Oncotarget

Priority Research Papers:

Prognostic relevance of miRNA-155 methylation in anaplastic glioma

Maximilian Georg Schliesser, Rainer Claus, Thomas Hielscher, Christiane Grimm, Dieter Weichenhan, Jonas Blaes, Benedikt Wiestler, Peter Hau, Johannes Schramm, Felix Sahm, Elisa K. Weiß, Markus Weiler, Constance Baer, Friederike Schmidt-Graf, Gabriele Schackert, Manfred Westphal, Anne Hertenstein, Patrick Roth, Norbert Galldiks, Christian Hartmann, Torsten Pietsch, Joerg Felsberg, Guido Reifenberger, Michael Christoph Sabel, Frank Winkler, Andreas von Deimling, Christoph Meisner, Peter Vajkoczy, Michael Platten, Michael Weller, Christoph Plass and Wolfgang Wick _

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Oncotarget. 2016; 7:82028-82045. https://doi.org/10.18632/oncotarget.13452

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Abstract

Maximilian Georg Schliesser1,3, Rainer Claus6,24, Thomas Hielscher7, Christiane Grimm1,3, Dieter Weichenhan6, Jonas Blaes3, Benedikt Wiestler1,3,25, Peter Hau10, Johannes Schramm11, Felix Sahm2,4, Elisa K. Weiß1,3, Markus Weiler1,3,8, Constance Baer6, Friederike Schmidt-Graf8,12, Gabriele Schackert13, Manfred Westphal14, Anne Hertenstein1,3, Patrick Roth8,15, Norbert Galldiks16, Christian Hartmann2,4,17, Torsten Pietsch19, Joerg Felsberg20,22, Guido Reifenberger20,22, Michael Christoph Sabel21, Frank Winkler1,3, Andreas von Deimling2,4, Christoph Meisner9, Peter Vajkoczy23, Michael Platten1,5,8, Michael Weller8,15, Christoph Plass6 and Wolfgang Wick1,3,8

1 Department of Neurology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany

2 Department of Neuropathology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany

3 Clinical Cooperation Unit of Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4 Clinical Cooperation Unit of Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany

5 Clinical Cooperation Unit of Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany

6 Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany

7 Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany

8 Department of General Neurology, University Hospital Tübingen, Germany

9 Department of Biostatistics, University Hospital Tübingen, Germany

10 Neurology Clinic, Regensburg University, Regensburg, Germany

11 Neurosurgery Clinic, University of Bonn Medical Center, TU Munich, Munich, Germany

12 Neurology Clinic, TU Munich, Munich, Germany

13 Neurosurgery Clinic, Dresden University Medical Center, Germany

14 Neurosurgery Clinic, University Clinic Hamburg, Eppendorf, Germany

15 Department of Neurology, University Hospital Zurich, Zurich, Switzerland

16 Neurology Clinic, Cologne University, Cologne, Germany

17 Department for Neuropathology, Institute of Pathology, Medical University of Hannover, Hannover, Germany

19 Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany

20 Department of Neuropathology, Heinrich-Heine-University, Germany

21 Department of Neurosurgery, Heinrich-Heine-University, Germany

22 DKTK, Partner Site Essen/Düsseldorf, Düsseldorf, Germany

23 Neurosurgery Clinic, Charité, Berlin, Germany

24 Department Hematology, Oncology and Stem Cell Transplantation, University Hospital Freiburg, Germany

25 Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany

Correspondence to:

Wolfgang Wick, email:

Keywords: anaplastic glioma, miR-155, IDH, NFκB, NOA-04

Received: May 09, 2016 Accepted: September 13, 2016 Published: November 18, 2016

Abstract

The outcome of patients with anaplastic gliomas varies considerably depending on single molecular markers, such as mutations of the isocitrate dehydrogenase (IDH) genes, as well as molecular classifications based on epigenetic or genetic profiles. Remarkably, 98% of the RNA within a cell is not translated into proteins. Of those, especially microRNAs (miRNAs) have been shown not only to have a major influence on physiologic processes but also to be deregulated and prognostic in malignancies.

To find novel survival markers and treatment options we performed unbiased DNA methylation screens that revealed 12 putative miRNA promoter regions with differential DNA methylation in anaplastic gliomas. Methylation of these candidate regions was validated in different independent patient cohorts revealing a set of miRNA promoter regions with prognostic relevance across data sets. Of those, miR-155 promoter methylation and miR-155 expression were negatively correlated and especially the methylation showed superior correlation with patient survival compared to established biomarkers.

Functional examinations in malignant glioma cells further cemented the relevance of miR-155 for tumor cell viability with transient and stable modifications indicating an onco-miRNA activity. MiR-155 also conferred resistance towards alkylating temozolomide and radiotherapy as consequence of nuclear factor (NF)κB activation.

Preconditioning glioma cells with an NFκB inhibitor reduced therapy resistance of miR-155 overexpressing cells. These cells resembled tumors with a low methylation of the miR-155 promoter and thus mir-155 or NFκB inhibition may provide treatment options with a special focus on patients with IDH wild type tumors.


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