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

Yannick Braun, Katharina Filipski, Simon Bernatz, Peter Baumgarten, Bastian Roller, Jenny Zinke, Pia S. Zeiner, Elena Ilina, Christian Senft, Michael W. Ronellenfitsch, Karl H. Plate, Oliver Bähr, Elke Hattingen, Joachim P. Steinbach, Michel Mittelbronn, Patrick N. Harter*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)379-393
Number of pages15
JournalNeuropathology and Applied Neurobiology
Volume47
Issue number3
DOIs
Publication statusPublished - Apr 2021

Keywords

  • DNA methylation
  • IDH mutation
  • glioma
  • metabolism
  • mitochondria

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