title: Prognostic relevance of miRNA-155 methylation in anaplastic glioma.
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.
authors.affiliation: Department of Neurology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany.|Clinical Cooperation Unit of Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Maximilian Georg
authors.initials: MG
authors.lastname: Schliesser
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.affiliation: Department of Neurology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany.|Clinical Cooperation Unit of Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Grimm
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.affiliation: Clinical Cooperation Unit of Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Blaes
authors.affiliation: Department of Neurology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany.|Clinical Cooperation Unit of Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Wiestler
authors.affiliation: Neurology Clinic, Regensburg University, Regensburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hau
authors.affiliation: Neurosurgery Clinic, University of Bonn Medical Center, TU Munich, Munich, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schramm
authors.affiliation: Department of Neuropathology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany.|Clinical Cooperation Unit of Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.affiliation: Department of Neurology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany.|Clinical Cooperation Unit of Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Elisa K
authors.initials: EK
authors.lastname: Weiß
authors.affiliation: Department of Neurology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany.|Clinical Cooperation Unit of Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of General Neurology, University Hospital Tübingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Weiler
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Constance
authors.initials: C
authors.lastname: Baer
authors.affiliation: Department of General Neurology, University Hospital Tübingen, Germany.|Neurology Clinic, TU Munich, Munich, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Schmidt-Graf
authors.affiliation: Neurosurgery Clinic, Dresden University Medical Center, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schackert
authors.affiliation: Neurosurgery Clinic, University Clinic Hamburg, Eppendorf, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.affiliation: Department of Neurology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany.|Clinical Cooperation Unit of Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Hertenstein
authors.affiliation: Department of General Neurology, University Hospital Tübingen, Germany.|Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Roth
authors.affiliation: Neurology Clinic, Cologne University, Cologne, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Galldiks
authors.affiliation: Department of Neuropathology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany.|Clinical Cooperation Unit of Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department for Neuropathology, Institute of Pathology, Medical University of Hannover, Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.affiliation: Department of Neuropathology, Heinrich-Heine-University, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.affiliation: Department of Neurosurgery, Heinrich-Heine-University, Germany.|Neurosurgery Clinic, Charité, Berlin, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Felsberg
authors.affiliation: Department of Neurosurgery, Heinrich-Heine-University, Germany.|Neurosurgery Clinic, Charité, Berlin, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.affiliation: DKTK, Partner Site Essen/Düsseldorf, Düsseldorf, Germany.
authors.forename: Michael Christoph
authors.initials: MC
authors.lastname: Sabel
authors.affiliation: Department of Neurology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany.|Clinical Cooperation Unit of Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Winkler
authors.affiliation: Department of Neuropathology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany.|Clinical Cooperation Unit of Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Department of Biostatistics, University Hospital Tübingen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Meisner
authors.affiliation: Department Hematology, Oncology and Stem Cell Transplantation, University Hospital Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Vajkoczy
authors.affiliation: Department of Neurology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany.|Clinical Cooperation Unit of Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of General Neurology, University Hospital Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.affiliation: Department of General Neurology, University Hospital Tübingen, Germany.|Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Department of Neurology, Heidelberg University Hospital and German Cancer Consortium, Clinical Cooperation Units, Germany.|Clinical Cooperation Unit of Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of General Neurology, University Hospital Tübingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D019175:DNA Methylation; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D034622:RNA Interference; D011836:Radiation Tolerance / Q000235:genetics; D000077204:Temozolomide; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D003606:Dacarbazine; D000077204:Temozolomide
keywords: IDH; NFκB; NOA-04; anaplastic glioma; miR-155