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

K. Karube, A. Enjuanes, I. Dlouhy, P. Jares, D. Martin-Garcia, F. Nadeu, G. R. Ordóñez, J. Rovira, G. Clot, C. Royo, A. Navarro, B. Gonzalez-Farre, A. Vaghefi, G. Castellano, C. Rubio-Perez, D. Tamborero, J. Briones, A. Salar, J. M. Sancho, S. Mercadal & 19 others E. Gonzalez-Barca, L. Escoda, H. Miyoshi, K. Ohshima, K. Miyawaki, Koji Kato, Koichi Akashi, A. Mozos, L. Colomo, M. Alcoceba, A. Valera, A. Carrió, D. Costa, N. Lopez-Bigas, R. Schmitz, L. M. Staudt, I. Salaverria, A. López-Guillermo, E. Campo

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)675-684
Number of pages10
JournalLeukemia
Volume32
Issue number3
DOIs
Publication statusPublished - Mar 1 2018

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Lymphoma, Large B-Cell, Diffuse
Mutation
Genes
B-Lymphocytes
Therapeutics
Germinal Center
Gene Dosage
Gene Expression Profiling
Drug Discovery
Tumor Suppressor Genes
Computer Simulation
Lymphoma
Clinical Trials
Genome
Pharmaceutical Preparations
Neoplasms

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Karube, K., Enjuanes, A., Dlouhy, I., Jares, P., Martin-Garcia, D., Nadeu, F., ... Campo, E. (2018). Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets. Leukemia, 32(3), 675-684. https://doi.org/10.1038/leu.2017.251

Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets. / Karube, K.; Enjuanes, A.; Dlouhy, I.; Jares, P.; Martin-Garcia, D.; Nadeu, F.; Ordóñez, G. R.; Rovira, J.; Clot, G.; Royo, C.; Navarro, A.; Gonzalez-Farre, B.; Vaghefi, A.; Castellano, G.; Rubio-Perez, C.; Tamborero, D.; Briones, J.; Salar, A.; Sancho, J. M.; Mercadal, S.; Gonzalez-Barca, E.; Escoda, L.; Miyoshi, H.; Ohshima, K.; Miyawaki, K.; Kato, Koji; Akashi, Koichi; Mozos, A.; Colomo, L.; Alcoceba, M.; Valera, A.; Carrió, A.; Costa, D.; Lopez-Bigas, N.; Schmitz, R.; Staudt, L. M.; Salaverria, I.; López-Guillermo, A.; Campo, E.

In: Leukemia, Vol. 32, No. 3, 01.03.2018, p. 675-684.

Research output: Contribution to journalArticle

Karube, K, Enjuanes, A, Dlouhy, I, Jares, P, Martin-Garcia, D, Nadeu, F, Ordóñez, GR, Rovira, J, Clot, G, Royo, C, Navarro, A, Gonzalez-Farre, B, Vaghefi, A, Castellano, G, Rubio-Perez, C, Tamborero, D, Briones, J, Salar, A, Sancho, JM, Mercadal, S, Gonzalez-Barca, E, Escoda, L, Miyoshi, H, Ohshima, K, Miyawaki, K, Kato, K, Akashi, K, Mozos, A, Colomo, L, Alcoceba, M, Valera, A, Carrió, A, Costa, D, Lopez-Bigas, N, Schmitz, R, Staudt, LM, Salaverria, I, López-Guillermo, A & Campo, E 2018, 'Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets', Leukemia, vol. 32, no. 3, pp. 675-684. https://doi.org/10.1038/leu.2017.251
Karube, K. ; Enjuanes, A. ; Dlouhy, I. ; Jares, P. ; Martin-Garcia, D. ; Nadeu, F. ; Ordóñez, G. R. ; Rovira, J. ; Clot, G. ; Royo, C. ; Navarro, A. ; Gonzalez-Farre, B. ; Vaghefi, A. ; Castellano, G. ; Rubio-Perez, C. ; Tamborero, D. ; Briones, J. ; Salar, A. ; Sancho, J. M. ; Mercadal, S. ; Gonzalez-Barca, E. ; Escoda, L. ; Miyoshi, H. ; Ohshima, K. ; Miyawaki, K. ; Kato, Koji ; Akashi, Koichi ; Mozos, A. ; Colomo, L. ; Alcoceba, M. ; Valera, A. ; Carrió, A. ; Costa, D. ; Lopez-Bigas, N. ; Schmitz, R. ; Staudt, L. M. ; Salaverria, I. ; López-Guillermo, A. ; Campo, E. / Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets. In: Leukemia. 2018 ; Vol. 32, No. 3. pp. 675-684.
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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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T1 - Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets

AU - Karube, K.

AU - Enjuanes, A.

AU - Dlouhy, I.

AU - Jares, P.

AU - Martin-Garcia, D.

AU - Nadeu, F.

AU - Ordóñez, G. R.

AU - Rovira, J.

AU - Clot, G.

AU - Royo, C.

AU - Navarro, A.

AU - Gonzalez-Farre, B.

AU - Vaghefi, A.

AU - Castellano, G.

AU - Rubio-Perez, C.

AU - Tamborero, D.

AU - Briones, J.

AU - Salar, A.

AU - Sancho, J. M.

AU - Mercadal, S.

AU - Gonzalez-Barca, E.

AU - Escoda, L.

AU - Miyoshi, H.

AU - Ohshima, K.

AU - Miyawaki, K.

AU - Kato, Koji

AU - Akashi, Koichi

AU - Mozos, A.

AU - Colomo, L.

AU - Alcoceba, M.

AU - Valera, A.

AU - Carrió, A.

AU - Costa, D.

AU - Lopez-Bigas, N.

AU - Schmitz, R.

AU - Staudt, L. M.

AU - Salaverria, I.

AU - López-Guillermo, A.

AU - Campo, E.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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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