Comparative analyses identify molecular signature of MRI-classified SVZ-associated glioblastoma
Comparative analyses identify molecular signature of MRI-classified SVZ-associated glioblastoma
复制标题
DOI：
10.1080/15384101.2017.1295186
复制
发表时间：
2017-01-01
期刊：
影响因子：
4.3
通讯作者：
Berger, Mitchel S.
中科院分区：
文献类型：
--
作者：
Lin, Chin-Hsing Annie;Rhodes, Christopher T.;Berger, Mitchel S.
胶质母细胞瘤(GBM)是一种高度侵袭性的脑癌，治疗选择有限。虽然识别导致GBM的基因的努力发现了与不同类型的GBM相关的突变和异常基因表达，但GBM患者通常根据MRI特征进行诊断和分类。因此，我们寻求在MRI分类的同时确定与脑室下区(SVZ)相关的I组和II组原发性GBM的分子代表。由于组I和组II的GBM具有干细胞样特征，我们比较了这两组原代GBM和内源性神经干细胞前体细胞的基因表达谱，揭示了这两种MRI分类的GBM的细胞周期、染色质状态、细胞形态发生和信号通路的失调。在没有IDH突变的情况下，几个与代谢相关的基因在这些亚型的原发GBM中差异表达，提示在肿瘤微环境中发生了代谢重编程。组蛋白赖氨酸甲基转移酶EZH2表达上调，组蛋白赖氨酸去甲基酶KDM2和KDM4表达下调。最后，通过非监督聚类比较，我们在MRI分类的I/II组GBM、来自TCGA的大量GBM亚型和胶质瘤干细胞之间的基因表达谱大数据集中识别出9个共同基因。这些普遍上调的基因在细胞周期、着丝粒组装、染色体分离和有丝分裂进程中具有已知的功能。我们的发现强调了所有GBM中对染色体完整性重要的基因表达的变化，这表明了GBM中染色体结构保真度受损的共同机制。
Glioblastoma (GBM) is a highly aggressive brain cancer with limited therapeutic options. While efforts to identify genes responsible for GBM have revealed mutations and aberrant gene expression associated with distinct types of GBM, patients with GBM are often diagnosed and classified based on MRI features. Therefore, we seek to identify molecular representatives in parallel with MRI classification for group I and group II primary GBM associated with the subventricular zone (SVZ). As group I and II GBM contain stem-like signature, we compared gene expression profiles between these 2 groups of primary GBM and endogenous neural stem progenitor cells to reveal dysregulation of cell cycle, chromatin status, cellular morphogenesis, and signaling pathways in these 2 types of MRI-classified GBM. In the absence of IDH mutation, several genes associated with metabolism are differentially expressed in these subtypes of primary GBM, implicating metabolic reprogramming occurs in tumor microenvironment. Furthermore, histone lysine methyltransferase EZH2 was upregulated while histone lysine demethylases KDM2 and KDM4 were downregulated in both group I and II primary GBM. Lastly, we identified 9 common genes across large data sets of gene expression profiles among MRI-classified group I/II GBM, a large cohort of GBM subtypes from TCGA, and glioma stem cells by unsupervised clustering comparison. These commonly upregulated genes have known functions in cell cycle, centromere assembly, chromosome segregation, and mitotic progression. Our findings highlight altered expression of genes important in chromosome integrity across all GBM, suggesting a common mechanism of disrupted fidelity of chromosome structure in GBM.