The genomic and transcriptional landscape of primary central nervous system lymphoma
Josefine Radke, Naveed Ishaque, Randi Koll, Zuguang Gu, Elisa Schumann, Lina Sieverling, Sebastian Uhrig, Daniel Hübschmann, Umut H. Toprak, Cristina López, Xavier Pastor Hostench, Simone Borgoni, Dilafruz Juraeva, Fabienne Pritsch, Nagarajan Paramasivam, Gnana Prakash Balasubramanian, Matthias Schlesner, Shashwat Sahay, Marc A. Weniger, Debora Pehl, Helena Radbruch, Anja Osterloh, Agnieszka Korfel, Martin Misch, Julia Onken, Katharina Faust, Peter Vajkoczy, Dag Moskopp, Yawen Wang, Andreas Jödicke, Lorenz Trümper, Ioannis Anagnostopoulos, Dido Lenze, Ralf Küppers, Michael Hummel, Clemens A. Schmitt, Otmar D. Wiestler, Stephan Wolf, Andreas Unterberg, Roland Eils, Christel Herold‐Mende, Benedikt Brors, Coordination (C1), Reiner Siebert, Susanne Wagner, Andrea Haake, Julia Richter, Gesine Richter, Roland Eils, Chris Lawerenz, Jürgen Eils, Jules N. A. Kerssemakers, Christina Jaeger-Schmidt, Ingrid Scholz, Anke Bergmann, Christoph Borst, Friederike Braulke, Birgit Burkhardt, Alexander Claviez, Martin Dreyling, Sonja Eberth, Hermann Einsele, Norbert Frickhofen, Siegfried Haas, Martin‐Leo Hansmann, Dennis Karsch, Nicole Klepl, Michael Kneba, Jasmin Lisfeld, Luisa Mantovani‐Löffler, Marius Rohde, German Ott, Christina Stadler, Peter Staib, Stephan Stilgenbauer, Thorsten Zenz, Normal Cells (WPN), Martin‐Leo Hansmann, Dieter Kube, Pathology and Analyte Preparation (WP2-3), Siegfried Haas, Wolfgang Hiddemann, Ulrike Kostezka, Peter Möller, Andreas Rosenwald, German Ott, Monika Szczepanowski, Sequencing and genomics (WP4-7), Ole Ammerpohl, Sietse Aukema, Vera Binder, Arndt Borkhardt, Andrea Haake, Jessica I. Hoell, Ellen Leich, Peter Lichter, Cristina López, Inga Nagel, Jordan Pischimariov, Bernhard Radlwimmer
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.