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, 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 Overall design: RNASeq of NF2, BAP1 AND h3k27me3 loss meningioma samples

脑膜瘤是最常见的原发性颅内肿瘤，患者预后存在显著异质性。尽管多数脑膜瘤为良性，但有相当一部分病例会在术后复发，为临床治疗带来严峻挑战。本研究通过对逾10000例脑膜瘤样本的DNA甲基化数据进行整合分析，鉴定出BAP1异常型脑膜瘤为一类分子特征独特、生物学行为具有侵袭性的中枢神经系统肿瘤亚型，其特征为BAP1基因位点附近的3p21染色体区域反复缺失，且由多种BAP1失活性突变驱动。虽然BAP1异常型脑膜瘤常呈现横纹肌样形态，但该特征并非此类肿瘤所特有，不应作为明确的分级判定标准。不过无进展生存分析结果显示，携带BAP1驱动型突变的脑膜瘤患者，其预后与WHO Ⅲ级脑膜瘤患者相当。基因表达谱分析显示，此类肿瘤存在PRC靶基因上调、多梳蛋白（Polycomb）信号通路失调，同时多种细胞因子与生长因子通路的表达水平也出现异常升高。本研究揭示的BAP1异常型脑膜瘤分子特征图谱，明确了潜在的通路特异性治疗靶点，该类靶点应作为未来研究的优先方向。实验整体设计：对携带NF2突变、BAP1突变及H3K27me3缺失的脑膜瘤样本开展RNA测序（RNASeq）