The genomic and transcriptional landscape of primary central nervous system lymphoma
Authors: Radke Josefine , Ishaque Naveed , Koll Randi , Gu Zuguang , Schumann Elisa , Sieverling Lina , Uhrig Sebastian , Hübschmann Daniel , Toprak Umut H. , López Cristina , Hostench Xavier Pastor , Borgoni Simone , Juraeva Dilafruz , Pritsch Fabienne , Paramasivam Nagarajan , Balasubramanian Gnana Prakash , Schlesner Matthias , Sahay Shashwat , Weniger Marc , Pehl Debora , Radbruch Helena , Osterloh Anja , Korfel Agnieszka , Misch Martin , Onken Julia , Faust Katharina , Vajkoczy Peter , Moskopp Dag , Wang Yawen , Jödicke Andreas , Trümper Lorenz , Anagnostopoulos Ioannis , Lenze Dido , Küppers Ralf , Hummel Michael , Schmitt Clemens A. , Wiestler Otmar D. , Wolf Stephan , Unterberg Andreas , Eils Roland , Herold-Mende Christel , Brors Benedikt ,   ICGC MMML-Seq Consortium,   Coordination (C1), Siebert Reiner , Wagner Susanne , Haake Andrea , Richter Julia , Richter Gesine ,   Data Center (C2), Eils Roland , Lawerenz Chris , Eils Jürgen , Kerssemakers Jules , Jaeger-Schmidt Christina , Scholz Ingrid ,   Clinical Centers (WP1), Bergmann Anke K. , Borst Christoph , Braulke Friederike , Burkhardt Birgit , Claviez Alexander , Dreyling Martin , Eberth Sonja , Einsele Hermann , Frickhofen Norbert , Haas Siegfried , Hansmann Martin-Leo , Karsch Dennis , Klepl Nicole , Kneba Michael , Lisfeld Jasmin , Mantovani-Löffler Luisa , Rohde Marius , Ott German , Stadler Christina , Staib Peter , Stilgenbauer Stephan , Zenz Thorsten ,   Normal Cells (WPN), Hansmann Martin-Leo , Kube Dieter ,   Pathology and Analyte Preparation (WP2-3), Haas Siegfried , Klapper Wolfram , Kostezka Ulrike , Möller Peter , Rosenwald Andreas , Ott German , Szczepanowski Monika ,   Sequencing and genomics (WP4-7), Ammerpohl Ole , Aukema Sietse M. , Binder Vera , Borkhardt Arndt , Haake Andrea , Hoell Jessica I. , Leich Ellen , Lichter Peter , López Cristina , Nagel Inga , Pischimariov Jordan , Radlwimmer Bernhard , Richter Julia , Rosenstiel Philip , Rosenwald Andreas , Schilhabel Markus , Schreiber Stefan , Vater Inga , Wagener Rabea , Siebert Reiner ,   Bioinformatics (WP8-9), Bernhart Stephan H. , Binder Hans , Doose Gero , Eils Roland , Hoffmann Steve , Hopp Lydia , Kleinheinz Kortine , Kretzmer Helene , Kreuz Markus , Korbel Jan , Langenberger David , Loeffler Markus , Rosolowski Maciej , Stadler Peter F. , Sungalee Stephanie , Siebert Reiner , Wiemann Stefan , Heppner Frank L. 
Published: May 2022

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 inMYD88L265P (67%) andCD79B(63%), andCDKN2Adeletions (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.TERTgene 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 andHLA-DRBloci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles,IGexpression and translocation patterns, as well as specific combinations of genetic alterations.