DNA Methylation Signatures Differentiate Meningiomas from Normal Dura [HumanMethylation450]

Meningiomas are the most common primary brain tumor. Though typically benign with a low mutational burden, histopathologic analysis has poor predictive value for malignant behavior and there are no proven chemotherapies. Although DNA methylation patterns distinguish subgroups of meningiomas and have higher predictive value for tumor behavior than histologic classification, little is known about differences in DNA methylation between meningiomas and surrounding normal dura tissue. Using multimodal studies of meningioma/dura pairs, we identified 4 distinct DNA methylation patterns. Diffuse DNA hypomethylation of malignant meningiomas readily facilitated their identification from lower grade tumors by unsupervised clustering. All clusters and 12/12 meningioma-dura pairs exhibited hypomethylation of the gene promoters of a module associated with the craniofacial patterning transcription factor FOXC1 and its upstream lncRNA FOXCUT. Furthermore, we identified an epigenetic continuum of increasing hypermethylation of polycomb repressive complex target promoters with increased histopathologic grade suggesting progressive epigenetic dysregulation is associated with increasing tumor aggressiveness. These findings are a starting point for future investigations of the role of epigenetic dysregulation of FOXC1 and cranial patterning genes in early stages of meningioma formation as well as studies of the utility of polycomb inhibitors for treatment of aggressive meningiomas. DNA methylation of matched meningioma/dura samples from 12 patients (11 WHO grade I, 1 WHO grade II) and 19 meningiomaswere assessed using Illumina HM450K methylation arrays. Also analyzed including were DNA methylation array data from 19 meningiomas (11 WHO grade I, 6 WHO grade II, and 4 WHO grade III) previously reported in GEO (GSE42882).

脑膜瘤（Meningiomas）是最常见的原发性脑肿瘤。尽管其通常为良性且突变负荷较低，但组织病理学分析对其恶性行为的预测价值有限，且目前尚无经证实有效的化疗方案。虽然DNA甲基化（DNA methylation）谱能够区分脑膜瘤的亚型，且相较于组织学分类对肿瘤行为的预测价值更高，但学界对脑膜瘤与周围正常硬脑膜组织之间的DNA甲基化差异仍知之甚少。本研究通过对脑膜瘤-硬脑膜配对样本进行多模态分析，鉴定出4种独特的DNA甲基化模式。恶性脑膜瘤的弥漫性DNA低甲基化特征可通过无监督聚类（unsupervised clustering）轻松将其与低级别肿瘤区分开来。所有聚类组别以及12对脑膜瘤-硬脑膜配对样本均表现出与颅面模式形成转录因子FOXC1及其上游长链非编码RNA（long non-coding RNA, lncRNA）FOXCUT相关模块的基因启动子低甲基化。此外，本研究发现随着组织病理学分级升高，多梳抑制复合体（Polycomb Repressive Complex）靶基因启动子的高甲基化程度呈表观遗传连续梯度变化，提示进行性表观遗传失调与肿瘤侵袭性增强密切相关。上述研究结果为后续探索FOXC1及颅面模式形成基因的表观遗传失调在脑膜瘤形成早期阶段的作用，以及评估多梳抑制剂治疗侵袭性脑膜瘤的应用价值提供了研究起点。本研究对12例患者的配对脑膜瘤-硬脑膜样本（11例为WHO I级，1例为WHO II级）以及19例脑膜瘤样本的DNA甲基化水平进行了检测，检测采用Illumina HM450K甲基化芯片（Illumina HM450K methylation arrays）。本研究同时分析了此前发表于GEO数据库（Gene Expression Omnibus）、编号为GSE42882的19例脑膜瘤样本的DNA甲基化芯片数据，其中包含11例WHO I级、6例WHO II级及4例WHO III级样本。