TY  - JOUR
A1  - Braun, Yannick
A1  - Filipski, Katharina Johanna
A1  - Bernatz, Simon
A1  - Baumgarten, Peter
A1  - Roller, Bastian
A1  - Zinke, Jenny
A1  - Zeiner, Pia Susan
A1  - Ilina, Elena
A1  - Senft, Christian
A1  - Ronellenfitsch, Michael Wilfried
A1  - Plate, Karl
A1  - Bähr, Roy Oliver
A1  - Hattingen, Elke
A1  - Steinbach, Joachim Peter
A1  - Mittelbronn, Michel Guy André
A1  - Harter, Patrick Nikolaus
T1  - Linking epigenetic signature and metabolic phenotype in IDH mutant and IDH wildtype diffuse glioma
T2  - Neuropathology & applied neurobiology
N2  - 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.
KW  - glioma
KW  - metabolism
KW  - mitochondria
KW  - DNA methylation
KW  - IDH mutation
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63862
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-638628
SN  - 1365-2990
N1  - Open access funding enabled and organized by Projekt DEAL.
VL  - 47
IS  - 3
SP  - 379
EP  - 393
PB  - Wiley-Blackwell
CY  - Oxford [u.a.]
ER  -