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 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, Reiner Siebert, Stefan Wiemann and Frank L. Heppner
Additional contact information
Josefine Radke: Humboldt-Universität zu Berlin, Berlin Institute of Health
Naveed Ishaque: Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin
Randi Koll: Humboldt-Universität zu Berlin, Berlin Institute of Health
Zuguang Gu: Molecular Precision Oncology Program, NCT Heidelberg
Elisa Schumann: Humboldt-Universität zu Berlin, Berlin Institute of Health
Lina Sieverling: German Cancer Research Center (DKFZ)
Sebastian Uhrig: Molecular Precision Oncology Program, NCT Heidelberg
Daniel Hübschmann: Molecular Precision Oncology Program, NCT Heidelberg
Umut H. Toprak: Division Neuroblastoma Genomics, German Cancer Research Center (DKFZ)
Cristina López: Ulm University & Ulm University Medical Center
Xavier Pastor Hostench: Molecular Precision Oncology Program, NCT Heidelberg
Simone Borgoni: German Cancer Research Center (DKFZ)
Dilafruz Juraeva: Molecular Precision Oncology Program, NCT Heidelberg
Fabienne Pritsch: Humboldt-Universität zu Berlin, Berlin Institute of Health
Nagarajan Paramasivam: Molecular Precision Oncology Program, NCT Heidelberg
Gnana Prakash Balasubramanian: Hopp Children’s Cancer Center, NCT Heidelberg (KiTZ)
Matthias Schlesner: German Cancer Research Center (DKFZ)
Shashwat Sahay: Universitätsmedizin Greifswald
Marc Weniger: Institute of Cell Biology (Cancer Research), Medical Faculty, University of Duisburg-Essen
Debora Pehl: Humboldt-Universität zu Berlin, Berlin Institute of Health
Helena Radbruch: Humboldt-Universität zu Berlin, Berlin Institute of Health
Anja Osterloh: Humboldt-Universität zu Berlin, Berlin Institute of Health
Agnieszka Korfel: Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
Martin Misch: Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
Julia Onken: Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
Katharina Faust: Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
Peter Vajkoczy: Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
Dag Moskopp: Vivantes Klinikum im Friedrichshain
Yawen Wang: Vivantes Klinikum im Friedrichshain
Andreas Jödicke: Vivantes Klinikum Neukölln
Lorenz Trümper: Georg-Augusts-University of Göttingen
Ioannis Anagnostopoulos: Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
Dido Lenze: Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
Ralf Küppers: Institute of Cell Biology (Cancer Research), Medical Faculty, University of Duisburg-Essen
Michael Hummel: Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
Clemens A. Schmitt: Johannes Kepler University, Kepler Universitätsklinikum
Otmar D. Wiestler: German Cancer Research Center (DKFZ)
Stephan Wolf: German Cancer Research Center (DKFZ)
Andreas Unterberg: University Hospital Heidelberg
Roland Eils: Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin
Christel Herold-Mende: University Hospital Heidelberg
Benedikt Brors: Molecular Precision Oncology Program, NCT Heidelberg
Reiner Siebert: Ulm University & Ulm University Medical Center
Stefan Wiemann: German Cancer Consortium (DKTK)
Frank L. Heppner: Humboldt-Universität zu Berlin, Berlin Institute of Health

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30050-y

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