Integrated genomic analyses of de novo pathways underlying atypical meningiomas.
Integrated genomic analyses of de novo pathways underlying atypical meningiomas.
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DOI：
10.1038/ncomms14433
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发表时间：
2017-02-14
影响因子：
16.6
通讯作者：
Günel M
中科院分区：
文献类型：
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作者：
Harmancı AS;Youngblood MW;Clark VE;Coşkun S;Henegariu O;Duran D;Erson-Omay EZ;Kaulen LD;Lee TI;Abraham BJ;Simon M;Krischek B;Timmer M;Goldbrunner R;Omay SB;Baranoski J;Baran B;Carrión-Grant G;Bai H;Mishra-Gorur K;Schramm J;Moliterno J;Vortmeyer AO;Bilgüvar K;Yasuno K;Young RA;Günel M
脑膜瘤大多是良性脑肿瘤，有可能成为非典型或恶性。在综合基因组学、转录组学和表观基因组学分析的基础上，我们比较了良性脑膜瘤和非典型脑膜瘤。在这里，我们发现大多数原发性（新生）非典型脑膜瘤显示NF2缺失，这与基因组不稳定或SMARCB1突变复发同时发生。这些肿瘤具有增加的H3K27me3信号和高甲基化表型，主要占据人胚胎干细胞中的多梳抑制复合物2（PRC2）结合位点，从而表型模仿更原始的细胞状态。与这一观察结果一致，非典型脑膜瘤表现出PRC2复合物的催化亚基EZH2以及E2F2和FOXM1转录网络的上调。重要的是，这些原发性非典型脑膜瘤不含有TERT启动子突变，而这种突变在从良性肿瘤进展的非典型肿瘤中已有报道。我们的研究结果建立了原发性非典型脑膜瘤的基因组图谱和潜在的治疗靶点。脑膜瘤大多是良性脑肿瘤，有可能变成非典型或恶性。在这里，作者表明，原发性非典型脑膜瘤在表观遗传学和遗传学上与良性和进展性肿瘤不同，突出了可能的治疗靶点，如PRC2。
Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state. Consistent with this observation, atypical meningiomas exhibit upregulation of EZH2, the catalytic subunit of the PRC2 complex, as well as the E2F2 and FOXM1 transcriptional networks. Importantly, these primary atypical meningiomas do not harbour TERT promoter mutations, which have been reported in atypical tumours that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas and potential therapeutic targets. Meningiomas are mostly benign brain tumours with the potential for becoming atypical or malignant. Here, the authors show that primary atypical meningiomas are epigenetically and genetically distinct from benign and progressed tumours, highlighting possible therapeutic targets such as PRC2.