Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations.
Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations.
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DOI：
10.1371/journal.pone.0007752
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发表时间：
2009-11-13
期刊：
影响因子：
3.7
通讯作者：
Holland E
中科院分区：
文献类型：
--
作者：
Brennan C;Momota H;Hambardzumyan D;Ozawa T;Tandon A;Pedraza A;Holland E
多形性胶质母细胞瘤(GBM)是一个伞形名称，包括一组不同类型的原发脑肿瘤。已经报道了几种基底膜的分类策略，一些是根据临床病程进行的，另一些是根据成人或发育过程中的细胞类型进行分类的。从实用和治疗的角度来看，根据信号转导通路的激活和通路成员基因的突变来分类基底膜对于靶向治疗的发展可能特别有价值。我们对27个胶质瘤手术标本进行了有针对性的蛋白质组学分析，以确定胶质瘤相关信号转导通路之间的协同激活模式，然后将这些结果与来自癌症基因组图谱(TCGA)的243个GBM样本的基因组和表达数据进行综合分析。在信号模式中，出现了三个GBM亚类，它们似乎与EGFR激活、PDGFR激活或RAS调节因子NF1的缺失有关。通过检测Notch配体、裂解的Notch受体和下游靶标Hes1的表达，EGFR信号通路具有显著的Notch通路激活。PDGF型表现为高水平的PDGFB配体和PDGFFR、β和NFKb的磷酸化。NF1缺失与MAPK和PI3K活性降低以及间充质标志物YKL40相对过表达有关。这三个信号类别似乎对应于来自TCGA的原始GBM样本的不同转录亚类，其中拷贝数异常和EGFR、PDGFRA和NF1的突变是标志性事件。对GBM样本的蛋白质组学分析显示，在胶质瘤相关信号通路中，蛋白质的表达和激活有三种模式。这三个类别由大致相等的数字组成，显示与受体扩增和突变相关的EGFR激活，主要由配体驱动的PDGF途径激活，或NF1表达的丧失。与这些前哨改变相关的信号活动提供了对胶质瘤生物学和治疗策略的洞察。
Glioblastoma multiforme (GBM) is an umbrella designation that includes a heterogeneous group of primary brain tumors. Several classification strategies of GBM have been reported, some by clinical course and others by resemblance to cell types either in the adult or during development. From a practical and therapeutic standpoint, classifying GBMs by signal transduction pathway activation and by mutation in pathway member genes may be particularly valuable for the development of targeted therapies. We performed targeted proteomic analysis of 27 surgical glioma samples to identify patterns of coordinate activation among glioma-relevant signal transduction pathways, then compared these results with integrated analysis of genomic and expression data of 243 GBM samples from The Cancer Genome Atlas (TCGA). In the pattern of signaling, three subclasses of GBM emerge which appear to be associated with predominance of EGFR activation, PDGFR activation, or loss of the RAS regulator NF1. The EGFR signaling class has prominent Notch pathway activation measured by elevated expression of Notch ligands, cleaved Notch receptor, and downstream target Hes1. The PDGF class showed high levels of PDGFB ligand and phosphorylation of PDGFRβ and NFKB. NF1-loss was associated with lower overall MAPK and PI3K activation and relative overexpression of the mesenchymal marker YKL40. These three signaling classes appear to correspond with distinct transcriptomal subclasses of primary GBM samples from TCGA for which copy number aberration and mutation of EGFR, PDGFRA, and NF1 are signature events. Proteomic analysis of GBM samples revealed three patterns of expression and activation of proteins in glioma-relevant signaling pathways. These three classes are comprised of roughly equal numbers showing either EGFR activation associated with amplification and mutation of the receptor, PDGF-pathway activation that is primarily ligand-driven, or loss of NF1 expression. The associated signaling activities correlating with these sentinel alterations provide insight into glioma biology and therapeutic strategies.
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DOI：
10.1073/pnas.0710052104
发表时间：
2007-12-11
影响因子：
11.1
作者：
Beroukhim, Rameen;Getz, Gad;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
11.5
作者：
Fomchenko, Elena I.;Holland, Eric C.
通讯作者：
Holland, Eric C.
影响因子：
50.3
作者：
Phillips, HS;Kharbanda, S;Aldape, K
通讯作者：
Aldape, K
DOI：
10.1126/science.1164382
发表时间：
2008-09-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Parsons DW;Jones S;Zhang X;Lin JC;Leary RJ;Angenendt P;Mankoo P;Carter H;Siu IM;Gallia GL;Olivi A;McLendon R;Rasheed BA;Keir S;Nikolskaya T;Nikolsky Y;Busam DA;Tekleab H;Diaz LA Jr;Hartigan J;Smith DR;Strausberg RL;Marie SK;Shinjo SM;Yan H;Riggins GJ;Bigner DD;Karchin R;Papadopoulos N;Parmigiani G;Vogelstein B;Velculescu VE;Kinzler KW
通讯作者：
Kinzler KW
影响因子：
2.1
作者：
Olshen, AB;Venkatraman, ES;Wigler, M
通讯作者：
Wigler, M