Author:
Klughammer Johanna,Kiesel Barbara,Roetzer Thomas,Fortelny Nikolaus,Kuchler Amelie,Sheffield Nathan C.,Datlinger Paul,Peter Nadine,Nenning Karl-Heinz,Furtner Julia,Nowosielski Martha,Augustin Marco,Mischkulnig Mario,Ströbel Thomas,Moser Patrizia,Freyschlag Christian F.,Kerschbaumer Johannes,Thomé Claudius,Grams Astrid E.,Stockhammer Günther,Kitzwoegerer Melitta,Oberndorfer Stefan,Marhold Franz,Weis Serge,Trenkler Johannes,Buchroithner Johanna,Pichler Josef,Haybaeck Johannes,Krassnig Stefanie,Ali Kariem Madhy,Campe Gord von,Payer Franz,Sherif Camillo,Preiser Julius,Hauser Thomas,Winkler Peter A.,Kleindienst Waltraud,Würtz Franz,Brandner-Kokalj Tanisa,Stultschnig Martin,Schweiger Stefan,Dieckmann Karin,Preusser Matthias,Langs Georg,Baumann Bernhard,Knosp Engelbert,Widhalm Georg,Marosi Christine,Hainfellner Johannes A.,Woehrer Adelheid,Bock Christoph
Abstract
AbstractGlioblastoma 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 the DNA methylation dynamics in matched primary and recurring glioblastoma tumors, based on a national population registry and a comprehensively annotated clinical cohort. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected formalin-fixed paraffin-embedded (FFPE) samples, and we validate bisulfite sequencing as a multi-purpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional tumor characteristics. Based on these data, we identified characteristic 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 provides a resource for dissecting DNA methylation heterogeneity in genetically diverse and heterogeneous tumors, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology in a representative national cohort, leveraging samples and data collected as part of routine clinical practice.
Publisher
Cold Spring Harbor Laboratory
Reference78 articles.
1. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013
2. Ferlay, J.S. I. ; Ervik, M. ; Forman, D. ; Bray, F. GLOBOCAN 2012 v1.0 Cancer Incidence and Mortality Worldwide. IARC CancerBase No. 11. (IARC press, Lyon, 2017).
3. Glioblastoma survival: has it improved? Evidence from population-based studies;Current Opinion in Neurology,2014
4. Bevacizumab plus Radiotherapy–Temozolomide for Newly Diagnosed Glioblastoma
5. A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma