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 Matthew 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

130 Citations (Scopus)

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

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Lymphoma, Large B-Cell, Diffuse
B-Lymphocytes
Cells
Germinal Center
B-Lymphocyte Subsets
Genomic Instability
Cluster Analysis
Mutation
Neoplasms

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., ... 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

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

In: Nature Medicine, Vol. 24, No. 5, 01.05.2018, p. 679-690.

Research output: Contribution to journalArticle

Chapuy, B, Stewart, C, Dunford, AJ, Kim, J, Kamburov, A, Redd, RA, Lawrence, MS, Roemer, MGM, Li, AJ, Ziepert, M, Staiger, AM, Wala, JA, Ducar, MD, Leshchiner, I, Rheinbay, E, Taylor-Weiner, A, Coughlin, CA, Hess, JM, Pedamallu, CS, Livitz, D, Rosebrock, D, Rosenberg, M, Tracy, AA, Horn, H, Van Hummelen, P, Feldman, AL, Link, BK, Novak, AJ, Cerhan, JR, Habermann, TM, Siebert, R, Rosenwald, A, Thorner, AR, Meyerson, ML, Golub, TR, Beroukhim, R, Wulf, GG, Ott, G, Rodig, SJ, Monti, S, Neuberg, DS, Loeffler, M, Pfreundschuh, M, Trümper, L, Getz, G & Shipp, MA 2018, 'Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes', Nature Medicine, vol. 24, no. 5, pp. 679-690. https://doi.org/10.1038/s41591-018-0016-8
Chapuy, Bjoern ; Stewart, Chip ; Dunford, Andrew J. ; Kim, Jaegil ; Kamburov, Atanas ; Redd, Robert A. ; Lawrence, Mike S. ; Roemer, Margaretha G.M. ; Li, Amy J. ; Ziepert, Marita ; Staiger, Annette M. ; Wala, Jeremiah A. ; Ducar, Matthew D. ; Leshchiner, Ignaty ; Rheinbay, Ester ; Taylor-Weiner, Amaro ; Coughlin, Caroline A. ; Hess, Julian M. ; Pedamallu, Chandra S. ; Livitz, Dimitri ; Rosebrock, Daniel ; Rosenberg, Mara ; Tracy, Adam A. ; Horn, Heike ; Van Hummelen, Paul ; Feldman, Andrew L ; Link, Brian K. ; Novak, Anne J ; Cerhan, James R ; Habermann, Thomas Matthew ; Siebert, Reiner ; Rosenwald, Andreas ; Thorner, Aaron R. ; Meyerson, Matthew L. ; Golub, Todd R. ; Beroukhim, Rameen ; Wulf, Gerald G. ; Ott, German ; Rodig, Scott J. ; Monti, Stefano ; Neuberg, Donna S. ; Loeffler, Markus ; Pfreundschuh, Michael ; Trümper, Lorenz ; Getz, Gad ; Shipp, Margaret A. / Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. In: Nature Medicine. 2018 ; Vol. 24, No. 5. pp. 679-690.
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AU - Chapuy, Bjoern

AU - Stewart, Chip

AU - Dunford, Andrew J.

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AU - Kamburov, Atanas

AU - Redd, Robert A.

AU - Lawrence, Mike S.

AU - Roemer, Margaretha G.M.

AU - Li, Amy J.

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AU - Livitz, Dimitri

AU - Rosebrock, Daniel

AU - Rosenberg, Mara

AU - Tracy, Adam A.

AU - Horn, Heike

AU - Van Hummelen, Paul

AU - Feldman, Andrew L

AU - Link, Brian K.

AU - Novak, Anne J

AU - Cerhan, James R

AU - Habermann, Thomas Matthew

AU - Siebert, Reiner

AU - Rosenwald, Andreas

AU - Thorner, Aaron R.

AU - Meyerson, Matthew L.

AU - Golub, Todd R.

AU - Beroukhim, Rameen

AU - Wulf, Gerald G.

AU - Ott, German

AU - Rodig, Scott J.

AU - Monti, Stefano

AU - Neuberg, Donna S.

AU - Loeffler, Markus

AU - Pfreundschuh, Michael

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AU - Getz, Gad

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