NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
Faculty of Science, Technology and Communication, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Cancer Res. 2019 Mar 15;79(6):1226-1238. doi: 10.1158/0008-5472.CAN-18-2076. Epub 2019 Jan 23.
Inevitable tumor recurrence and a poor median survival are frustrating reminders of the inefficacy of our current standard of care for patients with newly diagnosed glioblastoma (GBM), which includes surgery followed by radiotherapy and chemotherapy with the DNA alkylating agent temozolomide. Because resistance to genotoxic damage is achieved mainly through execution of the DNA damage response (DDR) and DNA repair pathways, knowledge of the changes in DNA repair and cell-cycle gene expression that occur during tumor development might help identify new targets and improve treatment. Here, we performed a gene expression analysis targeting components of the DNA repair and cell-cycle machineries in cohorts of paired tumor samples (i.e., biopsies from the same patient obtained at the time of primary tumor operation and at recurrence) from patients treated with radiotherapy or radiotherapy plus temozolomide. We identified and validated a 27-gene signature that resulted in the classification of GBM specimens into three groups, two of which displayed inverse expression profiles. Each group contained primary and recurrent samples, and the tumor at relapse frequently displayed a gene expression profile different from that of the matched primary biopsy. Within the groups that exhibited opposing gene expression profiles, the expression pattern of the gene signature at relapse was linked to progression-free survival. We provide experimental evidence that our signature exposes group-specific vulnerabilities against genotoxicants and inhibitors of the cell cycle and DDR, with the prospect of personalized therapeutic strategies. These findings suggest that classification of GBM tumors based on a DNA repair and cell-cycle gene expression signature exposes vulnerabilities to standard-of-care therapies and offers the potential for personalized therapeutic strategies.
新诊断的胶质母细胞瘤（GBM）患者目前的标准治疗包括手术，然后进行放疗和替莫唑胺化疗，然而不可避免的肿瘤复发和较差的中位生存期，令人沮丧地提醒我们，这种治疗方法是无效的。由于对遗传毒性损伤的抗性主要是通过执行 DNA 损伤反应（DDR）和 DNA 修复途径来实现的，因此了解在肿瘤发展过程中 DNA 修复和细胞周期基因表达的变化，可能有助于确定新的靶点并改善治疗效果。在这里，我们针对 DNA 修复和细胞周期机器的组件，对接受放疗或放疗加替莫唑胺治疗的患者的配对肿瘤样本（即，在原发性肿瘤手术时和复发时从同一患者获得的活检）进行了基因表达分析。我们确定并验证了一个由 27 个基因组成的特征签名，该签名可将 GBM 标本分为三组，其中两组显示出相反的表达模式。每组包含原发性和复发性样本，且复发时的肿瘤通常显示出与配对原发性活检不同的基因表达谱。在表现出相反基因表达模式的组中，复发时基因特征的表达模式与无进展生存期相关。我们提供了实验证据，证明我们的特征签名揭示了针对遗传毒性剂和细胞周期和 DDR 抑制剂的特定群体的脆弱性，有望实现个性化的治疗策略。这些发现表明，基于 DNA 修复和细胞周期基因表达特征对 GBM 肿瘤进行分类，可以揭示对标准治疗方法的脆弱性，并为个性化治疗策略提供潜力。
