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, Kennosuke
dc.contributor.author	Rubio Pérez, Carlota, 1990-
dc.contributor.author	Tamborero Noguera, David
dc.contributor.author	Salar Silvestre, Antonio
dc.contributor.author	Colomo Saperas, Luis Alberto
dc.contributor.author	López Bigas, Núria
dc.contributor.author	Miyoshi, Hiroaki
dc.date	2018
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): 675-684. DOI: 10.1038/leu.2017.251
dc.identifier.citation	0887-6924
dc.identifier.citation	http://dx.doi.org/10.1038/leu.2017.251
dc.identifier.uri	http://hdl.handle.net/10230/34421
dc.format	application/pdf
dc.language.iso	eng
dc.publisher	Nature Publishing Group
dc.relation	Leukemia 2018 Mar; 32(3): 675-684
dc.relation	info:eu-repo/grantAgreement/EC/FP7/600388
dc.relation	info:eu-repo/grantAgreement/ES/3PN/SAF2015-64885- R
dc.relation	info:eu-repo/grantAgreement/ES/3PN/SAF2015-74072-JIN
dc.relation	info:eu-repo/grantAgreement/EC/H2020/634143
dc.relation	info:eu-repo/grantAgreement/EC/H2020/682398
dc.rights	info:eu-repo/semantics/openAccess
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	http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject	B-cell lymphoma
dc.subject	Genetics research
dc.title	Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets
dc.type	info:eu-repo/semantics/article
dc.type	info:eu-repo/semantics/publishedVersion
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.abstract	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).

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