Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practice.

中文翻译：

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胶质母细胞瘤疾病进展的 DNA 甲基化景观在时间和空间上显示出广泛的异质性。

胶质母细胞瘤的特点是广泛的遗传和转录异质性，但对表观基因组在胶质母细胞瘤疾病进展中的作用知之甚少。在这里，我们使用来自通过国家患者登记处选择的高度注释的临床队列的数据，展示了匹配的原发性和复发性胶质母细胞瘤肿瘤中 DNA 甲基化的基因组规模图。我们在大量常规收集的 FFPE 样本中证明了 DNA 甲基化作图的可行性，并且我们验证了亚硫酸氢盐测序作为一种多用途检测方法，使我们能够推断出所分析的肿瘤样本的一系列不同的遗传、表观遗传和转录特征。基于这些数据，我们确定了原发性肿瘤和复发性肿瘤之间的细微差异，DNA甲基化和肿瘤微环境之间的联系，以及表观遗传肿瘤异质性与患者生存率的关联。总之，本研究为剖析遗传多样性和异质性癌症中的 DNA 甲基化异质性建立了一个开放资源，并证明了为国家队列整合表观基因组学、放射学和数字病理学的可行性，从而利用作为一部分收集的现有样本和数据的常规临床实践。