Haematologica (Aug 2023)
<i>BCL3</i> rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases
- Anna Carbo-Meix,
- Francesca Guijarro,
- Luojun Wang,
- Marta Grau,
- Romina Royo,
- Gerard Frigola,
- Heribert Playa-Albinyana,
- Marco M. Buhler,
- Guillem Clot,
- Marti Duran-Ferrer,
- Junyan Lu,
- Isabel Granada,
- Maria-Joao Baptista,
- Jose-Tomas Navarro,
- Blanca Espinet,
- Anna Puiggros,
- Gustavo Tapia,
- Laura Bandiera,
- Gabriella De Canal,
- Emanuela Bonoldi,
- Fina Climent,
- Inmaculada Ribera-Cortada,
- Mariana Fernandez-Caballero,
- Esmeralda de la Banda,
- Janilson do Nascimento,
- Alberto Pineda,
- Dolors Vela,
- Maria Rozman,
- Marta Aymerich,
- Charlotte Syrykh,
- Pierre Brousset,
- Miguel Perera,
- Lucrecia Yanez,
- Jesus Xavier Ortin,
- Esperanza Tuset,
- Thorsten Zenz,
- James R. Cook,
- Steven H. Swerdlow,
- Jose I. Martin-Subero,
- Dolors Colomer,
- Estella Matutes,
- Silvia Bea,
- Dolors Costa,
- Ferran Nadeu,
- Elias Campo
Affiliations
- Anna Carbo-Meix
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona
- Francesca Guijarro
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematopathology Section, laboratory of Pathology, Hospital Clínic de Barcelona, Barcelona
- Luojun Wang
- Hematopathology Section, laboratory of Pathology, Hospital Clínic de Barcelona, Barcelona
- Marta Grau
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona
- Romina Royo
- Barcelona Supercomputing Center (BSC), Barcelona
- Gerard Frigola
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematopathology Section, laboratory of Pathology, Hospital Clínic de Barcelona, Barcelona
- Heribert Playa-Albinyana
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid
- Marco M. Buhler
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich
- Guillem Clot
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona
- Marti Duran-Ferrer
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid
- Junyan Lu
- European Molecular Biology Laboratory, Heidelberg
- Isabel Granada
- Department of Hematology-Laboratory, Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Universitat Autònoma de Barcelona, Badalona
- Maria-Joao Baptista
- Department of Hematology-Laboratory, Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Universitat Autònoma de Barcelona, Badalona
- Jose-Tomas Navarro
- Department of Hematology-Laboratory, Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Universitat Autònoma de Barcelona, Badalona
- Blanca Espinet
- Molecular Cytogenetics Laboratory, Pathology Department, Hospital del Mar, Barcelona, Spain and Translational Research on Hematological Neoplasms Group (GRETNHE) - Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona
- Anna Puiggros
- Molecular Cytogenetics Laboratory, Pathology Department, Hospital del Mar, Barcelona, Spain and Translational Research on Hematological Neoplasms Group (GRETNHE) - Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona
- Gustavo Tapia
- Department of Pathology, Hospital Germans Trias i Pujol, Badalona
- Laura Bandiera
- Anatomia Istologia Patologica e Citogenetica, Dipartimento Ematologia, Oncologia e Medicina Molecolare, Niguarda Cancer Center, Milano
- Gabriella De Canal
- Anatomia Istologia Patologica e Citogenetica, Dipartimento Ematologia, Oncologia e Medicina Molecolare, Niguarda Cancer Center, Milano
- Emanuela Bonoldi
- Anatomia Istologia Patologica e Citogenetica, Dipartimento Ematologia, Oncologia e Medicina Molecolare, Niguarda Cancer Center, Milano
- Fina Climent
- Department o f Pathology, H ospital Universitari d e Bellvitge, I nstitut d’Investigació B iomèdica d e Bellvitge (IDIBELL), L'Hospitalet De Llobregat
- Inmaculada Ribera-Cortada
- Hospital Nostra Senyora de Meritxell, Escaldes-Engordany, Principat d'Andorra
- Mariana Fernandez-Caballero
- Department of Hematology-Laboratory, Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Universitat Autònoma de Barcelona, Badalona
- Esmeralda de la Banda
- Laboratory of Hematology, Hospital Universitari Bellvitge, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet De Llobregat
- Janilson do Nascimento
- Hospital Joan XXIII, Institut Català d'Oncologia, Tarragona
- Alberto Pineda
- Fundació Hospital de l'Esperit Sant, Badalona
- Dolors Vela
- Hematologia Clínica, Hospital General de Granollers, Granollers
- Maria Rozman
- Hematopathology Section, laboratory of Pathology, Hospital Clínic de Barcelona, Barcelona
- Marta Aymerich
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematopathology Section, laboratory of Pathology, Hospital Clínic de Barcelona, Barcelona
- Charlotte Syrykh
- Department of Pathology, Toulouse University Hospital Center, Cancer Institute University of Toulouse-Oncopole, 1 avenue Irène Joliot-Curie, 31059, Toulouse CEDEX 9
- Pierre Brousset
- Department of Pathology, Toulouse University Hospital Center, Cancer Institute University of Toulouse-Oncopole, 1 avenue Irène Joliot-Curie, 31059, Toulouse CEDEX 9, France; INSERM UMR1037 Cancer Research Center of Toulouse (CRCT), ERL 5294 National Center for Scientific Research (CNRS), University of Toulouse III Paul-Sabatier, Toulouse, France; Institut Carnot Lymphome CALYM, Laboratoire d'Excellence 'TOUCAN', Toulouse
- Miguel Perera
- Hematology Department, Hospital Dr Negrín, Las Palmas de Gran Canaria
- Lucrecia Yanez
- Hematology Department, Hospital Universitario Marqués de Valdecilla-Instituto de Investigación Valdecilla (IDIVAL), Santander
- Jesus Xavier Ortin
- Hematology Department, Hospital Verge de la Cinta, Tortosa
- Esperanza Tuset
- Hematology Department, Institut Català d'Oncologia, Hospital Dr. Josep Trueta, Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona
- Thorsten Zenz
- Department of Medical Oncology and Hematology, University Hospital and University of Zürich, Zurich
- James R. Cook
- Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH
- Steven H. Swerdlow
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
- Jose I. Martin-Subero
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Universitat de Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona
- Dolors Colomer
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematopathology Section, laboratory of Pathology, Hospital Clínic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Universitat de Barcelona, Barcelona
- Estella Matutes
- Hematopathology Section, laboratory of Pathology, Hospital Clínic de Barcelona, Barcelona
- Silvia Bea
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematopathology Section, laboratory of Pathology, Hospital Clínic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Universitat de Barcelona, Barcelona
- Dolors Costa
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematopathology Section, laboratory of Pathology, Hospital Clínic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid
- Ferran Nadeu
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid
- Elias Campo
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Hematopathology Section, laboratory of Pathology, Hospital Clínic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Universitat de Barcelona, Barcelona
- DOI
- https://doi.org/10.3324/haematol.2023.283209
- Journal volume & issue
-
Vol. 109,
no. 2
Abstract
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.