The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space

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. Genome-wide profiling of DNA methylation levels by RRBS in 499 samples, derived from 217 glioblastoma (IDH wildtype) patients (112 progression cohort, 105 validation cohort), 14 IDH muated brain tumor patients, and 5 normal brain controls. For each patient of the progression cohort samples from at least two and up to six tumor resections are available. For 6 patients multiple regions of each tumor were sampled. For 37 samples matched RNA-seq was performed. For 43 samples matched low-coverage whole genome sequencing was performed. *** Raw data requires controlled access and is deposited at EGAS00001002538 (EGA: https://www.ebi.ac.uk/ega/). Access to raw data can be requested from submitters ***