Integrated genomic characterization of IDH1-mutant glioma malignant progression.
Integrated genomic characterization of IDH1-mutant glioma malignant progression.
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DOI：
10.1038/ng.3457
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发表时间：
2016-01
期刊：
影响因子：
30.8
通讯作者：
Günel M
中科院分区：
文献类型：
--
作者：
Bai H;Harmancı AS;Erson-Omay EZ;Li J;Coşkun S;Simon M;Krischek B;Özduman K;Omay SB;Sorensen EA;Turcan Ş;Bakırcığlu M;Carrión-Grant G;Murray PB;Clark VE;Ercan-Sencicek AG;Knight J;Sencar L;Altınok S;Kaulen LD;Gülez B;Timmer M;Schramm J;Mishra-Gorur K;Henegariu O;Moliterno J;Louvi A;Chan TA;Tannheimer SL;Pamir MN;Vortmeyer AO;Bilguvar K;Yasuno K;Günel M
神经胶质瘤约占所有中枢神经系统肿瘤的 30% 和恶性脑肿瘤的 80%。为了了解 IDH1（编码异柠檬酸脱氢酶 1）突变的低级别神经胶质瘤恶性进展的分子机制，我们研究了 41 名患者的配对肿瘤样本，将较高级别、进展的样本与较低级别的样本进行比较。综合基因组分析，包括全外显子组测序和拷贝数、基因表达和 DNA 甲基化分析，证明了原始肿瘤的非线性克隆扩张，并确定了驱动进展的致癌途径。这些包括激活 MYC 和 RTK-RAS-PI3K 通路、上调 FOXM1 和 E2F2 介导的细胞周期转变，以及人类胚胎干细胞中 Polycomb 抑制复合物 2 结合的发育转录因子基因的表观遗传沉默。我们的结果不仅提供了对驱动神经胶质瘤进展的遗传和表观遗传机制的机制见解，而且还确定了溴结构域和外末端（BET）家族的抑制作为一种潜在的治疗方法。
Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.