title: The PCBP1 gene encoding poly(rC) binding protein I is recurrently mutated in Burkitt lymphoma.
abstract: The genetic hallmark of Burkitt lymphoma is the translocation t(8;14)(q24;q32), or one of its light chain variants, resulting in IG-MYC juxtaposition. However, these translocations alone are insufficient to drive lymphomagenesis, which requires additional genetic changes for malignant transformation. Recent studies of Burkitt lymphoma using next generation sequencing approaches have identified various recurrently mutated genes including ID3, TCF3, CCND3, and TP53. Here, by using similar approaches, we show that PCBP1 is a recurrently mutated gene in Burkitt lymphoma. By whole-genome sequencing, we identified somatic mutations in PCBP1 in 3/17 (18%) Burkitt lymphomas. We confirmed the recurrence of PCBP1 mutations by Sanger sequencing in an independent validation cohort, finding mutations in 3/28 (11%) Burkitt lymphomas and in 6/16 (38%) Burkitt lymphoma cell lines. PCBP1 is an intron-less gene encoding the 356 amino acid poly(rC) binding protein 1, which contains three K-Homology (KH) domains and two nuclear localization signals. The mutations predominantly (10/12, 83%) affect the KH III domain, either by complete domain loss or amino acid changes. Thus, these changes are predicted to alter the various functions of PCBP1, including nuclear trafficking and pre-mRNA splicing. Remarkably, all six primary Burkitt lymphomas with a PCBP1 mutation expressed MUM1/IRF4, which is otherwise detected in around 20-40% of Burkitt lymphomas. We conclude that PCBP1 mutations are recurrent in Burkitt lymphomas and might contribute, in cooperation with other mutations, to its pathogenesis.
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Rabea
authors.initials: R
authors.lastname: Wagener
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Sietse M
authors.initials: SM
authors.lastname: Aukema
authors.affiliation: Deutsches Krebsforschungszentrum Heidelberg (DKFZ), Division Theoretical Bioinformatics, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schlesner
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Haake
authors.affiliation: Non-Hodgkin Lymphoma Berlin-Frankfurt-Münster Group Study Center, Department of Pediatric Hematology and Oncology, University Children's Hospital, Münster, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Burkhardt
authors.affiliation: Department of Pediatrics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University, Kiel, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Claviez
authors.affiliation: Leibniz-Institute DSMZ- German Collection of Microorganisms and Cell Cultures GmbH, Braunschweig, Germany.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Drexler
authors.affiliation: Institute of Pathology, Campus Benjamin Franklin, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kreuz
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany.
authors.forename: Maciej
authors.initials: M
authors.lastname: Rosolowski
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: López
authors.affiliation: Institute of Pathology, Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Richter
authors.affiliation: Department of Pediatric Hematology and Oncology, Justus Liebig University, Giessen, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Rohde
authors.affiliation: Cell Networks, Bioquant, University of Heidelberg, Heidelberg, Germany.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Betts
authors.affiliation: Cell Networks, Bioquant, University of Heidelberg, Heidelberg, Germany.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Russell
authors.affiliation: Transcriptome Bioinformatics, LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
authors.forename: Stephan H
authors.initials: SH
authors.lastname: Bernhart
authors.affiliation: Transcriptome Bioinformatics, LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
authors.forename: Steve
authors.initials: S
authors.lastname: Hoffmann
authors.affiliation: Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schilhabel
authors.affiliation: Institute of Hematopathology, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Szczepanowski
authors.affiliation: Department of Hematology and Oncology, Georg-August University of Göttingen, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Trümper
authors.affiliation: Institute of Hematopathology, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D005260:Female; D015870:Gene Expression; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C094604:PCBP1 protein, human; D020033:Protein Isoforms; D016601:RNA-Binding Proteins