PMID- 30538135
OWN - NLM
STAT- MEDLINE
DCOM- 20191112
LR  - 20210202
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 133
IP  - 9
DP  - 2019 Feb 28
TI  - CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1(-) 
      mantle cell lymphoma.
PG  - 940-951
LID - 10.1182/blood-2018-07-862151 [doi]
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 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.
CI  - (c) 2019 by The American Society of Hematology.
FAU - Martin-Garcia, David
AU  - Martin-Garcia D
AUID- ORCID: 0000-0002-0289-5915
AD  - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, 
      Spain.
AD  - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain.
FAU - Navarro, Alba
AU  - Navarro A
AD  - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, 
      Spain.
AD  - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain.
FAU - Valdes-Mas, Rafael
AU  - Valdes-Mas R
AD  - Departamento de Bioquimica y Biologia Molecular, Instituto Universitario de 
      Oncologia, Universidad de Oviedo, Oviedo, Spain.
FAU - Clot, Guillem
AU  - Clot G
AUID- ORCID: 0000-0003-2588-7413
AD  - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, 
      Spain.
AD  - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain.
FAU - Gutierrez-Abril, Jesus
AU  - Gutierrez-Abril J
AD  - Departamento de Bioquimica y Biologia Molecular, Instituto Universitario de 
      Oncologia, Universidad de Oviedo, Oviedo, Spain.
FAU - Prieto, Miriam
AU  - Prieto M
AD  - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, 
      Spain.
AD  - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain.
FAU - Ribera-Cortada, Inmaculada
AU  - Ribera-Cortada I
AD  - Hospital Nostra Senyora de Meritxell, Escaldes-Engordany, Andorra.
FAU - Woroniecka, Renata
AU  - Woroniecka R
AD  - Cytogenetic Laboratory and.
FAU - Rymkiewicz, Grzegorz
AU  - Rymkiewicz G
AD  - Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie 
      Institute-Oncology Center, Warsaw, Poland.
FAU - Bens, Susanne
AU  - Bens S
AD  - Institute of Human Genetics, Ulm University Medical Center, Ulm University, Ulm, 
      Germany.
AD  - Institute of Human Genetics, Christian Albrechts University Kiel/University 
      Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
FAU - de Leval, Laurence
AU  - de Leval L
AUID- ORCID: 0000-0003-3994-516X
AD  - Institut de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, 
      Switzerland.
FAU - Rosenwald, Andreas
AU  - Rosenwald A
AD  - Institute of Pathology and.
AD  - Comprehensive Cancer Center Mainfranken, University of Wurzburg, Wurzburg, 
      Germany.
FAU - Ferry, Judith A
AU  - Ferry JA
AD  - Department of Pathology, Massachusetts General Hospital/Harvard Medical School, 
      Boston, MA.
FAU - Hsi, Eric D
AU  - Hsi ED
AD  - Cleveland Clinic Foundation, Cleveland, OH.
FAU - Fu, Kai
AU  - Fu K
AD  - Department of Pathology and Microbiology and.
AD  - Division of Oncology and Hematology, Department of Internal Medicine, College of 
      Medicine, University of Nebraska Medical Center, Omaha, NE.
FAU - Delabie, Jan
AU  - Delabie J
AUID- ORCID: 0000-0001-5023-0689
AD  - Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, 
      University of Toronto, Toronto, ON, Canada.
AD  - Oslo University Hospital, Oslo, Norway.
FAU - Weisenburger, Dennis
AU  - Weisenburger D
AD  - Department of Pathology, City of Hope National Medical Center, Duarte, CA.
FAU - de Jong, Daphne
AU  - de Jong D
AD  - VU University Medical Center, Amsterdam, The Netherlands.
FAU - Climent, Fina
AU  - Climent F
AD  - Hospital Universitari de Bellvitge-Institut d'Investigacio Biomedica de Bellvitge 
      (IDIBELL), L'Hospitalet de Llobregat, Spain.
FAU - O'Connor, Sheila J
AU  - O'Connor SJ
AD  - Haematological Malignancy Diagnostic Service (HMDS) Laboratory, St. James's 
      Institute of Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
FAU - Swerdlow, Steven H
AU  - Swerdlow SH
AD  - Department of Pathology, School of Medicine, University of Pittsburgh, 
      Pittsburgh, PA.
FAU - Torrents, David
AU  - Torrents D
AUID- ORCID: 0000-0002-6086-9037
AD  - Joint Barcelona Supercomputing Center (BSC)-Centre for Genomic Regulation 
      (CRG)-Institute for Research in Biomedicine (IRB) Research Programme in 
      Computational Biology, Barcelona, Spain.
AD  - Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Spain.
FAU - Beltran, Sergi
AU  - Beltran S
AUID- ORCID: 0000-0002-2810-3445
AD  - Centre Nacional d'Analisi Genomica (CNAG)-CRG, Barcelona, Spain.
FAU - Espinet, Blanca
AU  - Espinet B
AD  - Laboratori de Citogenetica Molecular, Servei de Patologia, Hospital del Mar, 
      Barcelona, Spain.
AD  - Grup de Recerca Translacional en Neoplasies Hematologiques, Cancer Research 
      Programme, Institut Hospital del Mar d'Investigacions Mediques (IMIM)-Hospital 
      del Mar, Barcelona, Spain.
FAU - Gonzalez-Farre, Blanca
AU  - Gonzalez-Farre B
AD  - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain.
AD  - Hematopathology Section, Hospital Clinic de Barcelona, Barcelona, Spain.
FAU - Veloza, Luis
AU  - Veloza L
AD  - Hematopathology Section, Hospital Clinic de Barcelona, Barcelona, Spain.
FAU - Costa, Dolors
AU  - Costa D
AD  - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain.
AD  - Hematopathology Section, Hospital Clinic de Barcelona, Barcelona, Spain.
FAU - Matutes, Estella
AU  - Matutes E
AD  - Hematopathology Section, Hospital Clinic de Barcelona, Barcelona, Spain.
FAU - Siebert, Reiner
AU  - Siebert R
AD  - Institute of Human Genetics, Ulm University Medical Center, Ulm University, Ulm, 
      Germany.
AD  - Institute of Human Genetics, Christian Albrechts University Kiel/University 
      Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
FAU - Ott, German
AU  - Ott G
AD  - Department of Clinical Pathology and.
AD  - Dr Margarete "Fischer Bosch Institute" of Clinical Pharmacology, Robert Bosch 
      Hospital, Stuttgart, Germany.
FAU - Quintanilla-Martinez, Leticia
AU  - Quintanilla-Martinez L
AUID- ORCID: 0000-0001-7156-5365
AD  - Institute of Pathology, Eberhard Karls University of Tubingen, Tubingen, Germany.
FAU - Jaffe, Elaine S
AU  - Jaffe ES
AUID- ORCID: 0000-0003-4632-0301
AD  - Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, 
      National Institutes of Health, Bethesda, MD; and.
FAU - Lopez-Otin, Carlos
AU  - Lopez-Otin C
AD  - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain.
AD  - Departamento de Bioquimica y Biologia Molecular, Instituto Universitario de 
      Oncologia, Universidad de Oviedo, Oviedo, Spain.
FAU - Salaverria, Itziar
AU  - Salaverria I
AUID- ORCID: 0000-0002-2427-9822
AD  - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, 
      Spain.
AD  - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain.
FAU - Puente, Xose S
AU  - Puente XS
AUID- ORCID: 0000-0001-9525-1483
AD  - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain.
AD  - Departamento de Bioquimica y Biologia Molecular, Instituto Universitario de 
      Oncologia, Universidad de Oviedo, Oviedo, Spain.
FAU - Campo, Elias
AU  - Campo E
AUID- ORCID: 0000-0001-9850-9793
AD  - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, 
      Spain.
AD  - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain.
AD  - Hematopathology Section, Hospital Clinic de Barcelona, Barcelona, Spain.
AD  - Department of Anatomic Pathology, University of Barcelona, Barcelona, Spain.
FAU - Bea, Silvia
AU  - Bea S
AUID- ORCID: 0000-0001-7192-2385
AD  - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, 
      Spain.
AD  - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181211
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (CCND1 protein, human)
RN  - 0 (CCND2 protein, human)
RN  - 0 (CCND3 protein, human)
RN  - 0 (Cyclin D2)
RN  - 0 (Cyclin D3)
RN  - 0 (Immunoglobulin Light Chains)
RN  - 0 (SOX11 protein, human)
RN  - 0 (SOXC Transcription Factors)
RN  - 136601-57-5 (Cyclin D1)
SB  - IM
MH  - Aged
MH  - Cyclin D1/genetics/metabolism
MH  - Cyclin D2/*genetics
MH  - Cyclin D3/*genetics
MH  - *Enhancer Elements, Genetic
MH  - Female
MH  - *Gene Rearrangement
MH  - Humans
MH  - Immunoglobulin Light Chains/*genetics
MH  - Lymphoma, Mantle-Cell/*genetics/pathology
MH  - Male
MH  - Middle Aged
MH  - Prognosis
MH  - SOXC Transcription Factors/genetics
MH  - Translocation, Genetic
PMC - PMC6396173
COIS- 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.
EDAT- 2018/12/13 06:00
MHDA- 2019/11/13 06:00
PMCR- 2020/02/28
CRDT- 2018/12/13 06:00
PHST- 2018/07/09 00:00 [received]
PHST- 2018/12/01 00:00 [accepted]
PHST- 2018/12/13 06:00 [pubmed]
PHST- 2019/11/13 06:00 [medline]
PHST- 2018/12/13 06:00 [entrez]
PHST- 2020/02/28 00:00 [pmc-release]
AID - S0006-4971(20)42747-8 [pii]
AID - 2019/862151 [pii]
AID - 10.1182/blood-2018-07-862151 [doi]
PST - ppublish
SO  - Blood. 2019 Feb 28;133(9):940-951. doi: 10.1182/blood-2018-07-862151. Epub 2018 
      Dec 11.