Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas.
Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas.
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DOI：
10.1126/scitranslmed.aah6904
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发表时间：
2016-11-23
影响因子：
17.1
通讯作者：
Venneti S
中科院分区：
文献类型：
--
作者：
Bayliss J;Mukherjee P;Lu C;Jain SU;Chung C;Martinez D;Sabari B;Margol AS;Panwalkar P;Parolia A;Pekmezci M;McEachin RC;Cieslik M;Tamrazi B;Garcia BA;La Rocca G;Santi M;Lewis PW;Hawkins C;Melnick A;David Allis C;Thompson CB;Chinnaiyan AM;Judkins AR;Venneti S
儿童后颅窝（PF）室管膜瘤导致大量的发病率和死亡率。这些肿瘤缺乏复发性基因突变，但这些室管膜瘤的子集表现出CpG岛（CpGi）高甲基化（PF组A; PFA），其发病机制涉及表观遗传学改变。此外，组织学分级不能可靠地预测预后，突出了开发更稳健的预后标志物的重要性。我们发现这些肿瘤的一个子集（PF-ve室管膜瘤）中的H3 K27 me 3总体减少，类似于H3 K27 M突变型胶质瘤。PF-ve肿瘤与PFA室管膜瘤具有许多临床和生物学相似性。基因组H3 K27 me 3分布与CpGi甲基化呈负相关，表明CpGi高甲基化导致PF-ve室管膜瘤中H3 K27 me 3水平降低。尽管CpG 1高甲基化和整体H3 K27 me 3减少，这些肿瘤在基因组的其余部分显示DNA低甲基化，并在有限的基因组位点表现出增加的H3 K27 me 3基因组富集，类似于H3 K27 M突变神经胶质瘤。PF-ve室管膜瘤与H3 K27 M胶质瘤的综合分析揭示了控制放射状胶质细胞生物学的选择因子的常见表观遗传失调，并且人类早期发育中的PF放射状胶质细胞表现出减少的H3 K27 me 3。最后，H3 K27 me 3免疫染色作为预后不良的生物标志物，并描绘放射学浸润性肿瘤，表明减少H3 K27 me 3可能是PF室管膜瘤的预后指标。
Childhood posterior fossa (PF) ependymomas cause substantial morbidity and mortality. These tumors lack recurrent genetic mutations but a subset of these ependymomas exhibit CpG-island (CpGi) hypermethylation (PF group A; PFA), implicating epigenetic alterations in their pathogenesis. Further, histological grade does not reliably predict prognosis, highlighting the importance of developing more robust prognostic markers. We discovered global H3K27me3 reduction in a subset of these tumors (PF−ve ependymomas) analogous to H3K27M mutant gliomas. PF−ve tumors exhibited many clinical and biological similarities with PFA ependymomas. Genomic H3K27me3 distribution showed an inverse relationship with CpGi methylation, suggesting that CpGi hypermethylation drives low H3K27me3 in PF−ve ependymomas. Despite CpGi hypermethylation and global H3K27me3 reduction, these tumors showed DNA hypomethylation in the rest of the genome and exhibited increased H3K27me3 genomic enrichment at limited genomic loci similar to H3K27M mutant gliomas. Combined integrative analysis of PF−ve ependymomas with H3K27M gliomas uncovered common epigenetic deregulation of select factors that control radial glial biology, and PF radial glia in early human development exhibited reduced H3K27me3. Finally, H3K27me3 immunostaining served as a biomarker of poor prognosis and delineated radiologically invasive tumors, suggesting that reduced H3K27me3 may be a prognostic indicator in PF ependymomas.
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