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

Nat Med
Authors
Keywords
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.

Year of Publication
2018
Journal
Nat Med
Volume
24
Issue
5
Pages
679-690
Date Published
2018 05
ISSN
1546-170X
DOI
10.1038/s41591-018-0016-8
PubMed ID
29713087
PubMed Central ID
PMC6613387
Links
Grant list
U54 HG003067 / HG / NHGRI NIH HHS / United States
P30 CA086862 / CA / NCI NIH HHS / United States
P01 CA163222 / CA / NCI NIH HHS / United States
U24 CA143845 / CA / NCI NIH HHS / United States
T32 HG002295 / HG / NHGRI NIH HHS / United States
R01 CA155010 / CA / NCI NIH HHS / United States
P50 CA097274 / CA / NCI NIH HHS / United States
U24 CA210999 / CA / NCI NIH HHS / United States