Division of Genetics, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
Neoplasia. 2010 Feb;12(2):183-91. doi: 10.1593/neo.91752.
The absence of biological markers allowing for the assessment of the evolution and prognosis of glioblastoma (GBM) is a major impediment to the clinical management of GBM patients. The observed variability in patients' treatment responses and in outcomes implies biological heterogeneity and the existence of unidentified patient categories. Here, we define for the first time three GBM patient categories with distinct and clinically predictive three-dimensional nuclear-telomeric architecture defined by telomere number, size, and frequency of telomeric aggregates. GBM patient samples were examined by three-dimensional fluorescent in situ hybridization of telomeres using two independent three-dimensional telomere-measurement tools (TeloView program [P(1)] and SpotScan system [P(2)]). These measurements identified three patients categories (categories 1-3), displaying significant differences in telomere numbers/nucleus (P(1) = .0275; P(2) <or= .0001), telomere length (P(1) and P(2) = .0275), and number of telomeric aggregates (P(1) = .0464; P(2) <or= .0001). These categories corresponded to patients with long-term, intermediate, and short-term survival, respectively (P = .0393). The time to progression analyses showed significant differences between the three categories (P = .0167). There was a correlation between time to progression, median survival, and nuclear telomere architecture. Our study suggests a link between patient outcome and three-dimensional nuclear-telomere organization and highlights the potential clinical power of telomere signatures as a new prognostic, predictive, and potentially pharmacodynamic biomarker in GBM. Furthermore, novel automated three-dimensional high-throughput scanning as developed here permits to obtain data from 300 nuclei in 20 minutes. This method is applicable to any cell type and scanning application.
目前缺乏能够评估胶质母细胞瘤（GBM）进展和预后的生物学标志物，这是GBM 临床治疗的主要障碍。患者对治疗的反应和结局存在可变性，这意味着存在生物学异质性和未被识别的患者亚类。在这里，我们首次定义了三种 GBM 患者类别，它们具有不同的、具有临床预测性的三维核端粒结构，由端粒数量、大小和端粒聚集的频率定义。通过使用两种独立的三维端粒测量工具（TeloView 程序[P(1)]和 SpotScan 系统[P(2)])对 GBM 患者样本进行端粒的三维荧光原位杂交检测。这些测量方法确定了三种患者类别（类别 1-3），它们在端粒数量/核（P(1) =.0275；P(2) <or=.0001）、端粒长度（P(1)和 P(2) =.0275）和端粒聚集数量（P(1) =.0464；P(2) <or=.0001）方面存在显著差异。这些类别分别对应于长期、中期和短期生存的患者（P =.0393）。进展时间分析显示这三个类别之间存在显著差异（P =.0167）。在三个类别之间存在时间进展、中位生存和核端粒结构之间的相关性。我们的研究表明患者结局与三维核端粒组织之间存在联系，并强调了端粒特征作为新的预后、预测和潜在药效学生物标志物在 GBM 中的潜在临床价值。此外，这里开发的新型自动化三维高通量扫描可以在 20 分钟内从 300 个核中获取数据。该方法适用于任何细胞类型和扫描应用。
