Linking epigenetic signature and metabolic phenotype in IDH mutant and IDH wildtype diffuse glioma

  • Aims: Changes in metabolism are known to contribute to tumour phenotypes. If and how metabolic alterations in brain tumours contribute to patient outcome is still poorly understood. Epigenetics impact metabolism and mitochondrial function. The aim of this study is a characterisation of metabolic features in molecular subgroups of isocitrate dehydrogenase mutant (IDHmut) and isocitrate dehydrogenase wildtype (IDHwt) gliomas. Methods: We employed DNA methylation pattern analyses with a special focus on metabolic genes, large-scale metabolism panel immunohistochemistry (IHC), qPCR-based determination of mitochondrial DNA copy number and immune cell content using IHC and deconvolution of DNA methylation data. We analysed molecularly characterised gliomas (n = 57) for in depth DNA methylation, a cohort of primary and recurrent gliomas (n = 22) for mitochondrial copy number and validated these results in a large glioma cohort (n = 293). Finally, we investigated the potential of metabolic markers in Bevacizumab (Bev)-treated gliomas (n = 29). Results: DNA methylation patterns of metabolic genes successfully distinguished the molecular subtypes of IDHmut and IDHwt gliomas. Promoter methylation of lactate dehydrogenase A negatively correlated with protein expression and was associated with IDHmut gliomas. Mitochondrial DNA copy number was increased in IDHmut tumours and did not change in recurrent tumours. Hierarchical clustering based on metabolism panel IHC revealed distinct subclasses of IDHmut and IDHwt gliomas with an impact on patient outcome. Further quantification of these markers allowed for the prediction of survival under anti-angiogenic therapy. Conclusion: A mitochondrial signature was associated with increased survival in all analyses, which could indicate tumour subgroups with specific metabolic vulnerabilities.
Author:Yannick Braun, Katharina Johanna FilipskiGND, Simon Bernatz, Peter BaumgartenORCiDGND, Bastian Roller, Jenny Zinke, Pia Susan ZeinerORCiD, Elena Ilina, Christian SenftORCiDGND, Michael Wilfried RonellenfitschORCiDGND, Karl Plate, Oliver Bähr, Elke HattingenORCiDGND, Joachim Peter SteinbachORCiDGND, Michel Mittelbronn, Patrick Nikolaus HarterORCiDGND
Parent Title (English):Neuropathology & applied neurobiology
Place of publication:Oxford [u.a.]
Document Type:Article
Date of Publication (online):2020/10/20
Date of first Publication:2020/10/20
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/03/15
Tag:DNA methylation; IDH mutation; glioma; metabolism; mitochondria
Page Number:15
First Page:379
Last Page:393
Open access funding enabled and organized by Projekt DEAL.
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0