Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway.
Cancer Res. 2021 Nov 1;81(21):5401-5412. doi: 10.1158/0008-5472.CAN-21-0730. Epub 2021 Sep 7.
Glioblastoma is an aggressive cancer of the brain and spine. While analysis of glioblastoma 'omics data has somewhat improved our understanding of the disease, it has not led to direct improvement in patient survival. Cancer survival is often characterized by differences in gene expression, but the mechanisms that drive these differences are generally unknown. We therefore set out to model the regulatory mechanisms associated with glioblastoma survival. We inferred individual patient gene regulatory networks using data from two different expression platforms from The Cancer Genome Atlas. We performed comparative network analysis between patients with long- and short-term survival. Seven pathways were identified as associated with survival, all of them involved in immune signaling; differential regulation of PD1 signaling was validated to correspond with outcome in an independent dataset from the German Glioma Network. In this pathway, transcriptional repression of genes for which treatment options are available was lost in short-term survivors; this was independent of mutational burden and only weakly associated with T-cell infiltration. Collectively, these results provide a new way to stratify patients with glioblastoma that uses network features as biomarkers to predict survival. They also identify new potential therapeutic interventions, underscoring the value of analyzing gene regulatory networks in individual patients with cancer. SIGNIFICANCE: Genome-wide network modeling of individual glioblastomas identifies dysregulation of PD1 signaling in patients with poor prognosis, indicating this approach can be used to understand how gene regulation influences cancer progression.
胶质母细胞瘤是一种侵袭性的脑和脊柱癌症。虽然对胶质母细胞瘤的“组学”数据的分析在一定程度上提高了我们对这种疾病的认识,但并没有直接提高患者的生存率。癌症的生存通常以基因表达的差异为特征,但驱动这些差异的机制通常是未知的。因此,我们着手建立与胶质母细胞瘤生存相关的调控机制模型。我们使用来自癌症基因组图谱的两个不同表达平台的数据来推断个体患者的基因调控网络。我们对长期和短期生存患者的网络进行了比较分析。确定了七个与生存相关的途径,它们都涉及免疫信号;在独立的德国神经胶质瘤网络数据集验证了 PD1 信号的差异调节与结果相关。在该途径中,短期存活者中可治疗的基因的转录抑制丢失;这与突变负担无关,仅与 T 细胞浸润有微弱关联。总之,这些结果为胶质母细胞瘤患者提供了一种新的分层方法,该方法将网络特征用作预测生存的生物标志物。它们还确定了新的潜在治疗干预措施,强调了在癌症患者中分析基因调控网络的价值。意义:对个体胶质母细胞瘤的全基因组网络建模确定了 PD1 信号在预后不良患者中的失调,表明这种方法可用于了解基因调控如何影响癌症进展。
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