Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes
| Autor: | Dimitri Livitz, Matthew D. Ducar, Donna Neuberg, Jaegil Kim, Daniel Rosebrock, Lorenz Trümper, Amaro Taylor-Weiner, Andrew Dunford, Marita Ziepert, Margaretha G.M. Roemer, Jeremiah Wala, Stefano Monti, Rameen Beroukhim, Ester Rheinbay, Michael Pfreundschuh, Andreas Rosenwald, Mara Rosenberg, German Ott, Andrew L. Feldman, Michael S. Lawrence, Gerald Wulf, Matthew Meyerson, Paul Van Hummelen, Brian K. Link, Anne J. Novak, Chandra Sekhar Pedamallu, Gad Getz, Annette M. Staiger, Scott J. Rodig, Atanas Kamburov, Heike Horn, Chip Stewart, Todd R. Golub, Margaret A. Shipp, Bjoern Chapuy, Thomas M. Habermann, Aaron R. Thorner, Markus Loeffler, Amy Li, Adam Tracy, Ignaty Leshchiner, Caroline A. Coughlin, Julian M. Hess, Robert A. Redd, Reiner Siebert, James R. Cerhan |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
DNA Copy Number Variations Computational biology Biology Article General Biochemistry Genetics and Molecular Biology Genetic Heterogeneity 03 medical and health sciences 0302 clinical medicine International Prognostic Index Mutation Rate hemic and lymphatic diseases medicine Humans B cell Gene Rearrangement Genetic heterogeneity Germinal center General Medicine CD79B medicine.disease Marginal zone Lymphoma Treatment Outcome 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Mutation Lymphoma Large B-Cell Diffuse Diffuse large B-cell lymphoma Genes Neoplasm |
| Zdroj: | Nature Medicine. 24:679-690 |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/s41591-018-0016-8 |
| Popis: | Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B-cell (ABC) and germinal center B-cell (GCB) subtypes. We carried out a a comprehensive genetic analysis of 304 primary DLBCLs that identifies low-frequency alterations, captured recurrent mutations, somatic copy number alterations (SCNAs) and structural variants (SVs), and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification. |
| Databáze: | OpenAIRE |
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