky  41   42 , Felix Sahm  1   2   39
Affiliations

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

Philipp Sievers et al. Neuro Oncol. .

Abstract

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."

Keywords: BAP1; Chromosome 3p loss; Meningioma; Polycomb signaling; rhabdoid.

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