title: Alterations of microRNA and microRNA-regulated messenger RNA expression in germinal center B-cell lymphomas determined by integrative sequencing analysis.
abstract: MicroRNA are well-established players in post-transcriptional gene regulation. However, information on the effects of microRNA deregulation mainly relies on bioinformatic prediction of potential targets, whereas proof of the direct physical microRNA/target messenger RNA interaction is mostly lacking. Within the International Cancer Genome Consortium Project "Determining Molecular Mechanisms in Malignant Lymphoma by Sequencing", we performed miRnome sequencing from 16 Burkitt lymphomas, 19 diffuse large B-cell lymphomas, and 21 follicular lymphomas. Twenty-two miRNA separated Burkitt lymphomas from diffuse large B-cell lymphomas/follicular lymphomas, of which 13 have shown regulation by MYC. Moreover, we found expression of three hitherto unreported microRNA. Additionally, we detected recurrent mutations of hsa-miR-142 in diffuse large B-cell lymphomas and follicular lymphomas, and editing of the hsa-miR-376 cluster, providing evidence for microRNA editing in lymphomagenesis. To interrogate the direct physical interactions of microRNA with messenger RNA, we performed Argonaute-2 photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation experiments. MicroRNA directly targeted 208 messsenger RNA in the Burkitt lymphomas and 328 messenger RNA in the non-Burkitt lymphoma models. This integrative analysis discovered several regulatory pathways of relevance in lymphomagenesis including Ras, PI3K-Akt and MAPK signaling pathways, also recurrently deregulated in lymphomas by mutations. Our dataset reveals that messenger RNA deregulation through microRNA is a highly relevant mechanism in lymphomagenesis.
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.
authors.forename: Kebria
authors.initials: K
authors.lastname: Hezaveh
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.|Department of Algorithmic Bioinformatics, Heinrich-Heine University, Duesseldorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kloetgen
authors.affiliation: Transcriptome Bioinformatics Group, LIFE Research Center for Civilization Diseases, University of Leipzig, Germany.|Bioinformatics Group, Department of Computer Science, University of Leipzig, Germany.|Interdisciplinary Center for Bioinformatics, University of Leipzig, Germany.
authors.forename: Stephan H
authors.initials: SH
authors.lastname: Bernhart
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.
authors.forename: Kunal Das
authors.initials: KD
authors.lastname: Mahapatra
authors.affiliation: Institute of Pathology, Charité - University Medicine Berlin, Germany.
authors.forename: Dido
authors.initials: D
authors.lastname: Lenze
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Richter
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Haake
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
authors.forename: Anke K
authors.initials: AK
authors.lastname: Bergmann
authors.affiliation: Division Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: Department of Pediatric Hematology and Oncology, University Hospital Münster, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Burkhardt
authors.affiliation: Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Claviez
authors.affiliation: Department of Human and Animal Cell Cultures, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Drexler
authors.affiliation: Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology and Bioquant, Heidelberg University, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.affiliation: Friedrich-Ebert Hospital Neumünster, Clinics for Hematology, Oncology and Nephrology, Neumünster, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Haas
authors.affiliation: Transcriptome Bioinformatics Group, LIFE Research Center for Civilization Diseases, University of Leipzig, Germany.|Bioinformatics Group, Department of Computer Science, University of Leipzig, Germany.
authors.forename: Steve
authors.initials: S
authors.lastname: Hoffmann
authors.affiliation: Department of Internal Medicine II: Hematology and Oncology, University Medical Centre, Campus Kiel, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Karsch
authors.affiliation: Hematopathology Section, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.affiliation: Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Kortine
authors.initials: K
authors.lastname: Kleinheinz
authors.affiliation: EMBL Heidelberg, Genome Biology, Heidelberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Korbel
authors.affiliation: Transcriptome Bioinformatics Group, LIFE Research Center for Civilization Diseases, University of Leipzig, Germany.|Bioinformatics Group, Department of Computer Science, University of Leipzig, Germany.
authors.forename: Helene
authors.initials: H
authors.lastname: Kretzmer
authors.affiliation: Institute for Medical Informatics Statistics and Epidemiology, Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kreuz
authors.affiliation: Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Küppers
authors.affiliation: Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Lawerenz
authors.affiliation: Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Leich
authors.affiliation: Institute for Medical Informatics Statistics and Epidemiology, Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
authors.affiliation: Hospital of Internal Medicine II, Hematology and Oncology, St-Georg Hospital Leipzig, Germany.
authors.forename: Luisa
authors.initials: L
authors.lastname: Mantovani-Loeffler
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: López
authors.affiliation: Department of Algorithmic Bioinformatics, Heinrich-Heine University, Duesseldorf, Germany.|Computational Biology of Infection Research, Helmholtz Center for Infection Research, Braunschweig, Germany.
authors.forename: Alice C
authors.initials: AC
authors.lastname: McHardy
authors.affiliation: Institute of Pathology, Medical Faculty of the Ulm University, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.affiliation: Department of Pediatric Hematology and Oncology University Hospital Giessen, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Rohde
authors.affiliation: Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schilhabel
authors.affiliation: Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schlesner
authors.affiliation: Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Scholz
authors.affiliation: Transcriptome Bioinformatics Group, LIFE Research Center for Civilization Diseases, University of Leipzig, Germany.|Bioinformatics Group, Department of Computer Science, University of Leipzig, Germany.|Interdisciplinary Center for Bioinformatics, University of Leipzig, Germany.|RNomics Group, Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany.|Max-Planck-Institute for Mathematics in Sciences, Leipzig, Germany.|Santa Fe Institute, NM, USA.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Stadler
authors.affiliation: Department of Internal Medicine III, University of Ulm, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: EMBL Heidelberg, Genome Biology, Heidelberg, Germany.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Sungalee
authors.affiliation: Hematopathology Section, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Szczepanowski
authors.affiliation: Department of Hematology and Oncology, Georg-August-University of Göttingen, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Trümper
authors.affiliation: Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Weniger
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
authors.affiliation: Institute of Pathology, Charité - University Medicine Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.forename: Jessica I
authors.initials: JI
authors.lastname: Hoell
mesh_terms: D000293:Adolescent; D002051:Burkitt Lymphoma / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D018858:Germinal Center; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008224:Lymphoma, Follicular / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D017393:RNA Editing; D012333:RNA, Messenger / Q000378:metabolism*; D017423:Sequence Analysis, RNA / Q000379:methods*
chemical_list: C555159:MIRN142 microRNA, human; C573498:MIRN376C microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger