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;
Abstract
<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>
Journal
-
- Blood
-
Blood 133 (9), 940-951, 2019-02-28
American Society of Hematology
- Tweet
Details 詳細情報について
-
- CRID
- 1360579816496519296
-
- ISSN
- 15280020
- 00064971
-
- Data Source
-
- Crossref