CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1− mantle cell lymphoma

  • David Martín-Garcia
    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
  • Alba Navarro
    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
  • Rafael Valdés-Mas
    Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain;
  • Guillem Clot
    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
  • Jesús Gutiérrez-Abril
    Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain;
  • Miriam Prieto
    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
  • Inmaculada Ribera-Cortada
    Hospital Nostra Senyora de Meritxell, Escaldes-Engordany, Andorra;
  • Renata Woroniecka
    Cytogenetic Laboratory and
  • Grzegorz Rymkiewicz
    Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Institute–Oncology Center, Warsaw, Poland;
  • Susanne Bens
    Institute of Human Genetics, Ulm University Medical Center, Ulm University, Ulm, Germany;
  • Laurence de Leval
    Institut de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland;
  • Andreas Rosenwald
    Institute of Pathology and
  • Judith A. Ferry
    Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA;
  • Eric D. Hsi
    Cleveland Clinic Foundation, Cleveland, OH;
  • Kai Fu
    Department of Pathology and Microbiology and
  • Jan Delabie
    Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada;
  • Dennis Weisenburger
    Department of Pathology, City of Hope National Medical Center, Duarte, CA;
  • Daphne de Jong
    VU University Medical Center, Amsterdam, The Netherlands;
  • Fina Climent
    Hospital Universitari de Bellvitge–Institut d’Investigació Biomédica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Spain;
  • Sheila J. O’Connor
    Haematological Malignancy Diagnostic Service (HMDS) Laboratory, St. James’s Institute of Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom;
  • Steven H. Swerdlow
    Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA;
  • David Torrents
    Joint Barcelona Supercomputing Center (BSC)–Centre for Genomic Regulation (CRG)–Institute for Research in Biomedicine (IRB) Research Programme in Computational Biology, Barcelona, Spain;
  • Sergi Beltran
    Centre Nacional d’Anàlisi Genòmica (CNAG)–CRG, Barcelona, Spain;
  • Blanca Espinet
    Laboratori de Citogenètica Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain;
  • Blanca González-Farré
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain;
  • Luis Veloza
    Hematopathology Section, Hospital Clínic de Barcelona, Barcelona, Spain;
  • Dolors Costa
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain;
  • Estella Matutes
    Hematopathology Section, Hospital Clínic de Barcelona, Barcelona, Spain;
  • Reiner Siebert
    Institute of Human Genetics, Ulm University Medical Center, Ulm University, Ulm, Germany;
  • German Ott
    Department of Clinical Pathology and
  • Leticia Quintanilla-Martinez
    Institute of Pathology, Eberhard Karls University of Tübingen, Tübingen, Germany;
  • Elaine S. Jaffe
    Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; and
  • Carlos López-Otín
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain;
  • Itziar Salaverria
    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
  • Xose S. Puente
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain;
  • Elias Campo
    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
  • Sílvia Beà
    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;

抄録

<jats:title>Abstract</jats:title> <jats:p>Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1− MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1−/D2− MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1−/SOX11+ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2 rearrangements in 39 cases (70%) but not CCND3 rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3 that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1− MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1 and CCNE2. These cases had blastoid morphology, high genomic complexity, and CDKN2A and RB1 deletions. Both genomic and gene-expression profiles of cyclin D1− MCL cases were indistinguishable from cyclin D1+ MCL. In conclusion, virtually all cyclin D1− MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1−/D2−/D3− MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1− MCL.</jats:p>

収録刊行物

  • Blood

    Blood 133 (9), 940-951, 2019-02-28

    American Society of Hematology

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