Molecular Subtypes of Diffuse Large B-cell Lymphoma are Associated with Distinct Pathogenic Mechanisms and Outcomes

By B. Chapuy, Chip Stewart, Andrew J. Dunford, Jaegil Kim, Atanas Kamburov, R. Redd, Mike S. Lawrence, M. Roemer, Amy Li, M. Ziepert and 36 more. Nature Medicine, 2018

1,686 citations recorded by the source corpus.

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. Comprehensive integration of mutational and structural alterations in clinically-annotated DLBCL patient samples provides a novel molecular classification of the disease.

Subfields: Cancer Research, Genetics, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/a3b5a71d6d3b87e47e14e5a032c5583241d1c757

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Citations in the corpus

• A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications (2020, methodology): “Moreover, in the Harvard cohort, each LymphGen subtype was drawn predominantly from a single genetic ‘‘cluster,’’ as defined previously (Chapuy et al., 2018), with a 75% overall agreement between the analytic methodologies (Figure S4C).”