Large B-cell lymphomas with CCND1 rearrangement have different immunoglobulin gene breakpoints and genomic profile than mantle cell lymphoma

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This study was supported by the PMP21/00015 project from the Instituto de Salud Carlos III (ISCIII) and the "NextGenerationEU/Mechanism for Recovery and Resilience (MRR)/PRTR, by PID2021-123054OB-I00 project from Ministry of Science and Innovation (MCIN) and FEDER "Una manera de hacer Europa" to E.C, by PI22/00203 project from ISCIII and FEDER (to EG and SB); and the Generalitat de Catalunya Suport Grups de Recerca AGAUR (2021-SGR-01172 to E.C. and 2021-SGR-01293 to S.B.). M.P. was supported by the 2022 Estela Matutes Fellowship. F.N. acknowledges research support European Hematology Association (EHA Junior Research Grant 2021, RG-202012-00245). E.C. is an Academia Researcher of the "Institucio Catalana de Recerca i Estudis Avancats" (ICREA) of the Generalitat de Catalunya.

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Montaner, AnnaAuthorPol, MelinaAuthorFrigola, GerardAuthorBalague, OlgaAuthorSalmeron-Villalobos, JuliaAuthorBashiri, MelikaAuthorRuiz-Gaspa, SilviaAuthorBea, SilviaAuthorSalaverria, ItziarAuthorGine, EvaAuthorLopez, CristinaAuthorNadeu, FerranAuthorCampo, EliasCorresponding Author

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Article

Publicated to:Blood Cancer Journal. 14 (1): 166- - 2024-09-23 14(1), DOI: 10.1038/s41408-024-01146-z

Authors: Ozogul, Ece; Montaner, Anna; Pol, Melina; Frigola, Gerard; Balague, Olga; Syrykh, Charlotte; Bousquets-Munoz, Pablo; Royo, Romina; Fontaine, Juliette; Traverse-Glehen, Alexandra; Buhler, Marco M; Giudici, Luca; Roncador, Marco; Zenz, Thorsten; Carras, Sylvain; Valmary-Degano, Severine; de Leval, Laurence; Bosch-Schips, Jan; Climent, Fina; Salmeron-Villalobos, Julia; Bashiri, Melika; Ruiz-Gaspa, Silvia; Costa, Dolors; Bea, Silvia; Salaverria, Itziar; Gine, Eva; Quintanilla-Martinez, Leticia; Brousset, Pierre; Raffeld, Mark; Jaffe, Elaine S; Puente, Xose S; Lopez, Cristina; Nadeu, Ferran; Campo, Elias

Affiliations

Barcelona Supercomp Ctr, Barcelona, Spain - Author

Canc Inst Univ Toulouse Oncopole, Toulouse Univ Hosp Ctr, 1 Ave Irene Joliot Curie, F-31059 Toulouse 9, France - Author

Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain - Author

Eberhard Karls Univ Tubingen, Univ Hosp Tubingen, Tubingen, Germany - Author

Ente Osped Cantonale EOC, Inst Pathol, CH-6900 Locarno, Switzerland - Author

Grenoble Alpes Univ, CHU Grenoble Alpes, Grenoble, France - Author

Hacettepe Univ, Fac Med, Pathol Dept, Ankara, Turkiye - Author

Hop Lyon Sud, Hosp Civils Lyon, Pierre Benite, France - Author

Hosp Clin Barcelona, Barcelona, Spain - Author

Hosp Univ Bellvitge IDIBELL, Lhospitalet De Llobregat, Spain - Author

Inst Adv Biosci, CNRS 5309, INSERMN UMR 1209, Grenoble, France - Author

Inst Carnot Lymphome CALYM, Lab Excellence Toucan, Toulouse, France - Author

Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain - Author

Lausanne Univ Hosp, Lausanne, Switzerland - Author

Lausanne Univ, Lausanne, Switzerland - Author

NCI, NIH, Bethesda, MD USA - Author

Univ Barcelona, Barcelona, Spain - Author

Univ Hosp Tubingen, Comprehens Canc Ctr, Tubingen, Germany - Author

Univ Hosp Zurich, Zurich, Switzerland - Author

Univ Oviedo, Inst Univ Oncol IUOPA, Dept Bioquim & Biol Mol, Oviedo 33006, Spain - Author

Univ Toulouse III Paul Sabatier, INSERM UMR1037, ERL Natl 5294, Canc Res Ctr Toulouse CRCT,CNRS, Toulouse, France - Author

Abstract

Mantle cell lymphoma (MCL) is genetically characterized by the IG::CCND1 translocation mediated by an aberrant V(D)J rearrangement. CCND1 translocations and overexpression have been identified in occasional aggressive B-cell lymphomas with unusual features for MCL. The mechanism generating CCND1 rearrangements in these tumors and their genomic profile are not known. We have reconstructed the IG::CCND1 translocations and the genomic profile of 13 SOX11-negative aggressive B-cell lymphomas using whole genome/exome and target sequencing. The mechanism behind the translocation was an aberrant V(D)J rearrangement in three tumors and by an anomalous IGH class-switch recombination (CSR) or somatic hypermutation (SHM) mechanism in ten. The tumors with a V(D)J-mediated translocation were two blastoid MCL and one high-grade B-cell lymphoma. None of them had a mutational profile suggestive of DLBCL. The ten tumors with CSR/SHM-mediated IGH::CCND1 were mainly large B-cell lymphomas, with mutated genes commonly seen in DLBCL and BCL6 rearrangements in 6. Two cases, which transformed from marginal zone lymphomas, carried mutations in KLF2, TNFAIP3 and KMT2D. These findings expand the spectrum of tumors carrying CCND1 rearrangement that may occur as a secondary event in DLBCL mediated by aberrant CSR/SHM and associated with a mutational profile different from that of MCL.

Keywords

AcquisitionActivation induced cytidine deaminaseAdultAgedAggressive b cell non hodgkin lymphomaAnemiaArid1a geneArid1b geneAtm proteinBcl6BendamustineBrg1 proteinCcnd1 protein, humanCd70 antigenCd79b antigenChromosome breakageChromosome breakpointsClonal evolutionCyclin d1Cyclophosphamide plus doxorubicin plus prednisolone plus rituximab plus vincristineDiffuse large b cell lymphomaExpressionFemaleGene rearrangementGene translocationGenes, immunoglobulinGeneticsHeterogeneityHumansIbrutinibImmunoglobulin geneImmunohistochemistryImmunophenotypingInguinal lymph nodeInhibitor of differentiation 3Interferon regulatory factor 4Kmt2d geneKruppel like factor 2LandscapLymphadenopathyLymphoma, large b-cell, diffuseLymphoma, mantle-cellMaleMantle cell lymphomaMarginal zone lymphomaMediastinumMediastinum massMiddle agedMultiple cycle treatmentMyc proteinMyeloid differentiation factor 88Nodal marginal zone lymphomaOrbit cancerP2ry8 genePathologyPcbp1 genePositron emission tomography-computed tomographyPrmd1 geneProtein bcl 2Protein bcl 6Protein expressionProtein kinase pim 1Q32)Somatic hypermutationSplenectomySplenic marginal zone lymphomaStomach biopsyStomach cancerSyne1 geneT(11/14)(q13TestisTonsilTonsil cancerTranscription factor sox11TranslocationTranslocation, geneticTreatment responseTumor necrosis factor alpha induced protein 3V(d)j recombinationVdj recombinationWhole exome sequencingWhole genome sequencing

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The work has been published in the journal Blood Cancer Journal due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 19/322, thus managing to position itself as a Q1 (Primer Cuartil), in the category Oncology. Notably, the journal is positioned above the 90th percentile.

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Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: France; Germany; Switzerland; Turkey; United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Pol, Melina) and Last Author (Campo Güerri, Elías).