ArticleLeukemia2021
Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas.
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Article in Leukemia, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44citing papers in PubMed
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44 citing papers in PubMed, 56 citations in OpenAlex.
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- "In situ" MYC rearrangement and amplification as a secondary change in a case of High-grade B cell lymphoma with 11q aberration.Annals of hematology · 2025Article
- Comparative DNA Methylation Profiling of Human and Murine ALK-Positive B-Cell Neoplasms.Genes, chromosomes & cancer · 2025Article
- Selective Enhancer Dependencies in MYC-Intact and MYC-Rearranged Germinal Center B-cell Diffuse Large B-cell Lymphoma.Blood cancer discovery · 2025Article
- Audit of B-cell cancer genes.Blood advances · 2025Review
- Subgrouping germinal center-derived B-cell lymphomas based on machine learning-deduced DNA methylation modules.Leukemia · 2025Article
- MYC-rearranged mature B-cell lymphomas in children and young adults are molecularly Burkitt Lymphoma.Blood cancer journal · 2024Article
- Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas.Nature communications · 2024Article
- Large B-cell lymphomas with CCND1 rearrangement have different immunoglobulin gene breakpoints and genomic profile than mantle cell lymphoma.Blood cancer journal · 2024Article
- MEF2B C-terminal mutations enhance transcriptional activity and stability to drive B cell lymphomagenesis.Nature communications · 2024Article
- Article
- The Molecular Landscape of Primary CNS Lymphomas (PCNSLs) in Children and Young Adults.Cancers · 2024Article
- Genetic alterations in mature B- and T-cell lymphomas - a practical guide to WHO-HAEM5.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2024Article
- Non-IG::MYC in diffuse large B-cell lymphoma confers variable genomic configurations and MYC transactivation potential.Leukemia · 2024Article
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Authors and funding
70 authors at 20 institutions in 5 countries.
Daniel Hübschmann *Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.ORCID http://orcid.org/0000-0002-6041-7049
Kortine Kleinheinz *Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Rabea Wagener *Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.
Stephan H Bernhart *Interdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, Germany.
Cristina López *Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.
Umut H ToprakDivision of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Stephanie SungaleeEMBL Heidelberg, Genome Biology, Heidelberg, Germany.
Naveed IshaqueDivision of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Helene KretzmerInterdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, Germany.
Markus KreuzInstitute for Medical Informatics Statistics and Epidemiology, Leipzig, Germany.
Sebastian M WaszakEMBL Heidelberg, Genome Biology, Heidelberg, Germany.ORCID http://orcid.org/0000-0003-3042-9521
Nagarajan ParamasivamDivision of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ole AmmerpohlInstitute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.
Sietse M AukemaIntitute of Human Genetics, Christian-Albrechts-University, Kiel, Germany.ORCID http://orcid.org/0000-0001-5824-0320
Renée BeekmanInstitut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Anke K BergmannIntitute of Human Genetics, Christian-Albrechts-University, Kiel, Germany.
Matthias BiegDivision of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Hans BinderInterdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, Germany.
Arndt BorkhardtUniversity of Duesseldorf, Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Düsseldorf, Germany.ORCID http://orcid.org/0000-0002-6121-4737
Christoph BorstDepartment of Internal Medicine/Hematology, Friedrich-Ebert-Hospital, Neumünster, Neumünster, Germany.
Benedikt BrorsDivision of Applied Bioinformatics (G200), German Cancer Research Center (DKFZ), Heidelberg, Germany.ORCID http://orcid.org/0000-0001-5940-3101
Philipp BrunsDivision of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Enrique Carrillo de Santa PauStructural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.ORCID http://orcid.org/0000-0002-2310-2267
Alexander ClaviezDepartment of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Gero DooseInterdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, Germany.
Andrea HaakeIntitute of Human Genetics, Christian-Albrechts-University, Kiel, Germany.
Dennis KarschDepartment for Internal Medicine II, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Siegfried HaasDepartment of Internal Medicine/Hematology, Friedrich-Ebert-Hospital, Neumünster, Neumünster, Germany.
Martin-Leo HansmannSenckenberg Institute of Pathology, University of Frankfurt Medical School, Frankfurt am Main, Germany.
Jessica I HoellUniversity of Duesseldorf, Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Düsseldorf, Germany.
Volker HovestadtDivision of Molecular Genetics, German Cancer Consortium (DKFK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Bingding HuangDivision of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.ORCID http://orcid.org/0000-0002-4748-2882
Michael HummelInstitute of Pathology, Charité - University Medicine Berlin, Berlin, Germany.
Christina Jäger-SchmidtDivision of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jules N A KerssemakersDivision of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.ORCID http://orcid.org/0000-0002-0460-7032
Jan O KorbelEMBL Heidelberg, Genome Biology, Heidelberg, Germany.ORCID http://orcid.org/0000-0002-2798-3794
Dieter KubeDepartment of Hematology and Oncology, Georg-Augusts-University of Göttingen, Göttingen, Germany.
Chris LawerenzDivision of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Dido LenzeInstitute of Pathology, Charité - University Medicine Berlin, Berlin, Germany.
Joost H A MartensDepartment of Molecular Biology, Radboud University, Faculty of Science, Nijmegen, The Netherlands.
German OttDepartment of Clinical Pathology, Robert-Bosch-Hospital and Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, Stuttgart, Germany.
Bernhard RadlwimmerDivision of Molecular Genetics, German Cancer Consortium (DKFK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Eva ReisingerDivision of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Julia RichterIntitute of Human Genetics, Christian-Albrechts-University, Kiel, Germany.ORCID http://orcid.org/0000-0002-9543-4084
Daniel RicoStructural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.ORCID http://orcid.org/0000-0002-6561-2310
Philip RosenstielInstitute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
Andreas RosenwaldInstitute of Pathology, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany.
Markus SchillhabelInstitute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
Stephan StilgenbauerDepartment for Internal Medicine III, Ulm University, Ulm, Germany.
Peter F StadlerBioinformatics Group, Department of Computer, University of Leipzig, Leipzig, Germany.ORCID http://orcid.org/0000-0002-5016-5191
José I Martín-SuberoInstitut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.ORCID http://orcid.org/0000-0001-8809-5195
Monika SzczepanowskiHematopathology Section, Christian-Albrechts-University, Kiel, Germany.ORCID http://orcid.org/0000-0001-5482-8880
Gregor WarsowDivision of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Marc A WenigerInstitute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Essen, Germany.
Marc ZapatkaDivision of Molecular Genetics, German Cancer Consortium (DKFK), German Cancer Research Center (DKFZ), Heidelberg, Germany.ORCID http://orcid.org/0000-0001-8287-5967
Alfonso ValenciaBarcelona Supercomputing Centre (BSC), Barcelona, Spain.
Hendrik G StunnenbergDepartment of Molecular Biology, Radboud University, Faculty of Science, Nijmegen, The Netherlands.
Peter LichterDivision of Molecular Genetics, German Cancer Consortium (DKFK), German Cancer Research Center (DKFZ), Heidelberg, Germany.ORCID http://orcid.org/0000-0002-2960-5279
Peter MöllerInstitute of Pathology, Medical Faculty of the Ulm University, Ulm, Germany.
Markus LoefflerInstitute for Medical Informatics Statistics and Epidemiology, Leipzig, Germany.
Roland EilsDivision of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Wolfram KlapperHematopathology Section, Christian-Albrechts-University, Kiel, Germany.ORCID http://orcid.org/0000-0001-7208-4117
Steve HoffmannInterdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, Germany.
Lorenz TrümperDepartment of Hematology and Oncology, Georg-Augusts-University of Göttingen, Göttingen, Germany.
ICGC MMML-Seq consortium
ICGC DE-Mining consortium
BLUEPRINT consortium
Ralf KüppersInstitute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Essen, Germany. ralf.kueppers@uk-essen.de.ORCID http://orcid.org/0000-0002-6691-7191
Matthias SchlesnerDivision of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany. matthias.schlesner@informatik.uni-augsburg.de.ORCID http://orcid.org/0000-0002-5896-4086
Reiner SiebertInstitute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany. reiner.siebert@uni-ulm.de.
German Cancer Research Center · DEChristian-Albrechts-Universität zu Kiel · DEUniversität Ulm · DELeipzig University · DEBerlin Institute of Health at Charité - Universitätsmedizin Berlin · DEConsorci Institut D'Investigacions Biomediques August Pi I Sunyer · ESFriedrich-Ebert-Krankenhaus · DEGerman Cancer Society · DEHeinrich Heine University Düsseldorf · DERadboud University Nijmegen · NLUniversity Hospital Schleswig-Holstein · DEUniversity of Göttingen · DEComprehensive Cancer Center Mainfranken · DEGoethe University Frankfurt · DEInstitució Catalana de Recerca i Estudis Avançats · ESMadrid Institute for Advanced Studies · ESMax Planck Institute for Molecular Genetics · DERobert Bosch Hospital · DESpanish National Cancer Research Centre · ESUniversity of Augsburg · DE
Funding
No grant is acknowledged in the PubMed record.
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.
Indexed as
AdultB-LymphocytesCell LineCell Line, TumorGenes, ImmunoglobulinGenomeGerminal CenterHeLa CellsHep G2 CellsHumansHuman Umbilical Vein Endothelial CellsImmunoglobulin Class SwitchingK562 CellsLymphoma, B-CellMCF-7 CellsMutation
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