Wedemeyer Michelle A, Muskens Ivo, Strickland Ben A, Aurelio Oscar, Martirosian Vahan, Wiemels Joseph L, Weisenberger Daniel J, Wang Kai, Mukerjee Debraj, Rhie Suhn K, Zada Gabriel
Department of Neurosurgery, University of California San Francisco, Benioff Children's Hospitals, San Francisco, California, USA.
Children's Cancer Research Laboratory, Center of Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Neurooncol Adv. 2022 Jun 6;4(1):vdac084. doi: 10.1093/noajnl/vdac084. eCollection 2022 Jan-Dec.
Meningiomas are the most common primary brain tumor. Though typically benign with a low mutational burden, tumors with benign histology may behave aggressively 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.
Whole-exome sequencing and methylation array profiling were performed on 12 dura/meningioma pairs (11 WHO grade I and 1 WHO grade II). Single-nucleotide polymorphism (SNP) genotyping and methylation array profiling were performed on an additional 19 meningiomas (9 WHO grade I, 5 WHO grade II, 4 WHO grade III).
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 increasing histopathologic grade.
These findings support future investigations of the role of epigenetic dysregulation of FOXC1 and cranial patterning genes in meningioma formation as well as studies of the utility of polycomb inhibitors for the treatment of malignant meningiomas.
脑膜瘤是最常见的原发性脑肿瘤。尽管通常为良性且突变负荷低，但组织学良性的肿瘤可能具有侵袭性，且尚无经证实的化疗方法。虽然DNA甲基化模式可区分脑膜瘤亚组，且对肿瘤行为的预测价值高于组织学分类，但对于脑膜瘤与周围正常硬脑膜组织之间DNA甲基化的差异知之甚少。
对12对硬脑膜/脑膜瘤样本（11例世界卫生组织（WHO）I级和1例WHO II级）进行全外显子测序和甲基化阵列分析。对另外19例脑膜瘤（9例WHO I级、5例WHO II级、4例WHO III级）进行单核苷酸多态性（SNP）基因分型和甲基化阵列分析。
通过对脑膜瘤/硬脑膜样本的多模式研究，我们确定了4种不同的DNA甲基化模式。恶性脑膜瘤的弥漫性DNA低甲基化通过无监督聚类很容易将其与低级别肿瘤区分开来。所有聚类以及12/12的脑膜瘤-硬脑膜样本均表现出与颅面模式转录因子FOXC1及其上游长链非编码RNA FOXCUT相关模块的基因启动子低甲基化。此外，我们发现随着组织病理学分级增加，多梳抑制复合物靶启动子的高甲基化程度增加存在表观遗传连续性。
这些发现支持未来对FOXC1和颅面模式基因的表观遗传失调在脑膜瘤形成中的作用进行研究，以及对多梳抑制剂治疗恶性脑膜瘤的效用进行研究。
