Linking epigenetic signature and metabolic phenotype in IDH mutant and IDH wildtype diffuse glioma. (7th November 2020)

• Record Type: Journal Article
• Authors: Braun, Yannick; Filipski, Katharina; Bernatz, Simon; Baumgarten, Peter; Roller, Bastian; Zinke, Jenny; Zeiner, Pia S.; Ilina, Elena; Senft, Christian; Ronellenfitsch, Michael W.; Plate, Karl H.; Bähr, Oliver; Hattingen, Elke; Steinbach, Joachim P.; Mittelbronn, Michel; Harter, Patrick N.
• Is Part Of: Neuropathology & applied neurobiology. Volume 47:Number 3(2021)
• Page Start: 379
• Page End: 393
• Publication Date: 2020-11-07
• Subjects: glioma -- metabolism -- mitochondria -- DNA methylation -- IDH mutation; Nervous system -- Diseases -- Pathology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/nan.12669
• Languages: English
• ISSNs: 0305-1846

Abstract

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 ( IDH mut) and isocitrate dehydrogenase wildtype ( IDH wt) 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 IDH mut and IDH wt gliomas. Promoter methylation of lactate dehydrogenase A negatively correlated with protein expression and was associated with IDH mut gliomas. Mitochondrial DNA copy number was increased in IDH mut tumours and did not change in recurrent tumours. Hierarchical clustering based on metabolism panel IHC revealed distinct subclasses of IDH mut and IDH wt 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. Abstract : Differential DNA methylation also affects metabolic genes in IDH mut and IDHwt diffuse gliomas. Mitochondrial signatures are associated with a better clinical outcome.