我们对脑膜瘤分子生物学理解的进步使得预测患者预后和肿瘤复发以及确定治疗设计新靶点的能力显着提高。具体来说，基于 DNA 甲基化的脑膜瘤分类极大地提高了我们对患者进行风险分层的能力，然而，这些 DNA 甲基化特征对脑膜瘤生物学的潜在影响出现了新的问题。本研究利用来自 486 个脑膜瘤样本的 RNA-seq 数据对应于三个脑膜瘤 DNA 甲基化组（Merlin 完整、免疫富集和有丝分裂），然后利用人脑膜瘤细胞系进行体外实验。我们鉴定了脑膜瘤 DNA 甲基化组之间 RNA 剪接的变化，包括与有丝分裂相关的个体剪接事件脑膜瘤并预测肿瘤复发和总体患者预后，并编译一组剪接事件，可以根据 RNA-seq 数据准确预测 DNA 甲基化分类。此外，我们使用 RT-PCR 在患者样本和脑膜瘤细胞系中验证了这些事件。此外，我们还发现了位于 RNA 剪接事件上游的 RNA 结合蛋白和剪接因子的改变，包括过度有丝分裂脑膜瘤中 SRSF1 的上调，我们证明这会驱动替代性 RNA 剪接变化。最后，我们设计了剪接转换反义寡核苷酸来靶向在有丝分裂脑膜瘤中观察到的 NASP 和 MFF 中的 RNA 剪接变化，为基于 RNA 的治疗设计提供了基本原理。RNA 剪接是脑膜瘤表型的重要驱动因素，可用于预测患者，并作为治疗漏洞的潜在利用。© 作者 2024。由牛津大学出版社代表神经肿瘤学会出版。

Advances in our understanding of the molecular biology of meningiomas have led to significant gains in the ability to predict patient prognosis and tumor recurrence and to identify novel targets for therapeutic design. Specifically, classification of meningiomas based on DNA methylation has greatly improved our ability to risk stratify patients, however new questions have arisen in terms of the underlying impact these DNA methylation signatures have on meningioma biology.This study utilizes RNA-seq data from 486 meningioma samples corresponding to three meningioma DNA methylation groups (Merlin-intact, Immune-enriched, and Hypermitotic), followed by in vitro experiments utilizing human meningioma cell lines.We identify alterations in RNA splicing between meningioma DNA methylation groups including individual splicing events that correlate with Hypermitotic meningiomas and predict tumor recurrence and overall patient prognosis and compile a set of splicing events that can accurately predict DNA methylation classification based on RNA-seq data. Furthermore, we validate these events using RT-PCR in patient samples and meningioma cell lines. Additionally, we identify alterations in RNA binding proteins and splicing factors that lie upstream of RNA splicing events, including upregulation of SRSF1 in Hypermitotic meningiomas which we show drives alternative RNA splicing changes. Finally, we design splice switching antisense oligonucleotides to target RNA splicing changes in NASP and MFF observed in Hypermitotic meningiomas, providing a rationale for RNA-based therapeutic design.RNA splicing is an important driver of meningioma phenotypes that can be useful in prognosticating patients and as a potential exploit for therapeutic vulnerabilities.© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.