BCL3 rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases
Anna Carbo-Meix
(1)
,
Francesca Guijarro
(1)
,
Luojun Wang
(1)
,
Marta Grau
(1)
,
Romina Royo
(2)
,
Gerard Frigola
(2)
,
Heribert Playa-Albinyana
(1, 3)
,
Marco M Buhler
(4)
,
Guillem Clot
(5)
,
Marti Duran-Ferrer
(1, 3)
,
Junyan Lu
(6)
,
Isabel Granada
(7, 8, 9)
,
Maria-Joao Baptista
(7, 8, 9)
,
Jose-Tomas Navarro
(7, 8, 9)
,
Blanca Espinet
(10, 11)
,
Anna Puiggros
(10, 11)
,
Gustavo Tapia
(12)
,
Laura Bandiera
(13, 14)
,
Gabriella de Canal
(13, 14)
,
Emanuela Bonoldi
(13, 14)
,
Fina Climent
(15, 16)
,
Inmaculada Ribera-Cortada
(17)
,
Mariana Fernandez-Caballero
(8, 9, 7)
,
Esmeralda de la Banda
(18, 16)
,
Janilson Do Nascimento
(7, 19)
,
Alberto Pineda
(20)
,
Dolors Vela
(21)
,
Maria Rozman
(22)
,
Marta Aymerich
(1)
,
Charlotte Syrykh
(23, 24)
,
Pierre Brousset
(23, 25)
,
Miguel Perera
(26)
,
Lucrecia Yanez
(27)
,
Jesus Xavier Ortin
(28)
,
Esperanza Tuset
(29)
,
Thorsten Zenz
(30)
,
James R Cook
(4, 31)
,
Steven H Swerdlow
(32)
,
Jose I Martin-Subero
(28)
,
Dolors Colomer
(1, 33)
,
Estella Matutes
(1, 33)
,
Silvia Bea
(1, 3)
,
Dolors Costa
(1, 3)
,
Ferran Nadeu
(1, 3)
,
Elias Campo
(1, 3)
1
IDIBAPS -
Institut d'Investigacions Biomèdiques August Pi i Sunyer
2 BSC-CNS - Barcelona Supercomputing Center - Centro Nacional de Supercomputacion
3 CIBERONC - Centro de Investigación Biomédica en Red de Cáncer
4 University hospital of Zurich [Zurich]
5 Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
6 EMBL - European Molecular Biology Laboratory [Heidelberg]
7 Institut Català d'Oncologia [Barcelona]
8 IJC - Josep Carreras Leukaemia Research Institute
9 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
10 IMIM-Hospital del Mar
11 Laboratoris de Citologia Hematológica/Citogenética Molecular. Servei de Patologia, GRETNHE
12 GTPUH - Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain]
13 Ematologia, Oncologia e Medicina Molecolare
14 Fondazione Oncologia Niguarda [Milano, Italie]
15 Hospitalet de Llobregat
16 IDIBELL - Institut d'Investigació Biomèdica de Bellvitge = Bellvitge Biomedical Research Institute
17 Hôpital Nostra Senyora de Meritxell
18 Bellvitge University Hospital = Bellvitge Hospital Universitari
19 Hospital Universitari Joan XXIII = University hospital Joan XXIII
20 Laboratori Hospital de l'Esperit Sant
21 Hospital General of Granollers
22 Hospital Clínic de Barcelona [Catalonia, Spain]
23 CRCT - Centre de Recherches en Cancérologie de Toulouse
24 Service Anatomie et cytologie pathologiques [CHU Toulouse]
25 CALYM - Institut Carnot Lymphome
26 Hospital Universitario de Gran Canaria Dr Negrin
27 IDIVAL - Marqués de Valdecilla Research Institute - Instituto de Investigación Marqués de Valdecilla [Santander]
28 Hospital Verge de la Cinta,
29 IDIBGI - Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta - Girona Biomedical Research Institute
30 Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
31 UZH - Universität Zürich [Zürich] = University of Zurich
32 University of Pittsburgh School of Medicine
33 ICMiD - Hospital Clínic de Barcelona
2 BSC-CNS - Barcelona Supercomputing Center - Centro Nacional de Supercomputacion
3 CIBERONC - Centro de Investigación Biomédica en Red de Cáncer
4 University hospital of Zurich [Zurich]
5 Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
6 EMBL - European Molecular Biology Laboratory [Heidelberg]
7 Institut Català d'Oncologia [Barcelona]
8 IJC - Josep Carreras Leukaemia Research Institute
9 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
10 IMIM-Hospital del Mar
11 Laboratoris de Citologia Hematológica/Citogenética Molecular. Servei de Patologia, GRETNHE
12 GTPUH - Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain]
13 Ematologia, Oncologia e Medicina Molecolare
14 Fondazione Oncologia Niguarda [Milano, Italie]
15 Hospitalet de Llobregat
16 IDIBELL - Institut d'Investigació Biomèdica de Bellvitge = Bellvitge Biomedical Research Institute
17 Hôpital Nostra Senyora de Meritxell
18 Bellvitge University Hospital = Bellvitge Hospital Universitari
19 Hospital Universitari Joan XXIII = University hospital Joan XXIII
20 Laboratori Hospital de l'Esperit Sant
21 Hospital General of Granollers
22 Hospital Clínic de Barcelona [Catalonia, Spain]
23 CRCT - Centre de Recherches en Cancérologie de Toulouse
24 Service Anatomie et cytologie pathologiques [CHU Toulouse]
25 CALYM - Institut Carnot Lymphome
26 Hospital Universitario de Gran Canaria Dr Negrin
27 IDIVAL - Marqués de Valdecilla Research Institute - Instituto de Investigación Marqués de Valdecilla [Santander]
28 Hospital Verge de la Cinta,
29 IDIBGI - Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta - Girona Biomedical Research Institute
30 Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
31 UZH - Universität Zürich [Zürich] = University of Zurich
32 University of Pittsburgh School of Medicine
33 ICMiD - Hospital Clínic de Barcelona
Résumé
The t(14;19)(q32;q13) often juxtaposes BCL3 with immunoglobulin heavy chain (IGH) resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3 rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in chronic lymphocytic leukemia (CLL) but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter four tumors transformed to a large B-cell lymphoma. We designed a novel fluorescence in situ hybridization assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively.
Domaines
Sciences du Vivant [q-bio]Origine | Publication financée par une institution |
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Licence |