期刊
LEUKEMIA
卷 32, 期 3, 页码 675-684出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2017.251
关键词
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资金
- Ministerio de Economia y Competitividad [SAF2015-64885-R]
- Generalitat de Catalunya Suport Grups de Recerca [AGAUR 2014-SGR-795]
- Instituto de Salud Carlos III, Spanish Ministry of Health [PI12/01536, PI16/00420]
- Red Tematica de Investigacion Cooperativa en Cancer (RTICC) [RD12/0036/0036, RD12/0036/0023, RD12/0036/0069, BIO/SA78/15]
- European Regional Development Fund 'Una manera de fer Europa', CERCA Programme/Generalitat de Catalunya
- Uehara Memorial Foundation (Japan)
- People Programme (Marie Curie Actions) of the Seventh Framework Programme of the European Union [600388]
- Agency of Competitiveness for Companies of the Government of Catalonia
- ACCIO
- FPI fellowship
- Hospital Clinic
- La Fundacio la Marato de TV3
- EU [634143]
- European Research Council [682398]
- [SAF2015-74072-JIN]
- NATIONAL CANCER INSTITUTE [ZIABC011006] Funding Source: NIH RePORTER
- Grants-in-Aid for Scientific Research [16K09875] Funding Source: KAKEN
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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