Prognostic relevance of miRNA-155 methylation in anaplastic glioma

// Maximilian Georg Schliesser 1,3 , Rainer Claus 6,24 , Thomas Hielscher 7 , Christiane Grimm 1,3 , Dieter Weichenhan 6 , Jonas Blaes 3 , Benedikt Wiestler 1,3,25 , Peter Hau 10 , Johannes Schramm 11 , Felix Sahm 2,4 , Elisa K. Weis 1,3 , Markus Weiler 1,3,8 , Constance Baer 6 , Friederike Schmidt-Graf 8,12 , Gabriele Schackert 13 , Manfred Westphal 14 , Anne Hertenstein 1,3 , Patrick Roth 8,15 , Norbert Galldiks 16 , Christian Hartmann 2,4,17 , Torsten Pietsch 19 , Joerg Felsberg 20,22 , Guido Reifenberger 20,22 , Michael Christoph Sabel 21 , Frank Winkler 1,3 , Andreas von Deimling 2,4 , Christoph Meisner 9 , Peter Vajkoczy 23 , Michael Platten 1,5,8 , Michael Weller 8,15 , Christoph Plass 6 and Wolfgang Wick 1,3,8 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 Tubingen, Germany 9 Department of Biostatistics, University Hospital Tubingen, 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/Dusseldorf, Dusseldorf, Germany 23 Neurosurgery Clinic, Charite, 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 Universitat Munchen, 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.