Longitudinal molecular trajectories of diffuse glioma in adults
Longitudinal molecular trajectories of diffuse glioma in adults
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DOI：
10.1038/s41586-019-1775-1
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发表时间：
2019-12-05
期刊：
影响因子：
64.8
通讯作者：
Verhaak, Roel G. W.
中科院分区：
文献类型：
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作者：
Barthel, Floris P.;Johnson, Kevin C.;Verhaak, Roel G. W.
在弥漫性胶质瘤成人患者中驱动普遍治疗抗性的进化过程仍不清楚（12）。在这里，我们分析了222例成人胶质瘤患者的时间分离的DNA测序数据和匹配的临床注释。通过分析弥漫性胶质瘤三种主要亚型的突变和拷贝数，我们发现在疾病初始阶段检测到的驱动基因在复发时保留，因为几乎没有复发特异性基因改变的证据。烷化剂治疗导致胶质瘤亚型中不同比率的超变表型，超变与总生存率的差异无关。获得性非整倍体经常在复发性胶质瘤中检测到，其特征在于IDH突变，但没有染色体臂1 p/19 q的共缺失，并进一步与细胞周期的获得性改变和不良结局相融合。每个肿瘤的克隆结构随时间推移保持相似，但亚克隆选择的存在与生存率降低相关。最后，初次和复发胶质瘤之间的免疫编辑水平没有差异。总的来说，我们的研究结果表明，最强的选择性压力发生在早期胶质瘤的发展，目前的治疗塑造这种演变在很大程度上是随机的方式。
The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear(12). Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, where as there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar overtime, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrentgliomas. Collectively, our results suggest that the strongest selective pressures occur during earlyglioma development and that current therapies shape this evolution in a largely stochastic manner.