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Leukemia. 2018 Mar;32(3):675-684. doi: 10.1038/leu.2017.251. Epub 2017 Aug 14.

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

Author information

1
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
2
Department of Pathology and Cell Biology, Graduate School of Medicine and Faculty of Medicine, University of the Ryukyus, Nishihara, Japan.
3
CIBERONC, Madrid, Spain.
4
DREAMgenics, S.L., Asturias, Spain.
5
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
6
Servei de Patologia, Hospital de Sant Pau, Barcelona, Spain.
7
Department of Pathology, Hospital del Mar, Universitat Pompeu Fabra, Barcelona, Spain.
8
ICO-Hospital Germans Trias i Pujol, Barcelona, Spain.
9
ICO-Hospital Duran i Reynals, L'Hospitalet, Barcelona, Spain.
10
Department of Hematology, Hospital Universitari Joan XXIII, Tarragona, Spain.
11
Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
12
Department of Medicine and Biosystemic Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
13
Unidad de Biología Molecular/Histocompatibilidad, Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain.
14
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
15
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

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.

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