Journal Article

The genomic and transcriptional landscape of primary central nervous system lymphoma

Weniger, Marc, Faust, Katharina, Toprak, Umut H., Sieverling, Lina, Hübschmann, Daniel, Juraeva, Dilafruz, Misch, Martin, Pritsch, Fabienne, Gu, Zuguang, Wang, Yawen, Ishaque, Naveed, Küppers, Ralf, Jödicke, Andreas, Wolf, Stephan, Koll, Randi, Eils, Roland, López, Cristina, Trümper, Lorenz, Sahay, Shashwat, Schlesner, Matthias, Korfel, Agnieszka, Pehl, Debora, Wiemann, Stefan, Anagnostopoulos, Ioannis, Hostench, Xavier Pastor, Radbruch, Helena, Siebert, Reiner, Vajkoczy, Peter, Moskopp, Dag, Paramasivam, Nagarajan, Lenze, Dido, Unterberg, Andreas, Schmitt, Clemens A., Hummel, Michael, Onken, Julia, Herold-Mende, Christel, Wiestler, Otmar D., Schumann, Elisa, Uhrig, Sebastian, Radke, Josefine, Borgoni, Simone, Osterloh, Anja, Balasubramanian, Gnana Prakash, Brors, Benedikt, Heppner, Frank L.

2022

Overview

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. Primary lymphomas of the central nervous system (PCNSL) are defined as diffuse large B-cell lymphomas (DLBCL) confined to the CNS. Here, the authors complete whole genome sequencing and RNA-seq to characterize 51 PCNSLs, and find common mutations in immune pathways and upregulated TERT expression and find distinct pathway differences between DLBCL and other primary CNS lymphomas.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 38/23 / 38/77 / 38/90 / 38/91 / 45 / 45/22 / 45/88 / 49/39 / 692/4028/67/1922 / 692/4028/67/1990/291/1621/1915 / 692/4028/67/69 / B-cell lymphoma / B-cell receptor / Central nervous system / Chromosome 6 / DNA biosynthesis / Epstein-Barr virus / Gene expression / Gene sequencing / Genomes / Histocompatibility antigen HLA / Humanities and Social Sciences / Immunoglobulins / Loci / Lymphocytes B / Lymphoma / Mitosis / multidisciplinary / Mutation / MyD88 protein / Nervous system / NF-κB protein / Science / Science (multidisciplinary) / Transcriptomes / Translocation / Whole genome sequencing