The genomic and transcriptional landscape of primary central nervous system lymphoma
Josefine Radke(Universitätsmedizin Greifswald), Naveed Ishaque(Berlin Institute of Health at Charité - Universitätsmedizin Berlin), Randi Koll(Humboldt-Universität zu Berlin), Zuguang Gu(National Center for Tumor Diseases), Elisa Schumann(Humboldt-Universität zu Berlin), Lina Sieverling(German Cancer Research Center), Sebastian Uhrig(National Center for Tumor Diseases), Daniel Hübschmann(German Cancer Research Center), Umut H. Toprak(German Cancer Research Center), Cristina López(Universität Ulm), Xavier Pastor Hostench(National Center for Tumor Diseases), Simone Borgoni(German Cancer Research Center), Dilafruz Juraeva(National Center for Tumor Diseases), Fabienne Pritsch(Humboldt-Universität zu Berlin), Nagarajan Paramasivam(National Center for Tumor Diseases), Gnana Prakash Balasubramanian(German Cancer Research Center), Matthias Schlesner(University of Augsburg), Shashwat Sahay(Universitätsmedizin Greifswald), Marc A. Weniger(Deutschen Konsortium für Translationale Krebsforschung), Debora Pehl(Humboldt-Universität zu Berlin), Helena Radbruch(Humboldt-Universität zu Berlin), Anja Osterloh(Humboldt-Universität zu Berlin), Agnieszka Korfel(Humboldt-Universität zu Berlin), Martin Misch(Humboldt-Universität zu Berlin), Julia Onken(Humboldt-Universität zu Berlin), Katharina Faust(Humboldt-Universität zu Berlin), Peter Vajkoczy(Humboldt-Universität zu Berlin), Dag Moskopp(Klinikum im Friedrichshain), Yawen Wang(Klinikum im Friedrichshain), Andreas Jödicke(Vivantes Klinikum), Lorenz Trümper(University of Göttingen), Ioannis Anagnostopoulos(Humboldt-Universität zu Berlin), Dido Lenze(Humboldt-Universität zu Berlin), Ralf Küppers(Deutschen Konsortium für Translationale Krebsforschung), Michael Hummel(Humboldt-Universität zu Berlin), Clemens A. Schmitt(Humboldt-Universität zu Berlin), Otmar D. Wiestler(German Cancer Research Center), Stephan Wolf(German Cancer Research Center), Andreas Unterberg(Heidelberg University), Roland Eils(Berlin Institute of Health at Charité - Universitätsmedizin Berlin), Christel Herold‐Mende(Heidelberg University), Benedikt Brors(National Center for Tumor Diseases), Coordination (C1)(Universität Ulm), Reiner Siebert(Universität Ulm), Susanne Wagner(Christian-Albrechts-Universität zu Kiel), Andrea Haake(Christian-Albrechts-Universität zu Kiel), Julia Richter(Christian-Albrechts-Universität zu Kiel), Gesine Richter(Berlin Institute of Health at Charité - Universitätsmedizin Berlin), Roland Eils(German Cancer Research Center), Chris Lawerenz(German Cancer Research Center), Jürgen Eils(German Cancer Research Center), Jules N. A. Kerssemakers(German Cancer Research Center), Christina Jaeger-Schmidt(German Cancer Research Center), Ingrid Scholz(Christian-Albrechts-Universität zu Kiel), Anke Bergmann(Friedrich-Ebert-Krankenhaus), Christoph Borst(University of Göttingen), Friederike Braulke(University Hospital Münster), Birgit Burkhardt(University Hospital Schleswig-Holstein), Alexander Claviez(München Klinik), Martin Dreyling(München Klinik), Sonja Eberth(Universitätsklinikum Würzburg), Hermann Einsele(Helios Dr. Horst Schmidt Kliniken Wiesbaden), Norbert Frickhofen(Friedrich-Ebert-Krankenhaus), Siegfried Haas(Goethe University Frankfurt), Martin‐Leo Hansmann, Dennis Karsch(University of Göttingen), Nicole Klepl, Michael Kneba(University Hospital Münster), Jasmin Lisfeld(Klinikum St. Georg), Luisa Mantovani‐Löffler(University Hospital Münster), Marius Rohde(Robert Bosch Hospital), German Ott(University of Göttingen), Christina Stadler(Sankt-Antonius-Hospital Eschweiler), Peter Staib(Universität Ulm), Stephan Stilgenbauer(National Center for Tumor Diseases), Thorsten Zenz(Goethe University Frankfurt), Normal Cells (WPN)(University of Göttingen), Martin‐Leo Hansmann(Friedrich-Ebert-Krankenhaus), Dieter Kube(Christian-Albrechts-Universität zu Kiel), Pathology and Analyte Preparation (WP2-3)(University Hospital Ulm), Siegfried Haas(Universität Ulm), Wolfgang Hiddemann(University of Würzburg), Ulrike Kostezka(Robert Bosch Hospital), Peter Möller(Christian-Albrechts-Universität zu Kiel), Andreas Rosenwald(Christian-Albrechts-Universität zu Kiel), German Ott(Christian-Albrechts-Universität zu Kiel), Monika Szczepanowski(Heinrich Heine University Düsseldorf), Sequencing and genomics (WP4-7)(Heinrich Heine University Düsseldorf), Ole Ammerpohl(Christian-Albrechts-Universität zu Kiel), Sietse Aukema(Heinrich Heine University Düsseldorf), Vera Binder(University of Würzburg), Arndt Borkhardt(German Cancer Research Center), Andrea Haake(Christian-Albrechts-Universität zu Kiel), Jessica I. Hoell(Christian-Albrechts-Universität zu Kiel), Ellen Leich(University of Würzburg), Peter Lichter(German Cancer Research Center), Cristina López(Universität Ulm), Inga Nagel, Jordan Pischimariov(University of Würzburg), Bernhard Radlwimmer, Julia Richter(Christian-Albrechts-Universität zu Kiel), Philip Rosenstiel(Christian-Albrechts-Universität zu Kiel), Andreas Rosenwald(Christian-Albrechts-Universität zu Kiel), Markus B. Schilhabel(Christian-Albrechts-Universität zu Kiel), Stefan Schreiber(Leipzig University), Inga Vater(Leipzig University), Rabea Wagener(Leipzig University), Reiner Siebert(Universität Ulm), Bioinformatics (WP8-9)(Leipzig University), Stephan H. Bernhart(Leipzig University), Hans Binder(Heidelberg University), Gero Doose(Leipzig University), Roland Eils(Berlin Institute of Health at Charité - Universitätsmedizin Berlin), Steve Hoffmann, Lydia Hopp(Leipzig University), Kortine Kleinheinz, Helene Kretzmer, Markus Kreuz(Leipzig University), Jan O. Korbel, David Langenberger(Christian-Albrechts-Universität zu Kiel), Markus Loeffler(German Cancer Research Center), Maciej Rosołowski(German Center for Neurodegenerative Diseases), Peter F. Stadler, Stéphanie Sungalee, Reiner Siebert(Universität Ulm), Stefan Wiemann(German Cancer Research Center), Frank L. Heppner(German Center for Neurodegenerative Diseases)
Cited by 140Open Access
Abstract
Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations.
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