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Nat Commun. 2019 Mar 29;10(1):1459. doi: 10.1038/s41467-019-08578-3.

Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma.

Author information

1
Institute of Human Genetics, Ulm University and Ulm University Medical Center, 89081, Ulm, Germany.
2
Institute of Human Genetics, Christian-Albrechts-University, 24105, Kiel, Germany.
3
Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
4
Department for Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology and Bioquant, University of Heidelberg, 69120, Heidelberg, Germany.
5
Hematopathology Section, Christian-Albrechts-University, 24105, Kiel, Germany.
6
Pediatric Hematology and Oncology, University Hospital Giessen, 35392, Giessen, Germany.
7
Interdisciplinary Center for Bioinformatics, University of Leipzig, 04107, Leipzig, Germany.
8
Bioinformatics Group, Department of Computer, University of Leipzig, 04107, Leipzig, Germany.
9
Transcriptome Bioinformatics, LIFE Research Center for Civilization Diseases, University of Leipzig, 04107, Leipzig, Germany.
10
Department of Pediatric Immunology, Hematology and Oncology, University Hospital, 69120, Heidelberg, Germany.
11
German Cancer Research Center (DKFZ), Division of Stem Cells and Cancer, Heidelberg, Germany and Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120, Heidelberg, Germany.
12
Bioinformatics and Omics Data Analytics (B240), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
13
Faculty of Biosciences, Heidelberg University, 69120, Heidelberg, Germany.
14
Cell Networks, Bioquant and Biochemistry CenterBiochemie Zentrum Heidelberg (BZH), University of Heidelberg, 69120, Heidelberg, Germany.
15
Institute for Medical Informatics Statistics and Epidemiology, 04107, Leipzig, Germany.
16
Genome Biology Unit, EMBL Heidelberg, 69117, Heidelberg, Germany.
17
Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
18
Division of Applied Bioinformatics (G200), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
19
Medical Faculty Heidelberg, Heidelberg University, 69120, Heidelber, Germany.
20
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, 14195, Berlin, Germany.
21
Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, 24105, Kiel, Germany.
22
Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, 40225, Düsseldorf, Germany.
23
Senckenberg Institute of Pathology, University of Frankfurt Medical School, 60590, Frankfurt am Main, Germany.
24
Institute of Pathology, Charité - University Medicine Berlin, 10117, Berlin, Germany.
25
Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105, Kiel, Germany.
26
Institute of Pathology, Comprehensive Cancer Center Mainfranken, University of Würzburg, 97080, Würzburg, Germany.
27
Pathodiagnostik Berlin, 12099, Berlin, Germany.
28
Department for Internal Medicine III, Ulm University, 89081, Ulm, Germany.
29
Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, 45147, Essen, Germany.
30
Institute of Pathology, University of Ulm and University Hospital of Ulm, 89081, Ulm, Germany.
31
Department of Hematology and Oncology, Georg-August-University of Göttingen, 37075, Göttingen, Germany.
32
Computational Biology, Leibniz Institute on Ageing-Fritz Lipmann Institut (FLI), 07745, Jena, Germany.
33
University Hospital Münster - Pediatric Hematology and Oncology, 48149, Münster, Germany.
34
Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. m.schlesner@Dkfz-Heidelberg.de.
35
Bioinformatics and Omics Data Analytics (B240), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. m.schlesner@Dkfz-Heidelberg.de.
36
Institute of Human Genetics, Ulm University and Ulm University Medical Center, 89081, Ulm, Germany. reiner.siebert@uni-ulm.de.
37
Institute of Human Genetics, Christian-Albrechts-University, 24105, Kiel, Germany. reiner.siebert@uni-ulm.de.

Abstract

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.

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