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Nat Med. 2018 Oct;24(10):1611-1624. doi: 10.1038/s41591-018-0156-x. Epub 2018 Aug 27.

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

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
2
Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
3
Comprehensive Cancer Center, Central Nervous System Tumor Unit, Medical University of Vienna, Vienna, Austria.
4
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
5
Department of Biomedical Imaging and Image-guided Therapy, Computational Imaging Research Lab, Medical University of Vienna, Vienna, Austria.
6
Department of Biomedical Imaging and Image-guided Therapy, Division of Neuroradiology and Musculoskeletal Radiology, Medical University of Vienna, Vienna, Austria.
7
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
8
Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
9
University Medical Center, Neurology, German Cancer Research Center, Heidelberg, Germany.
10
Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.
11
Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria.
12
Department of Neurosurgery, Medical University of Innsbruck, Innsbruck, Austria.
13
Department of Neuroradiology, Medical University of Innsbruck, Innsbruck, Austria.
14
Department of Pathology, University Hospital of St. Poelten, Karl Landsteiner University of Health Sciences, St. Poelten, Austria.
15
Department of Neurology, University Hospital of St. Poelten, Karl Landsteiner University of Health Sciences, St. Poelten, Austria.
16
Department of Neurosurgery, University Hospital of St. Poelten, Karl Landsteiner University of Health Sciences, St. Poelten, Austria.
17
Department of Neuropathology, Neuromed Campus Wagner-Jauregg, Kepler University Hospital, Johannes Kepler University of Linz, Linz, Austria.
18
Department of Neuroradiology, Neuromed Campus Wagner-Jauregg, Kepler University Hospital, Johannes Kepler University of Linz, Linz, Austria.
19
Department of Neurosurgery, Neuromed Campus Wagner-Jauregg, Kepler University Hospital, Johannes Kepler University of Linz, Linz, Austria.
20
Department of Internal Medicine, Neuromed Campus Wagner-Jauregg, Kepler University Hospital, Johannes Kepler University of Linz, Linz, Austria.
21
Diagnostic & Research Center for Molecular BioMedicine, Department of Neuropathology, Institute of Pathology, Medical University of Graz, Graz, Austria.
22
Department of Pathology, Medical Faculty, Otto-von-Guericke University of Magdeburg, Magdeburg, Germany.
23
Department of Neurosurgery, Medical University of Graz, Graz, Austria.
24
Department of Neurology, Medical University of Graz, Graz, Austria.
25
Department of Neurosurgery, Krankenanstalt Rudolfstiftung, Vienna, Austria.
26
Department of Pathology, Krankenanstalt Rudolfstiftung, Vienna, Austria.
27
Department of Neurosurgery, Christian-Doppler-Klinik, Paracelsus Private Medical University, Salzburg, Austria.
28
Department of Neurology, Christian-Doppler-Klinik, Paracelsus Private Medical University, Salzburg, Austria.
29
Institute of Pathology, State Hospital Klagenfurt, Klagenfurt, Austria.
30
Department of Neurology, State Hospital Klagenfurt, Klagenfurt, Austria.
31
Department of Neurosurgery, General Hospital Wiener Neustadt, Wiener Neustadt, Austria.
32
Department of Radiotherapy, Medical University of Vienna, Vienna, Austria.
33
Department of Medicine I, Medical University of Vienna, Vienna, Austria.
34
Comprehensive Cancer Center, Central Nervous System Tumor Unit, Medical University of Vienna, Vienna, Austria. adelheid.woehrer@meduniwien.ac.at.
35
Institute of Neurology, Medical University of Vienna, Vienna, Austria. adelheid.woehrer@meduniwien.ac.at.
36
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
37
Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, Germany.
38
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.

Abstract

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.

PMID:
30150718
PMCID:
PMC6181207
[Available on 2019-10-01]
DOI:
10.1038/s41591-018-0156-x

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