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Article

High-Resolution Cartography of the Transcriptome and Methylome Landscapes of Diffuse Gliomas

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IZBI, Interdisciplinary Centre for Bioinformatics, Universität Leipzig, Härtelstr. 16-18, 04107 Leipzig, Germany
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IMISE, Institute for Medical Informatics, Statistics and Epidemiology, Universität of Leipzig, Härtelstr. 16-18, 04107 Leipzig, Germany
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Research Group of Bioinformatics, Institute of Molecular Biology of the National Academy of Sciences of the Republic of Armenia, 7 Hasratyan Str., Yerevan 0014, Armenia
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Armenian Bioinformatics Institute (ABI), 7 Hasratyan Str., Yerevan 0014, Armenia
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Hopp Children’s Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 430, 69120 Heidelberg, Germany
*
Authors to whom correspondence should be addressed.
Academic Editors: Alan Hutson and Song Liu
Cancers 2021, 13(13), 3198; https://doi.org/10.3390/cancers13133198
Received: 3 June 2021 / Revised: 23 June 2021 / Accepted: 24 June 2021 / Published: 26 June 2021
(This article belongs to the Special Issue Bioinformatics, Big Data and Cancer)
A high degree of molecular heterogeneity is a fundamental characteristic of diffuse gliomas, a brain tumor entity, which splits into several subtypes of different but overall adverse prognosis. Heterogeneity is governed by a handful of key mutations—first of all, of the isocitrate dehydrogenase gene. It drastically affects DNA methylation on a genome-wide scale. DNA methylation acts as an important regulator of gene transcription with consequences for glioma physiology. We here present a combined gene expression and DNA methylation study with the focus on lower-grade (II–III), adult-type gliomas. It aimed at deciphering glioma heterogeneity into molecular subtypes at a finer granularity level and at characterizing the underlying modes of gene regulation. Our analysis made use of high-resolution molecular portrayal, a machine learning approach to visualize complex genomic data. The results support the importance of epigenetics for glioma diversity and, in consequence, for prognosis and epigenetics-directed treatment.
Molecular mechanisms of lower-grade (II–III) diffuse gliomas (LGG) are still poorly understood, mainly because of their heterogeneity. They split into astrocytoma- (IDH-A) and oligodendroglioma-like (IDH-O) tumors both carrying mutations(s) at the isocitrate dehydrogenase (IDH) gene and into IDH wild type (IDH-wt) gliomas of glioblastoma resemblance. We generated detailed maps of the transcriptomes and DNA methylomes, revealing that cell functions divided into three major archetypic hallmarks: (i) increased proliferation in IDH-wt and, to a lesser degree, IDH-O; (ii) increased inflammation in IDH-A and IDH-wt; and (iii) the loss of synaptic transmission in all subtypes. Immunogenic properties of IDH-A are diverse, partly resembling signatures observed in grade IV mesenchymal glioblastomas or in grade I pilocytic astrocytomas. We analyzed details of coregulation between gene expression and DNA methylation and of the immunogenic micro-environment presumably driving tumor development and treatment resistance. Our transcriptome and methylome maps support personalized, case-by-case views to decipher the heterogeneity of glioma states in terms of data portraits. Thereby, molecular cartography provides a graphical coordinate system that links gene-level information with glioma subtypes, their phenotypes, and clinical context. View Full-Text
Keywords: grade II–IV gliomas; gene expression; DNA methylation; tumor heterogeneity; molecular subtypes; tumor evolution; self-organizing maps machine learning; integrative bioinformatics grade II–IV gliomas; gene expression; DNA methylation; tumor heterogeneity; molecular subtypes; tumor evolution; self-organizing maps machine learning; integrative bioinformatics
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MDPI and ACS Style

Willscher, E.; Hopp, L.; Kreuz, M.; Schmidt, M.; Hakobyan, S.; Arakelyan, A.; Hentschel, B.; Jones, D.T.W.; Pfister, S.M.; Loeffler, M.; Loeffler-Wirth, H.; Binder, H. High-Resolution Cartography of the Transcriptome and Methylome Landscapes of Diffuse Gliomas. Cancers 2021, 13, 3198. https://doi.org/10.3390/cancers13133198

AMA Style

Willscher E, Hopp L, Kreuz M, Schmidt M, Hakobyan S, Arakelyan A, Hentschel B, Jones DTW, Pfister SM, Loeffler M, Loeffler-Wirth H, Binder H. High-Resolution Cartography of the Transcriptome and Methylome Landscapes of Diffuse Gliomas. Cancers. 2021; 13(13):3198. https://doi.org/10.3390/cancers13133198

Chicago/Turabian Style

Willscher, Edith, Lydia Hopp, Markus Kreuz, Maria Schmidt, Siras Hakobyan, Arsen Arakelyan, Bettina Hentschel, David T.W. Jones, Stefan M. Pfister, Markus Loeffler, Henry Loeffler-Wirth, and Hans Binder. 2021. "High-Resolution Cartography of the Transcriptome and Methylome Landscapes of Diffuse Gliomas" Cancers 13, no. 13: 3198. https://doi.org/10.3390/cancers13133198

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