DNA demethylation is associated with malignant progression of lower-grade gliomas
DNA demethylation is associated with malignant progression of lower-grade gliomas
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DOI：
10.1038/s41598-019-38510-0
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发表时间：
2019-02-13
影响因子：
4.6
通讯作者：
Mukasa, Akitake
中科院分区：
文献类型：
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作者：
Nomura, Masashi;Saito, Kuniaki;Mukasa, Akitake
为了阐明低级别胶质瘤恶性进展的机制，分别对122例、36例和31例胶质瘤使用甲基化阵列、全外显子组测序和RNA测序进行分子分析。该队列包括24对匹配的初始低级别胶质瘤和复发肿瘤，其中大多数显示恶性进展。近一半的IDH突变型胶质母细胞瘤从低级别胶质瘤发展而来，在其相应的初始肿瘤的先前甲基化的基因组区域中表现出特征性的部分DNA去甲基化，其具有胶质瘤CpG岛甲基化表型（G-CIMP）。在这些胶质母细胞瘤中，细胞周期相关基因、RB和PI 3 K-AKT通路基因经常发生改变。值得注意的是，晚期复制结构域显著富集在去甲基化区域，这些区域大多位于非调控区域，这表明恶性转化期间DNA甲基化的丧失可能主要涉及被动去甲基化，这是由于在加速细胞分裂期间甲基化的维持延迟。尽管如此，有限数量的基因，包括IGF 2BP 3，可能驱动细胞增殖，被认为是由于其启动子的去甲基化而上调。我们的数据表明，在复发性胶质瘤的一个子集中发现的G-CIMP谱的去甲基化反映了伴随恶性转化的细胞分裂加速。由这种表观遗传变化激活的致癌基因是潜在的治疗靶点。
To elucidate the mechanisms of malignant progression of lower-grade glioma, molecular profiling using methylation array, whole-exome sequencing, and RNA sequencing was performed for 122, 36 and 31 gliomas, respectively. This cohort included 24 matched pairs of initial lower-grade gliomas and recurrent tumors, most of which showed malignant progression. Nearly half of IDH-mutant glioblastomas that had progressed from lower-grade gliomas exhibited characteristic partial DNA demethylation in previously methylated genomic regions of their corresponding initial tumors, which had the glioma CpG island methylator phenotype (G-CIMP). In these glioblastomas, cell cycle-related genes, RB and PI3K-AKT pathway genes were frequently altered. Notably, late-replicating domain was significantly enriched in the demethylated regions that were mostly located in non-regulatory regions, suggesting that the loss of DNA methylation during malignant transformation may involve mainly passive demethylation due to a delay in maintenance of methylation during accelerated cell division. Nonetheless, a limited number of genes including IGF2BP3, which potentially drives cell proliferation, were presumed to be upregulated due to demethylation of their promoter. Our data indicated that demethylation of the G-CIMP profile found in a subset of recurrent gliomas reflects accelerated cell divisions accompanied by malignant transformation. Oncogenic genes activated by such epigenetic change represent potential therapeutic targets.