Sievers Philipp, Arora Sonali, Hielscher Thomas, Savran Dilan, Schrimpf Daniel, Banan Rouzbeh, Vonhören David, Pusch Stefan, Sill Martin, Appay Romain, Wirsching Hans-Georg, Hortobagyi Tibor, Dohmen Hildegard, Acker Till, Kohlhof-Meinecke Patricia, Schweizer Leonille, Wefers Annika K, Harter Patrick N, Hartmann Christian, Beschorner Rudi, Schittenhelm Jens, Behling Felix, Tabatabai Ghazaleh, Mawrin Christian, Snuderl Matija, Maas Sybren L N, Wesseling Pieter, Brandner Sebastian, Korshunov Andrey, Ratliff Miriam, Krieg Sandro M, Wick Wolfgang, Jones David T W, Pfister Stefan M, Holland Eric C, von Deimling Andreas, Szulzewsky Frank, Sahm Felix
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Neuro Oncol. 2025 Apr 18. doi: 10.1093/neuonc/noaf105.
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."
脑膜瘤是最常见的原发性颅内肿瘤，患者预后差异很大。虽然大多数脑膜瘤是良性的，但相当一部分在术后会复发，带来了巨大的治疗挑战。BAP1基因失活被认为是侵袭性脑膜瘤的一个标志物，但其确切的分子和临床作用仍知之甚少。
为了全面研究BAP1改变的脑膜瘤，我们使用了6例已知BAP1改变的脑膜瘤作为发现集。对这些样本以及11151例参考脑膜瘤进行全基因组DNA甲基化分析，采用无监督可视化方法确定了一个独特的分子簇（n = 42）。与参考脑膜瘤队列相比，通过DNA/RNA测序、组织病理学检查和临床数据回顾性分析对这些肿瘤进行了进一步特征分析，从而全面表征了这种罕见的肿瘤亚型。
我们的综合分析表明，BAP1改变的脑膜瘤是一种独特的中枢神经系统肿瘤亚型，其特征是3号染色体p21区域反复缺失，并由多种BAP1失活改变驱动。虽然在某些病例中存在横纹肌样形态，但并非独有，不应将其用作分级标准。无进展生存分析显示，中位生存期为21个月（95%CI：12 - 无可用数据），2年总生存率为79%（95%CI：60% - 100%），突出了这些肿瘤的侵袭性。基因表达谱分析显示PRC靶基因上调、多梳信号失调以及多个细胞和生长因子途径表达升高。
BAP1改变的脑膜瘤代表一种独特的侵袭性中枢神经系统肿瘤亚型，与PRC失调和3号染色体反复缺失有关。这些发现支持将其命名为“BAP1改变的脑膜瘤”。
