空间转录组分析揭示了涉及脑室下区的异柠檬酸脱氢酶1（IDH1）野生型胶质母细胞瘤中Notch信号通路相关的预后标志物。
Spatial transcriptome analysis reveals Notch pathway-associated prognostic markers in IDH1 wild-type glioblastoma involving the subventricular zone.
作者信息
Jungk Christine, Mock Andreas, Exner Janina, Geisenberger Christoph, Warta Rolf, Capper David, Abdollahi Amir, Friauf Sara, Lahrmann Bernd, Grabe Niels, Beckhove Philipp, von Deimling Andreas, Unterberg Andreas, Herold-Mende Christel
机构信息
Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Department of Neuropathology, Heidelberg University Hospital; CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
出版信息
BMC Med. 2016 Oct 26;14(1):170. doi: 10.1186/s12916-016-0710-7.
BACKGROUND
The spatial relationship of glioblastoma (GBM) to the subventricular zone (SVZ) is associated with inferior patient survival. However, the underlying molecular phenotype is largely unknown. We interrogated an SVZ-dependent transcriptome and potential location-specific prognostic markers.
METHODS
mRNA microarray data of a discovery set (n = 36 GBMs) were analyzed for SVZ-dependent gene expression and process networks using the MetaCore™ workflow. Differential gene expression was confirmed by qPCR in a validation set of 142 IDH1 wild-type GBMs that was also used for survival analysis.
RESULTS
Microarray analysis revealed a transcriptome distinctive of SVZ+ GBM that was enriched for genes associated with Notch signaling. No overlap was found to The Cancer Genome Atlas's molecular subtypes. Independent validation of SVZ-dependent expression confirmed four genes with simultaneous prognostic impact: overexpression of HES4 (p = 0.034; HR 1.55) and DLL3 (p = 0.017; HR 1.61) predicted inferior, and overexpression of NTRK2 (p = 0.049; HR 0.66) and PIR (p = 0.025; HR 0.62) superior overall survival (OS). Additionally, overexpression of DLL3 was predictive of shorter progression-free survival (PFS) (p = 0.043; HR 1.64). Multivariate analysis revealed overexpression of HES4 to be independently associated with inferior OS (p = 0.033; HR 2.03), and overexpression of DLL3 with inferior PFS (p = 0.046; HR 1.65).
CONCLUSIONS
We identified four genes with SVZ-dependent expression and prognostic significance, among those HES4 and DLL3 as part of Notch signaling, suggesting further evaluation of location-tailored targeted therapies.
背景
胶质母细胞瘤（GBM）与脑室下区（SVZ）的空间关系与患者较差的生存率相关。然而，其潜在的分子表型在很大程度上尚不清楚。我们研究了一种依赖SVZ的转录组和潜在的位置特异性预后标志物。
方法
使用MetaCore™工作流程分析了一个发现集（n = 36个GBM）的mRNA微阵列数据，以确定依赖SVZ的基因表达和过程网络。通过qPCR在142个IDH1野生型GBM的验证集中确认差异基因表达，该验证集也用于生存分析。
结果
微阵列分析揭示了一种SVZ + GBM独特的转录组，该转录组富含与Notch信号相关的基因。未发现与癌症基因组图谱的分子亚型有重叠。对依赖SVZ的表达进行独立验证，确认了四个具有同时预后影响的基因：HES4（p = 0.034；HR 1.55）和DLL3（p = 0.017；HR 1.61）的过表达预示较差的总体生存率（OS），而NTRK2（p = 0.049；HR 0.66）和PIR（p = 0.025；HR 0.62）的过表达预示较好的总体生存率。此外，DLL3的过表达预示无进展生存期（PFS）较短（p = 0.043；HR 1.64）。多变量分析显示，HES4的过表达与较差的OS独立相关（p = 0.033；HR 2.03），而DLL3的过表达与较差的PFS独立相关（p = 0.046；HR 1.65）。
结论
我们鉴定出四个具有依赖SVZ表达和预后意义的基因，其中HES4和DLL3作为Notch信号的一部分，提示进一步评估针对特定位置的靶向治疗。
Zotero 插件