Department of Neurosurgery, Nagoya University School of Medicine, Japan.
Cancer Sci. 2012 Oct;103(10):1871-9. doi: 10.1111/j.1349-7006.2012.02377.x. Epub 2012 Aug 7.
Recent gene expression and copy number profilings of glioblastoma multiforme (GBM) by The Cancer Genome Atlas (TCGA) Research Network suggest the existence of distinct subtypes of this tumor. However, these approaches might not be easily applicable in routine clinical practice. In the current study, we aimed to establish a proteomics-based subclassification of GBM by integrating their genomic and epigenomic profiles. We subclassified 79 newly diagnosed GBM based on expression patterns determined by comprehensive immunohistochemical observation in combination with their DNA copy number and DNA methylation patterns. The clinical relevance of our classification was independently validated in TCGA datasets. Consensus clustering identified the four distinct GBM subtypes: Oligodendrocyte Precursor (OPC) type, Differentiated Oligodendrocyte (DOC) type, Astrocytic Mesenchymal (AsMes) type and Mixed type. The OPC type was characterized by highly positive scores of Olig2, PDGFRA, p16, p53 and synaptophysin. In contrast, the AsMes type was strongly associated with strong expressions of nestin, CD44 and podoplanin, with a high glial fibrillary acidic protein score. The median overall survival of OPC-type patients was significantly longer than that of the AsMes-type patients (19.9 vs 12.8 months). This finding was in agreement with the Oncomine analysis of TCGA datasets, which revealed that PDGFRA and Olig2 were favorable prognostic factors and podoplanin and CD44 were associated with a poor clinical outcome. This is the first study to establish a subclassification of GBM on the basis of immunohistochemical analysis. Our study will shed light on personalized therapies that might be feasible in daily neuropathological practice.
最近，癌症基因组图谱（TCGA）研究网络对胶质母细胞瘤（GBM）进行了基因表达和拷贝数分析，提示这种肿瘤存在不同的亚型。然而，这些方法在常规临床实践中可能不容易应用。在本研究中，我们旨在通过整合基因组和表观基因组谱，建立基于蛋白质组学的 GBM 亚分类。我们根据综合免疫组织化学观察确定的表达模式，结合 DNA 拷贝数和 DNA 甲基化模式，对 79 例新诊断的 GBM 进行了分类。我们的分类在 TCGA 数据集中进行了独立验证。一致性聚类确定了四种不同的 GBM 亚型：少突胶质前体细胞（OPC）型、分化型少突胶质细胞（DOC）型、星形胶质细胞间充质（AsMes）型和混合型。OPC 型的特点是 Olig2、PDGFRA、p16、p53 和突触素的高阳性评分。相比之下，AsMes 型与 nestin、CD44 和 podoplanin 的强烈表达密切相关，具有较高的神经胶质纤维酸性蛋白评分。OPC 型患者的中位总生存期明显长于 AsMes 型患者（19.9 个月比 12.8 个月）。这一发现与 TCGA 数据集的 Oncomine 分析一致，该分析显示 PDGFRA 和 Olig2 是有利的预后因素，而 podoplanin 和 CD44 与不良的临床结局相关。这是第一项基于免疫组织化学分析建立 GBM 亚分类的研究。我们的研究将为可能在日常神经病理实践中可行的个性化治疗提供启示。
