Copy number profiling across glioblastoma populations has implications for clinical trial design
Copy number profiling across glioblastoma populations has implications for clinical trial design
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DOI：
10.1093/neuonc/noy108
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发表时间：
2018-10-01
期刊：
影响因子：
15.9
通讯作者：
Holland, Eric C.
中科院分区：
文献类型：
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作者：
Cimino, Patrick J.;McFerrin, Lisa;Holland, Eric C.
背景拷贝数改变形成胶质母细胞瘤的预后分子亚型，在中位总生存期方面具有明显差异。在这项研究中，我们利用来自几个胶质母细胞瘤队列的分子数据来确定随机队列以及具有选择偏倚的队列中拷贝数亚型的分布，这些队列对具有固有更好结局的患者具有选择偏倚。建立了4个胶质母细胞瘤患者队列的拷贝数亚型频率。两个随机选择的队列包括癌症基因组图谱（TCGA）和德国胶质瘤网络（GGN）。两个更具选择性的队列包括在新诊断的胶质母细胞瘤老年患者中进行的II期试验ARTE和一个多机构队列，该队列专注于配对切除的初始/复发胶质母细胞瘤。配对的初始/复发队列也有可用的外显子组数据，这允许进行多维尺度分析的评估。较小的选择性胶质母细胞瘤队列富集了与更好的生存相关的拷贝数亚型，反映了选择那些表现足够好以进入临床试验或被认为足够好以在复发时接受切除的患者。将外显子组数据添加到拷贝数数据提供了反映结果的额外数据。弥漫性神经胶质瘤患者的总体预后是通过初次肿瘤切除时的DNA结构预测的。胶质母细胞瘤人群中分子特征的变化反映了临床试验中患者选择的固有偏差，即更长的生存期。因此，在招募患者进行临床试验时，包括分子谱分析（包括拷贝数）可能很重要，以便平衡组并外推与一般胶质母细胞瘤人群的相关性。
Background. Copy number alterations form prognostic molecular subtypes of glioblastoma with clear differences in median overall survival. In this study, we leverage molecular data from several glioblastoma cohorts to define the distribution of copy number subtypes across random cohorts as well as cohorts with selection biases for patients with inherently better outcome.Methods. Copy number subtype frequency was established for 4 glioblastoma patient cohorts. Two randomly selected cohorts include The Cancer Genome Atlas (TCGA) and the German Glioma Network (GGN). Two more selective cohorts include the phase II trial ARTE in elderly patients with newly diagnosed glioblastoma and a multiinstitutional cohort focused on paired resected initial/recurrent glioblastoma. The paired initial/recurrent cohort also had exome data available, which allowed for evaluation of multidimensional scaling analysis.Results. Smaller selective glioblastoma cohorts are enriched for copy number subtypes that are associated with better survival, reflecting the selection of patients who do well enough to enter a clinical trial or who are deemed well enough to undergo resection at recurrence. Adding exome data to copy number data provides additional data reflective of outcome.Conclusions. The overall outcome for diffuse glioma patients is predicted by DNA structure at initial tumor resection. Molecular signature shifts across glioblastoma populations reflect the inherent bias of patient selection toward longer survival in clinical trials. Therefore it may be important to include molecular profiling, including copy number, when enrolling patients for clinical trials in order to balance arms and extrapolate relevance to the general glioblastoma population.