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

Bjoern Chapuy, Chip Stewart, Andrew J. Dunford, Jaegil Kim, Atanas Kamburov, Robert A. Redd, Mike S. Lawrence, Margaretha G.M. Roemer, Amy J. Li, Marita Ziepert, Annette M. Staiger, Jeremiah A. Wala, Matthew D. Ducar, Ignaty Leshchiner, Ester Rheinbay, Amaro Taylor-Weiner, Caroline A. Coughlin, Julian M. Hess, Chandra S. Pedamallu, Dimitri LivitzDaniel Rosebrock, Mara Rosenberg, Adam A. Tracy, Heike Horn, Paul Van Hummelen, Andrew L. Feldman, Brian K. Link, Anne J. Novak, James R. Cerhan, Thomas M. Habermann, Reiner Siebert, Andreas Rosenwald, Aaron R. Thorner, Matthew L. Meyerson, Todd R. Golub, Rameen Beroukhim, Gerald G. Wulf, German Ott, Scott J. Rodig, Stefano Monti, Donna S. Neuberg, Markus Loeffler, Michael Pfreundschuh, Lorenz Trümper, Gad Getz, Margaret A. Shipp

Research output: Contribution to journalArticle

193 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)679-690
Number of pages12
JournalNature Medicine
Volume24
Issue number5
DOIs
StatePublished - May 1 2018

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Chapuy, B., Stewart, C., Dunford, A. J., Kim, J., Kamburov, A., Redd, R. A., Lawrence, M. S., Roemer, M. G. M., Li, A. J., Ziepert, M., Staiger, A. M., Wala, J. A., Ducar, M. D., Leshchiner, I., Rheinbay, E., Taylor-Weiner, A., Coughlin, C. A., Hess, J. M., Pedamallu, C. S., ... Shipp, M. A. (2018). Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nature Medicine, 24(5), 679-690. https://doi.org/10.1038/s41591-018-0016-8