Format

Send to

Choose Destination
Blood. 2019 Feb 28;133(9):940-951. doi: 10.1182/blood-2018-07-862151. Epub 2018 Dec 11.

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

Author information

1
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
2
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
3
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
4
Hospital Nostra Senyora de Meritxell, Escaldes-Engordany, Andorra.
5
Cytogenetic Laboratory and.
6
Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland.
7
Institute of Human Genetics, Ulm University Medical Center, Ulm University, Ulm, Germany.
8
Institute of Human Genetics, Christian Albrechts University Kiel/University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
9
Institut de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
10
Institute of Pathology and.
11
Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
12
Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA.
13
Cleveland Clinic Foundation, Cleveland, OH.
14
Department of Pathology and Microbiology and.
15
Division of Oncology and Hematology, Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE.
16
Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
17
Oslo University Hospital, Oslo, Norway.
18
Department of Pathology, City of Hope National Medical Center, Duarte, CA.
19
VU University Medical Center, Amsterdam, The Netherlands.
20
Hospital Universitari de Bellvitge-Institut d'Investigació Biomédica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain.
21
Haematological Malignancy Diagnostic Service (HMDS) Laboratory, St. James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
22
Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
23
Joint Barcelona Supercomputing Center (BSC)-Centre for Genomic Regulation (CRG)-Institute for Research in Biomedicine (IRB) Research Programme in Computational Biology, Barcelona, Spain.
24
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
25
Centre Nacional d'Anàlisi Genòmica (CNAG)-CRG, Barcelona, Spain.
26
Laboratori de Citogenètica Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain.
27
Grup de Recerca Translacional en Neoplàsies Hematològiques, Cancer Research Programme, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM)-Hospital del Mar, Barcelona, Spain.
28
Hematopathology Section, Hospital Clínic de Barcelona, Barcelona, Spain.
29
Department of Clinical Pathology and.
30
Dr Margarete "Fischer Bosch Institute" of Clinical Pharmacology, Robert Bosch Hospital, Stuttgart, Germany.
31
Institute of Pathology, Eberhard Karls University of Tübingen, Tübingen, Germany.
32
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; and.
33
Department of Anatomic Pathology, University of Barcelona, Barcelona, Spain.

Abstract

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.

PMID:
30538135
PMCID:
PMC6396173
[Available on 2020-02-28]
DOI:
10.1182/blood-2018-07-862151

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center