Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets

Karube, Kennosuke; Rubio Pérez, Carlota, 1990-; Tamborero Noguera, David; Salar Silvestre, Antonio; Colomo Saperas, Luis Alberto; López Bigas, Núria; Miyoshi, Hiroaki

Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets

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dc.contributor.author Karube, Kennosukeca
dc.contributor.author Rubio Pérez, Carlota, 1990-ca
dc.contributor.author Tamborero Noguera, Davidca
dc.contributor.author Salar Silvestre, Antonioca
dc.contributor.author Colomo Saperas, Luis Albertoca
dc.contributor.author López Bigas, Núriaca
dc.contributor.author Miyoshi, Hiroakica
dc.date.accessioned 2018-04-20T07:17:13Z
dc.date.available 2018-04-20T07:17:13Z
dc.date.issued 2018
dc.description.abstract Genome studies of diffuse large B-cell lymphoma (DLBCL) have revealed a large number of somatic mutations and structural alterations. However, the clinical significance of these alterations is still not well defined. In this study, we have integrated the analysis of targeted next-generation sequencing of 106 genes and genomic copy number alterations (CNA) in 150 DLBCL. The clinically significant findings were validated in an independent cohort of 111 patients. Germinal center B-cell and activated B-cell DLBCL had a differential profile of mutations, altered pathogenic pathways and CNA. Mutations in genes of the NOTCH pathway and tumor suppressor genes (TP53/CDKN2A), but not individual genes, conferred an unfavorable prognosis, confirmed in the independent validation cohort. A gene expression profiling analysis showed that tumors with NOTCH pathway mutations had a significant modulation of downstream target genes, emphasizing the relevance of this pathway in DLBCL. An in silico drug discovery analysis recognized 69 (46%) cases carrying at least one genomic alteration considered a potential target of drug response according to early clinical trials or preclinical assays in DLBCL or other lymphomas. In conclusion, this study identifies relevant pathways and mutated genes in DLBCL and recognizes potential targets for new intervention strategies.
dc.description.sponsorship This study was supported by the Ministerio de Economía y Competitividad, Grant No. SAF2015-64885- R (to EC), Generalitat de Catalunya Suport Grups de Recerca AGAUR 2014-SGR-795 (to EC), Instituto de Salud Carlos III, Spanish Ministry of Health, PI12/01536 (to AL-G) and PI16/00420 (to AL-G), the Red Temática de Investigación Cooperativa en Cáncer (RTICC) grant RD12/0036/0036 (to EC), RD12/0036/0023 (to AL-G), RD12/0036/0069 (to MA), BIO/SA78/15 (to MA) and the European Regional Development Fund 'Una manera de fer Europa', CERCA Programme/Generalitat de Catalunya. EC is an Academia Researcher of the 'Institució Catalana de Recerca i Estudis Avançats' (ICREA) of the Generalitat de Catalunya. KK has received a research fellowship from the Uehara Memorial Foundation (Japan). DT is supported by the People Programme (Marie Curie Actions) of the Seventh Framework Programme of the European Union (FP7/2007-2013) under REA grant agreement number 600388 and by the Agency of Competitiveness for Companies of the Government of Catalonia, ACCIÓ and SAF2015-74072-JIN. CR-P is supported by an FPI fellowship. ID is supported by 'Josep Font' grant from Hospital Clinic. This work was also supported by La Fundació la Marató de TV3 and EU H2020 Programme 2014-2020 under grant agreements no. 634143 (MedBioinformatics), and the European Research Council (consolidator grant 682398) (to NL-B).
dc.format.mimetype application/pdf
dc.identifier.citation Karube K, Enjuanes A, Dlouhy I, Jares P, Martin-Garcia D, Nadeu F et al. Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets. Leukemia. 2018 Mar;32(3):675-84. DOI: 10.1038/leu.2017.251
dc.identifier.doi http://dx.doi.org/10.1038/leu.2017.251
dc.identifier.issn 0887-6924
dc.identifier.uri http://hdl.handle.net/10230/34421
dc.language.iso eng
dc.publisher Nature Publishing Groupca
dc.relation.ispartof Leukemia. 2018 Mar;32(3):675-84
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/600388
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2015-64885- R
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2015-74072-JIN
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/634143
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/682398
dc.rights © This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article' s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.keyword B-cell lymphoma
dc.subject.keyword Genetics research
dc.title Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targetsca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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