{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T15:42:05Z","timestamp":1792597325750,"version":"4.5.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T00:00:00Z","timestamp":1744934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius-Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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\u2005=\u200542) 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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 \u201cmeningioma, BAP1-altered.\u201d<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/neuonc\/noaf105","type":"journal-article","created":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T08:14:21Z","timestamp":1744964061000},"page":"2326-2340","source":"Crossref","is-referenced-by-count":16,"title":["Molecular signatures define <i>BAP1<\/i>-altered meningioma as a distinct CNS tumor with deregulation of Polycomb repressive complex target genes"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3237-6021","authenticated-orcid":false,"given":"Philipp","family":"Sievers","sequence":"first","affiliation":[{"name":"Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ) , Heidelberg ,","place":["Germany"]},{"name":"Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg , Heidelberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonali","family":"Arora","sequence":"additional","affiliation":[{"name":"Human Biology Division, Fred Hutchinson Cancer Center , Seattle, WA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Hielscher","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, German Cancer Research Center (DKFZ) , Heidelberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilan","family":"Savran","sequence":"additional","affiliation":[{"name":"Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ) , Heidelberg ,","place":["Germany"]},{"name":"Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg , Heidelberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Schrimpf","sequence":"additional","affiliation":[{"name":"Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ) , Heidelberg ,","place":["Germany"]},{"name":"Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg , Heidelberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rouzbeh","family":"Banan","sequence":"additional","affiliation":[{"name":"Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ) , Heidelberg ,","place":["Germany"]},{"name":"Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg , Heidelberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Vonh\u00f6ren","sequence":"additional","affiliation":[{"name":"Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ) , Heidelberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3407-4249","authenticated-orcid":false,"given":"Stefan","family":"Pusch","sequence":"additional","affiliation":[{"name":"Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ) , Heidelberg ,","place":["Germany"]},{"name":"Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg , Heidelberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7616-7665","authenticated-orcid":false,"given":"Martin","family":"Sill","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ) , Heidelberg ,","place":["Germany"]},{"name":"Hopp Children\u2019s Cancer Center Heidelberg (KiTZ) , Heidelberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Appay","sequence":"additional","affiliation":[{"name":"Institute of Neurophysiopathol, CNRS, INP, Aix-Marseille University , Marseille ,","place":["France"]},{"name":"Department of Pathology and Neuropathology, APHM , CHU Timone, Marseille 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,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Till","family":"Acker","sequence":"additional","affiliation":[{"name":"Department of Pathology, Klinikum Stuttgart , Stuttgart ,","place":["Germany"]},{"name":"Institute of Neuropathology, Justus-Liebig University Giessen , Giessen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Kohlhof-Meinecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonille","family":"Schweizer","sequence":"additional","affiliation":[{"name":"Frankfurt Cancer Institute (FCI) , Frankfurt am Main ,","place":["Germany"]},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt\/Mainz, German Cancer Research Center (DKFZ) , Heidelberg ,","place":["Germany"]},{"name":"Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University , Frankfurt am Main ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika K","family":"Wefers","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Regensburg University Hospital , Regensburg ,","place":["Germany"]},{"name":"Institute of Neuropathology, University Medical Center Hamburg-Eppendorf , Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick N","family":"Harter","sequence":"additional","affiliation":[{"name":"Bavarian Cancer Research Center (BZKF) , 91054, Erlangen ,","place":["Germany"]},{"name":"Center for Neuropathology and Prion Research, Faculty of Medicine LMU Munich, Ludwig-Maximilians-University (LMU) , Munich ,","place":["Germany"]},{"name":"German Cancer Consortium (DKTK), Partner Site Munich, A Partnership Between the DKFZ Heidelberg and the University Hospital of the LMU , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Institute of Pathology, Hannover Medical School (MHH) , Hannover ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudi","family":"Beschorner","sequence":"additional","affiliation":[{"name":"Center for Neuro-Oncology, Comprehensive Cancer Center T\u00fcbingen-Stuttgart, University Hospital T\u00fcbingen, Eberhard-Karls-University T\u00fcbingen , T\u00fcbingen ,","place":["Germany"]},{"name":"Department of Neuropathology, University of T\u00fcbingen, Eberhard-Karls-University T\u00fcbingen , T\u00fcbingen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9168-6209","authenticated-orcid":false,"given":"Jens","family":"Schittenhelm","sequence":"additional","affiliation":[{"name":"Center for 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,","place":["Germany"]},{"name":"Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg , Heidelberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9464-6544","authenticated-orcid":false,"given":"Miriam","family":"Ratliff","sequence":"additional","affiliation":[{"name":"Clinical Cooperation Unit Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ) , Heidelberg ,","place":["Germany"]},{"name":"Neurosurgery Clinic, University Hospital Mannheim , Mannheim ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandro M","family":"Krieg","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Heidelberg University Hospital , Heidelberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6171-634X","authenticated-orcid":false,"given":"Wolfgang","family":"Wick","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital , Heidelberg ,","place":["Germany"]},{"name":"Clinical Cooperation Unit Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ) , Heidelberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T W","family":"Jones","sequence":"additional","affiliation":[{"name":"National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital ,","place":["Germany"]},{"name":"Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) , Heidelberg ,","place":["Germany"]},{"name":"Hopp Children\u2019s Cancer Center Heidelberg (KiTZ) , Heidelberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan M","family":"Pfister","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, University Hospital Heidelberg , Heidelberg ,","place":["Germany"]},{"name":"National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital ,","place":["Germany"]},{"name":"Division of Pediatric Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ) , Heidelberg ,","place":["Germany"]},{"name":"Hopp Children\u2019s Cancer Center Heidelberg (KiTZ) , Heidelberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric C","family":"Holland","sequence":"additional","affiliation":[{"name":"Human Biology Division, Fred Hutchinson Cancer Center , 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