IDH Mutation and Neuroglial Developmental Features Define Clinically Distinct Subclasses of Lower Grade Diffuse Astrocytic Glioma
IDH Mutation and Neuroglial Developmental Features Define Clinically Distinct Subclasses of Lower Grade Diffuse Astrocytic Glioma
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DOI：
10.1158/1078-0432.ccr-11-2977
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发表时间：
2012-05-01
影响因子：
11.5
通讯作者：
Huse, Jason T.
中科院分区：
文献类型：
--
作者：
Gorovets, Daniel;Kannan, Kasthuri;Huse, Jason T.
目的：弥漫性胶质瘤是最常见的原发性脑肿瘤。尽管最近在胶质母细胞瘤[世界卫生组织（WHO）IV]的理解方面取得了重大进展，但其最恶性的亚型、较低级别（WHO II和III）胶质瘤变体仍然相对研究不足，特别是鉴于其显著的临床异质性。因此，我们试图识别和表征低级别弥漫性星形细胞胶质瘤的临床相关分子亚类。实验设计：我们对我们自己机构收集的101例低级别弥漫性星形细胞胶质瘤进行了多维分子分析，包括全球转录分析，并使用来自大型独立患者队列的可获得的基因表达和拷贝数数据验证了我们的发现。我们发现IDH突变状态在分子和临床上描述了不同的胶质瘤亚群，IDH突变型（IDH mt）肿瘤表现出TP 53突变、血小板源性生长因子受体（PDGFR）A过表达和延长的生存期，IDH野生型（IDH wt）肿瘤表现出EGFR扩增、PTEN丢失和不利的疾病结局。此外，全球表达谱显示低级别弥漫性星形细胞胶质瘤中有三个强大的分子亚类，其中两个主要是IDH mt，一个几乎完全是IDH wt。IDH mt亚类根据TP 53突变、DNA拷贝数异常以及与室管膜下区神经发生不同阶段的联系而相互区分。后者的发现暗示离散池的神经胶质祖细胞作为细胞的起源IDH MT tumors.Conclusion的不同亚类的细胞：我们已经阐明了分子不同的亚类较低级别的弥漫性星形胶质细胞胶质瘤，决定临床行为，并显示基本协会与IDH突变状态和神经胶质细胞发育阶段。临床癌症研究; 18（9）; 2490-501。(C)2012年AACR。
Purpose: Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma [World Health Organization (WHO) IV], its most malignant subtype, lower grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notable clinical heterogeneity. Accordingly, we sought to identify and characterize clinically relevant molecular subclasses of lower grade diffuse astrocytic gliomas.Experimental Design: We conducted multidimensional molecular profiling, including global transcriptional analysis, on 101 lower grade diffuse astrocytic gliomas collected at our own institution and validated our findings using publically available gene expression and copy number data from large independent patient cohorts.Results: We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, platelet-derived growth factor receptor (PDGFR) A overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone. This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors.Conclusion: We have elucidated molecularly distinct subclasses of lower grade diffuse astrocytic glioma that dictate clinical behavior and show fundamental associations with both IDH mutational status and neuroglial developmental stage. Clin Cancer Res; 18(9); 2490-501. (C) 2012 AACR.