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 D12 MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclinD12/D22MCL remains elusive. To identify other potentialmechanisms driving MCL pathogenesis, we investigated 56 cyclin D12/SOX111 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 5 2) and IGL (n 5 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 D12 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 D12 MCL cases were indistinguishable from cyclin D11 MCL. In conclusion, virtually all cyclin D12 MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D12/D22/D32 MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D12 MCL.
Original language | English |
---|---|
Pages (from-to) | 940-951 |
Number of pages | 12 |
Journal | Blood |
Volume | 133 |
Issue number | 9 |
DOIs | |
Publication status | Published - 1 Jan 2019 |
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In: Blood, Vol. 133, No. 9, 01.01.2019, p. 940-951.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D12 mantle cell lymphoma
AU - Martín-Garcia, David
AU - Navarro, Alba
AU - Valdés-Mas, Rafael
AU - Clot, Guillem
AU - Gutiérrez-Abril, Jesús
AU - Prieto, Miriam
AU - Ribera-Cortada, Inmaculada
AU - Woroniecka, Renata
AU - Rymkiewicz, Grzegorz
AU - Bens, Susanne
AU - de Leval, Laurence
AU - Rosenwald, Andreas
AU - Ferry, Judith A
AU - Hsi, Eric D
AU - Fu, Kai
AU - Delabie, Jan
AU - Weisenburger, Dennis
AU - de Jong, Daphne
AU - Climent, Fina
AU - O'Connor, Sheila J
AU - Swerdlow, Steven H
AU - Torrents, David
AU - Beltran, Sergi
AU - Espinet, Blanca
AU - González-Farré, Blanca
AU - Veloza, Luis
AU - Costa, Dolors
AU - Matutes, Estella
AU - Siebert, Reiner
AU - Ott, German
AU - Quintanilla-Martinez, Leticia
AU - Jaffe, Elaine S
AU - López-Otín, Carlos
AU - Salaverria, Itziar
AU - Puente, Xose S
AU - Campo, Elias
AU - Beà, Sílvia
N1 - Funding Information: 1Institutd’InvestigacionsBiomèdiquesAugustPiiSunyer(IDIBAPS),Barcelona,Spain;2CentrodeInvestigaciónBiomédicaenReddeCáncer(CIBERONC),Madrid, Spain; 3Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain; 4Hospital Nostra Senyora de Meritxell, Escaldes-Engordany, Andorra; 5Cytogenetic Laboratory and 6Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Institute– Oncology Center, Warsaw, Poland; 7Institute of Human Genetics, Ulm University Medical Center, Ulm University, Ulm, Germany;8Institute of Human Genetics, Christian Albrechts University Kiel/University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; 9Institut de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; 10Institute of Pathology and 11Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany; 12Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA; 13Cleveland Clinic Foundation, Cleveland, OH; 14Department of Pathology and Microbiology and 15Division of Oncology and Hematology, Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE; 16Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 17Oslo University Hospital, Oslo, Norway; 18Department of Pathology, City of Hope National Medical Center, Duarte, CA; 19VU University Medical Center, Amsterdam, The Netherlands; 20Hospital Universitari de Bellvitge–Institut d’Investigació Biomédica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Spain; 21Haematological Malignancy Diagnostic Service (HMDS) Laboratory, St. James’s Institute of Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom; 22Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA; 23Joint Barcelona Supercomputing Center (BSC)–Centre for Genomic Regulation (CRG)–Institute for Research in Biomedicine (IRB) Research Programme in Computational Biology, Barcelona, Spain; 24Institució Catalana de Recerca i Estudis Avançats(ICREA),Barcelona,Spain;25CentreNacionald’AnàlisiGenòmica(CNAG)–CRG,Barcelona,Spain;26LaboratorideCitogenèticaMolecular,Serveide Patologia,HospitaldelMar,Barcelona,Spain;27GrupdeRecercaTranslacionalenNeoplàsiesHematològiques,CancerResearchProgramme,InstitutHospitaldel Mar d’Investigacions Mèdiques (IMIM)–Hospital del Mar, Barcelona, Spain; 28Hematopathology Section, Hospital Clínic de Barcelona, Barcelona, Spain; 29Department of Clinical Pathology and 30Dr Margarete “Fischer Bosch Institute” of Clinical Pharmacology, Robert Bosch Hospital, Stuttgart, Germany; 31InstituteofPathology,EberhardKarlsUniversityofTübingen,Tübingen,Germany;32LaboratoryofPathology,CenterforCancerResearch,NationalCancer Institute, National Institutes of Health, Bethesda, MD; and 33Department of Anatomic Pathology, University of Barcelona, Barcelona, Spain Funding Information: The authors thank the Hematopathology Collection for sample procurement; Silvia Martín, Noelia García, Candida Gómez, Cristina Cap-devila, and Maria Rodríguez-Rivera for excellent technical assistance; the Molecular Cytogenetic Platform of IMIM, Hospital del Mar (Barcelona) for providing BAC clones; the support of the technical staff of the Molecular Cytogenetic laboratories of the Institutes of Human Genetics in Kiel and Ulm; and Montserrat Puiggros from the Barcelona Supercomputing Center for support in WGS analysis. The authors also thank the contributors of individual cases: Iwona Wlodarska (Leuven, Belgium), Philippe Gaulard (Creteil, France), Wendy Erber (Crawley, Australia), Pilar Forcada (Terrassa, Spain), Grevelyn Sosa Rotundo (Madrid, Spain), Alejandra Carvajal (San Jose, Costa Rica), Camille Gonzalez (New York, NY), Nhora Silva Perez (Cali, Colombia), Lluís Rodríguez (Vic, Spain). The arrays were performed at qGenomics (www.qgenomics.com), CeGen (PTI3/0001, ISCIII-SGEFI/ FEDER), and the IDIBAPS Genomics core facility. This work was developed at the Centro Esther Koplowitz (CEK), Barcelona, Spain. Funding Information: This work was supported by research funding from Fondo de Inves-tigaciones Sanitarias, Instituto de Salud Carlos III PI14/00571 and PI17/ 01061 (S. Beà); Fundació La Marató de TV3-Càncer/2013410 (S. Beà); Fundació Crèdit Andorrà, Ministerio de Economía y Competitividad, SAF2015-64885-R (E.C.); SAF2017-87811-R (X.S.P.) from Plan Nacional de I+D+I, Generalitat de Catalunya Suport Grups de Recerca 2017-SGR-709 (S. Beà); 2017-SGR-1142 (E.C.); and the European Regional Development Fund Una Manera de fer Europa, CERCA Programme/Generalitat de Catalunya. Personal staff (Miriam Prieto and Noelia García) are supported by Acció Instrumental d’Incorporació de Científics i Tecnòlegs PERIS 2016 (SLT002/16/00347 and SLT002/16/00336 from Generalitat de Catalunya). Funding Information: Conflict-of-interest disclosure: E.C. has received research funding from Gilead Sciences; has been a consultant for Takeda, Celgene, and Gilead; and is an author in a Lymphoma and Leukemia Molecular Profiling Project (LLMPP) patent “Method for selecting and treating lymphoma types” PCT/ US14/64161. The remaining authors declare no competing financial interests. Publisher Copyright: © 2019 American Society of Hematology. All rights reserved. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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 D12 MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclinD12/D22MCL remains elusive. To identify other potentialmechanisms driving MCL pathogenesis, we investigated 56 cyclin D12/SOX111 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 5 2) and IGL (n 5 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 D12 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 D12 MCL cases were indistinguishable from cyclin D11 MCL. In conclusion, virtually all cyclin D12 MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D12/D22/D32 MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D12 MCL.
AB - 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 D12 MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclinD12/D22MCL remains elusive. To identify other potentialmechanisms driving MCL pathogenesis, we investigated 56 cyclin D12/SOX111 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 5 2) and IGL (n 5 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 D12 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 D12 MCL cases were indistinguishable from cyclin D11 MCL. In conclusion, virtually all cyclin D12 MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D12/D22/D32 MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D12 MCL.
UR - http://www.scopus.com/inward/record.url?scp=85064671065&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/blood-2018-07-862151
DO - https://doi.org/10.1182/blood-2018-07-862151
M3 - Article
C2 - 30538135
SN - 0006-4971
VL - 133
SP - 940
EP - 951
JO - Blood
JF - Blood
IS - 9
ER -