Mutational patterns and regulatory networks in epigenetic subgroups of meningioma (H033)

DNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign-1, 2, 3, intermediate-A, B and malignant.

Here, we set out to identify subgroup-specific mutational patterns and pathway regulation. Whole-genome-sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic and 22 radiation-induced (Mrad) meningiomas. RNA sequencing was added for 18 cases and chromatin-immunoprecipitation for the enhancer mark H3K27ac followed by sequencing (ChIP-seq) for 16 samples.

Besides the known mutations in meningioma, structural alterations were found to contribute to the spectrum of mechanisms inactivating NF2 in sporadic meningioma similar to previous reports for Mrad. Aberrations of DMD were found to be enriched in MCs with NF2 mutations and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. The mutational signature AC3 was detected in both sporadic meningioma and Mrad, but distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. In general, the malignant MC presented a significantly higher exposure to AC3 and higher genomic instability beyond the mutational load than the other MCs. Pathway analysis of the ChIP-seq clusters revealed that the FOXM1 is most differentially activated in high-grade cases, along with super enhancer recruitment near HOX genes and respective upregulation of expression.

This data further elucidate the biological mechanisms differentiating meningiomas of different WHO grade and epigenetic subgroups and suggest leveraging the genomic instability as novel therapeutic targets.EGA study EGAS00001003481

DNA甲基化模式可界定脑膜瘤的临床相关亚型。我们此前已确立6种脑膜瘤甲基化类别（Meningioma Methylation Classes，MC）：良性1型、2型、3型、中间型A、中间型B以及恶性型。

本研究旨在鉴定亚型特异性的突变模式与通路调控特征。我们对来自62例患者的、覆盖所有MC及WHO分级的62份样本开展全基因组测序，所有样本均匹配外周血对照，其中包括40例散发性脑膜瘤与22例辐射诱导型（Mrad）脑膜瘤。此外，我们对18份样本进行了RNA测序，对16份样本开展了针对增强子标记H3K27ac的染色质免疫沉淀测序（Chromatin Immunoprecipitation Sequencing，ChIP-seq）。

除脑膜瘤已知突变外，我们发现结构变异同样参与散发性脑膜瘤中NF2基因失活的多种机制，这与此前针对辐射诱导型脑膜瘤的研究结果一致。我们观察到，DMD畸变在携带NF2突变的MC中显著富集；与NF2野生型病例相比，DMD是NF2突变型病例中差异上调最显著的基因之一。突变特征AC3在散发性脑膜瘤与辐射诱导型脑膜瘤中均有检出，但在散发病例中呈全基因组分布，而在辐射诱导型病例中则富集于基因组断裂点附近。总体而言，与其他MC相比，恶性MC的AC3突变特征暴露水平显著更高，且除突变负荷外，基因组不稳定性也更强。对ChIP-seq聚类结果的通路分析显示，FOXM1在高级别病例中差异激活最为显著，同时HOX基因附近出现超级增强子募集，且对应基因的表达亦显著上调。

本数据集进一步阐明了区分不同WHO分级脑膜瘤与表观遗传亚型的生物学机制，并提示可将基因组不稳定性作为新型治疗靶点。本研究的EGA编号为EGAS00001003481。