Focal structural variants revealed by whole genome sequencing disrupt the histone demethylase KDM4C in B-cell lymphomas.

Autor: Lopez C; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, 89081, Germany; Institute of Human Genetics, Christian-Albrechts-University, Kiel, 24105., Schleussner N; Max-Delbruck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, 13125, Germany; Hematology, Oncology and Tumor Immunology, Charite - Universitatsmedizin Berlin, Berlin, 12200, Germany, and Experimental and Clinical Research Center, a joint cooperation between the MDC and the Charite, Berlin, 13125., Bernhart SH; Interdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, 04107, Germany; Bioinformatics Group, Department of Computer, University of Leipzig, Leipzig, 04107, Germany; Transcriptome Bioinformatics, LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, 04107., Kleinheinz K; Department for Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology and Bioquant, University of Heidelberg, Heidelberg, 69120., Sungalee S; EMBL Heidelberg, Genome Biology Unit, Heidelberg, 69117., Sczakiel HL; Max-Delbruck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, 13125, Germany; Hematology, Oncology and Tumor Immunology, Charite - Universitatsmedizin Berlin, Berlin, 12200, Germany, and Experimental and Clinical Research Center, a joint cooperation between the MDC and the Charite, Berlin, 13125., Kretzmer H; Interdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, 04107, Germany; Bioinformatics Group, Department of Computer, University of Leipzig, Leipzig, 04107, Germany; Transcriptome Bioinformatics, LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, 04107, Germany; Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin., Toprak UH; Bioinformatics and Omics Data Analytics (B240), German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, 69120, Germany; Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), Division of Neuroblastoma Genomics (B087, German Cancer Research Center (DKFZ), Heidelberg, 69120., Glaser S; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, 89081., Wagener R; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, 89081, Germany; Institute of Human Genetics, Christian-Albrechts-University, Kiel, 24105., Ammerpohl O; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, 89081, Germany; Institute of Human Genetics, Christian-Albrechts-University, Kiel, 24105., Bens S; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, 89081, Germany; Institute of Human Genetics, Christian-Albrechts-University, Kiel, 24105., Giefing M; Institute of Human Genetics, Christian-Albrechts-University, Kiel, 24105, Germany; Institute of Human Genetics, Polish Academy of Sciences, Poznan, 60-479, Poland., Sanchez JCG; BioQuant and Biochemie Zentrum Heidelberg (BZH), Heidelberg University, Heidelberg, 69120., Apic G; BioQuant and Biochemie Zentrum Heidelberg (BZH), Heidelberg University, Heidelberg, 69120., Hubschmann D; German Cancer Consortium (DKTK), Heidelberg, 69120, Germany; Heidelberg Institute of Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, 69120, Germany; Computational Oncology, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, 69120., Janz M; Max-Delbruck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, 13125, Germany; Hematology, Oncology and Tumor Immunology, Charite - Universitatsmedizin Berlin, Berlin, 12200, Germany, and Experimental and Clinical Research Center, a joint cooperation between the MDC and the Charite, Berlin, 13125., Kreuz M; Institute for Medical Informatics Statistics and Epidemiology, Leipzig, 04107., Mottok A; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, 89081., Muller JM; Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Albert-Ludwigs-Universitat Freiburg, Freiburg, 79104., Seufert J; Bioinformatics and Omics Data Analytics (B240), German Cancer Research Center (DKFZ), Heidelberg, 69120., Hoffmann S; Interdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, 04107, Germany; Bioinformatics Group, Department of Computer, University of Leipzig, Leipzig, 04107, Germany; Transcriptome Bioinformatics, LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, 04107, Germany; Leibniz Institute on Ageing-Fritz Lipmann Institute (FLI), Computational Biology, Jena, 07745., Korbel JO; EMBL Heidelberg, Genome Biology Unit, Heidelberg, 69117., Russell RB; BioQuant and Biochemie Zentrum Heidelberg (BZH), Heidelberg University, Heidelberg, 69120., Schule R; Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Albert-Ludwigs-Universitat Freiburg, Freiburg, 79104, Germany; BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, 79104., Trumper L; Department of Hematology and Oncology, Georg-August-University of Gottingen, Gottingen, 37075., Klapper W; Hematopathology Section, Christian-Albrechts-University, Kiel, 24105., Radlwimmer B; Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120, Heidelberg., Lichter P; Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120, Heidelberg., Kuppers R; Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, 45147, Germany, and German Cancer Consortium (DKTK)., Schlesner M; Bioinformatics and Omics Data Analytics (B240), German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany; Biomedical Informatics, Data Mining and Data Analytics, Augsburg University, Augsburg, 86159., Mathas S; Max-Delbruck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, 13125, Germany; Hematology, Oncology and Tumor Immunology, Charite - Universitatsmedizin Berlin, Berlin, 12200, Germany, and Experimental and Clinical Research Center, a joint cooperation between the MDC and the Charite, Berlin, 13125., Siebert R; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, 89081, Germany; Institute of Human Genetics, Christian-Albrechts-University, Kiel, 24105.
Jazyk: angličtina
Zdroj: Haematologica [Haematologica] 2023 Feb 01; Vol. 108 (2), pp. 543-554. Date of Electronic Publication: 2023 Feb 01.
DOI: 10.3324/haematol.2021.280005
Abstrakt: Histone methylation-modifiers, such as EZH2 and KMT2D, are recurrently altered in B-cell lymphomas. To comprehensively describe the landscape of alterations affecting genes encoding histone methylation-modifiers in lymphomagenesis we investigated whole genome and transcriptome data of 186 mature B-cell lymphomas sequenced in the ICGC MMML-Seq project. Besides confirming common alterations of KMT2D (47% of cases), EZH2 (17%), SETD1B (5%), PRDM9 (4%), KMT2C (4%), and SETD2 (4%), also identified by prior exome or RNA-sequencing studies, we here found recurrent alterations to KDM4C in chromosome 9p24, encoding a histone demethylase. Focal structural variation was the main mechanism of KDM4C alterations, and was independent from 9p24 amplification. We also identified KDM4C alterations in lymphoma cell lines including a focal homozygous deletion in a classical Hodgkin lymphoma cell line. By integrating RNA-sequencing and genome sequencing data we predict that KDM4C structural variants result in loss-offunction. By functional reconstitution studies in cell lines, we provide evidence that KDM4C can act as a tumor suppressor. Thus, we show that identification of structural variants in whole genome sequencing data adds to the comprehensive description of the mutational landscape of lymphomas and, moreover, establish KDM4C as a putative tumor suppressive gene recurrently altered in subsets of B-cell derived lymphomas.
Databáze: MEDLINE
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