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Nat Med. 2018 May;24(5):679-690. doi: 10.1038/s41591-018-0016-8. Epub 2018 Apr 30.

Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
2
Harvard Medical School, Boston, MA, USA.
3
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
4
Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
5
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
6
Boston University School of Medicine, Section of Computational Biomedicine, Boston, MA, USA.
7
Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig, Leipzig, Germany.
8
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tuebingen, Tuebingen, Germany.
9
Department of Clinical Pathology, Robert-Bosch Krankenhaus, Stuttgart, Germany.
10
Dana-Farber Cancer Institute, Center for Cancer Genome Discovery, Boston, MA, USA.
11
Mayo Clinic, Rochester, MN, USA.
12
University of Iowa, Iowa City, IA, USA.
13
Department for Human Genetics, University Ulm, Ulm, Germany.
14
Department of Pathology, University of Würzburg, Würzburg, Germany.
15
Department of Hematology and Oncology, Georg-August University Göttingen, Göttingen, Germany.
16
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
17
Department of Medicine I, Saarland University, Homburg, Germany.
18
Harvard Medical School, Boston, MA, USA. gadgetz@broadinstitute.org.
19
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. gadgetz@broadinstitute.org.
20
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. gadgetz@broadinstitute.org.
21
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. margaret_shipp@dfci.harvard.edu.
22
Harvard Medical School, Boston, MA, USA. margaret_shipp@dfci.harvard.edu.

Abstract

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 comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, 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.

PMID:
29713087
PMCID:
PMC6613387
DOI:
10.1038/s41591-018-0016-8
[Indexed for MEDLINE]
Free PMC Article

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