PURPOSE Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization. EXPERIMENTAL DESIGN PDXs were established from glioblastoma, IDH-wildtype (n = 93), glioblastoma, IDH-mutant (n = 2), diffuse midline glioma, H3 K27M-mutant (n = 1), and both primary (n = 60) and recurrent (n = 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES, n = 83), RNA-sequencing (n = 68), and genome-wide methylation profiling (n = 76). WES data from 24 patient tumors was compared with derivative models. RESULTS PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show characteristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of TERT, EGFR, PTEN, TP53, BRAF, and IDH1, most at frequencies comparable with human glioblastoma. However, PDGFRA amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes. MGMT promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including EGFR amplification. However, in four patient-PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection. CONCLUSIONS Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.

中文翻译：

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患者来源的异种移植物的广泛基因组和表型表征反映了胶质母细胞瘤的多样性。

目的胶质母细胞瘤是最常见和致命的原发性脑肿瘤。新疗法的开发依赖于相关临床前模型的可用性。我们建立了一个由96个胶质母细胞瘤患者衍生的异种移植物（PDX）组成的小组，并对其进行了基因组和表型鉴定。实验设计PDXs是由胶质母细胞瘤，IDH野生型（n = 93），胶质母细胞瘤，IDH突变（n = 2），弥漫性中线神经胶质瘤，H3 K27M突变（n = 1）和原发性（n = 60）建立的和复发性（n = 34）肿瘤。表征肿瘤生长速率，组织病理学和治疗反应。通过全外显子组测序（WES，n = 83），RNA测序（n = 68）和全基因组范围的甲基化分布（n = 76）进行整合的分子谱分析。将来自24个患者肿瘤的WES数据与衍生模型进行了比较。结果PDX概括了患者肿瘤的许多关键表型和分子特征。原位PDX显示出特征性的肿瘤形态和侵袭模式，但是在很大程度上缺乏微血管的增殖和坏死。PDX捕获常见和稀有的分子驱动因子，包括TERT，EGFR，PTEN，TP53，BRAF和IDH1的改变，大多数发生在与人类胶质母细胞瘤相当的频率上。但是，没有PDGFRA扩增。RNA测序和全基因组甲基化分析表明胶质母细胞瘤分子亚型的广泛代表。MGMT启动子甲基化与替莫唑胺反应的生存期增加有关。24种匹配的患者肿瘤的WES显示保留了大多数遗传驱动因子改变，包括EGFR扩增。但是，在四对PDX患者中，植入时会增加或丢失驱动程序改变，与克隆选择一致。结论我们的PDX面板捕获了胶质母细胞瘤的分子异质性，并概括了许多显着的遗传和表型特征。所有模型和基因组数据均可向研究人员公开提供。