Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas.

Bernhard Radlwimmer, Peter F Stadler, Stephan Stilgenbauer, Markus Schillhabel, Andreas Rosenwald, Philip Rosenstiel, Daniel Rico, Julia Richter, Eva Reisinger, José I Martín-Subero, German Ott, Joost H A Martens, Dido Lenze, Chris Lawerenz, Dieter Kube, Jan O Korbel, Jules N A Kerssemakers, Peter Möller, Reiner Siebert, Matthias Schlesner, Ralf Küppers, Lorenz Trümper, Steve Hoffmann, Wolfram Klapper, Roland Eils, Markus Loeffler, Christina Jäger-Schmidt, Peter Lichter, Hendrik G Stunnenberg, Alfonso Valencia, Marc Zapatka, Marc A Weniger, Gregor Warsow, Monika Szczepanowski, Helene Kretzmer, Matthias Bieg, Anke K Bergmann, Renée Beekman, Sietse M Aukema, Ole Ammerpohl, Nagarajan Paramasivam, Sebastian M Waszak, Markus Kreuz, Hans Binder, Naveed Ishaque, Stephanie Sungalee, Umut H Toprak, Cristina López, Stephan H Bernhart, Rabea Wagener, Kortine Kleinheinz, Daniel Hübschmann, Arndt Borkhardt, Christoph Borst, Benedikt Brors, Philipp Bruns, Enrique Carrillo de Santa Pau, Alexander Claviez, Gero Doose, Andrea Haake, Dennis Karsch, Siegfried Haas, Martin-Leo Hansmann, Jessica I Hoell, Volker Hovestadt, Bingding Huang, Michael Hummel

Journal: Leukemia 2021;35(7):2002-2016

PMID: 33953289

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Abstract

B cells have the unique property to somatically alter their immunoglobulin (IG) genes by V(D)J recombination, somatic hypermutation (SHM) and class-switch recombination (CSR). Aberrant targeting of these mechanisms is implicated in lymphomagenesis, but the mutational processes are poorly understood. By performing whole genome and transcriptome sequencing of 181 germinal center derived B-cell lymphomas (gcBCL) we identified distinct mutational signatures linked to SHM and CSR. We show that not only SHM, but presumably also CSR causes off-target mutations in non-IG genes. Kataegis clusters with high mutational density mainly affected early replicating regions and were enriched for SHM- and CSR-mediated off-target mutations. Moreover, they often co-occurred in loci physically interacting in the nucleus, suggesting that mutation hotspots promote increased mutation targeting of spatially co-localized loci (termed hypermutation by proxy). Only around 1% of somatic small variants were in protein coding sequences, but in about half of the driver genes, a contribution of B-cell specific mutational processes to their mutations was found. The B-cell-specific mutational processes contribute to both lymphoma initiation and intratumoral heterogeneity. Overall, we demonstrate that mutational processes involved in the development of gcBCL are more complex than previously appreciated, and that B cell-specific mutational processes contribute via diverse mechanisms to lymphomagenesis.

Address: Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department for Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology and Bioquant, University of Heidelberg, Heidelberg, Germany.; Heidelberg Institute of Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.; Computational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.; Intitute of Human Genetics, Christian-Albrechts-University, Kiel, Germany.; University of Duesseldorf, Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Düsseldorf, Germany.; Interdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, Germany.; Bioinformatics Group, Department of Computer, University of Leipzig, Leipzig, Germany.; Transcriptome Bioinformatics, LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.; Bioinformatics and Omics Data Analytics (B240), German Cancer Research Center (DKFZ), Heidelberg, Germany.; EMBL Heidelberg, Genome Biology, Heidelberg, Germany.; DKFZ-HIPO, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.; Institute for Medical Informatics Statistics and Epidemiology, Leipzig, Germany.; Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.; Hematopathology Section, Christian-Albrechts-University, Kiel, Germany.; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.; Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.; Department of Internal Medicine/Hematology, Friedrich-Ebert-Hospital, Neumünster, Neumünster, Germany.; Division of Applied Bioinformatics (G200), German Cancer Research Center (DKFZ), Heidelberg, Germany.; Structural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Computational Biology Group, Precision Nutrition and Cancer Research Program, IMDEA Food Institute, Madrid, Spain.; Department for Internal Medicine II, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.; Senckenberg Institute of Pathology, University of Frankfurt Medical School, Frankfurt am Main, Germany.; Division of Molecular Genetics, German Cancer Consortium (DKFK), German Cancer Research Center (DKFZ), Heidelberg, Germany.; College of Big Data and Internet, Shenzhen Technology University, Shenzhen, China.; Institute of Pathology, Charité - University Medicine Berlin, Berlin, Germany.; Department of Hematology and Oncology, Georg-Augusts-University of Göttingen, Göttingen, Germany.; Department of Molecular Biology, Radboud University, Faculty of Science, Nijmegen, The Netherlands.; Department of Clinical Pathology, Robert-Bosch-Hospital and Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, Stuttgart, Germany.; Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.; Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.; Institute of Pathology, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany.; Department for Internal Medicine III, Ulm University, Ulm, Germany.; Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Essen, Germany.; German Cancer Consortium (DKTK), Essen, Germany.; Barcelona Supercomputing Centre (BSC), Barcelona, Spain.; ICREA, Barcelona, Spain.; Institute of Pathology, Medical Faculty of the Ulm University, Ulm, Germany.; Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Essen, Germany. [email protected].; German Cancer Consortium (DKTK), Essen, Germany. [email protected].; Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].; Bioinformatics and Omics Data Analytics (B240), German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].; Institute for Informatics, Faculty of Computer Science and Medical Faculty, University of Augsburg, Augsburg, Germany. [email protected].; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany. [email protected].; Intitute of Human Genetics, Christian-Albrechts-University, Kiel, Germany. [email protected].

DOI: 10.1038/s41375-021-01251-z

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MeSH Terms: Adult, B-Lymphocytes, Cell Line, Cell Line, Tumor, Genes, Immunoglobulin, Genome, Germinal Center, HeLa Cells, Hep G2 Cells, Human Umbilical Vein Endothelial Cells, Humans, Immunoglobulin Class Switching, K562 Cells, Lymphoma, B-Cell, MCF-7 Cells, Mutation, Somatic Hypermutation, Immunoglobulin, V(D)J Recombination