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

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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.

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Fig. 1: Recurrently mutated genes in 304 primary DLBCLs.
Fig. 2: Mutational signatures operating in primary DLBCLs.
Fig. 3: Chromosomal rearrangements in primary DLBCLs.
Fig. 4: Recurrent SCNAs and outcome association of individual genetic factors.
Fig. 5: Identification of groups of tumors with coordinate genetic signatures.
Fig. 6: Type and incidence of MYD88 mutations, cAID mutational signature activity, inferred timing of genetic drivers, and outcome association of DLBCL clusters.

Change history

  • 28 June 2018

    In the version of this article originally published, an asterisk was omitted from Fig. 1a. The asterisk has been added to the figure. Additionally, a “NOTCH2” label was erroneously included in Fig. 4a. The label has been removed. The errors have been corrected in the PDF and HTML versions of this article.

  • 28 June 2018

    In the version of this article originally published, some text above the “Tri–nucleotide sequence motifs” label in Fig. 2a appeared incorrectly. The text was garbled and should have appeared as nucleotide codes.

    Additionally, the labels on the bars in Fig. 2c were not italicized in the original publication. These are gene symbols, and they should have been italicized.

    The colored labels above the graphs in Fig. 4b were also erroneously not italicized. These labels represent gene names and loci, and they should have been italicized.

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Acknowledgements

We thank all of the members of the Broad Institute's Biological Samples Genetic Analysis Genome Sequencing Platforms. In addition, we thank all of the patients and their physicians for trial participation and donating the samples. This work was supported by a Claudia Adams Barr Program in Basic Cancer Research (B.C.), a Medical Oncology Translational Grant Program (B.C.), two LLS Translational Research Awards (M.A.S.), and the Lymphoma Target Testing Center (M.A.S.). The computational work for this study was supported by grants U54HG003067, P01CA163222, R01CA18246, U24CA143845, U24CA210999, and R01CA155010 from the National Cancer Institute and the National Human Genome Research Institute, as well as Leukemia & Lymphoma Society grant 0812-14. The Mayo group was supported by a grant from the US National Institutes of Health (P50 CA97274). R.S., M.L., and L.T. received Funding from BMBF (Federal Ministry of Research, Germany; Kennzeichen FZK 031A428B and FZK 031A428H). The Ricover60 Trial was supported by a research grant from Deutsche Krebshilfe (M.P.).

Author information

B.C., C.S., G.G., and M.A.S. conceived the project and provided leadership. B.C., C.S., A.D., J.K., A.K., R.R., M.L, A.J.L., G.G., and M.A.S analyzed the data. M.G.M.R., M.Z., A.M.S., J. W., M.D.D., I.L., E.R., A.T.-W, C.C., J.H., C.P., D.L., D.R., M.R., A.T., H.H., P.v.H., A.L.F., B.R.L., A.J.N., J.R.C., T.M.H., R.S., A.R., A.R.T., M.M., T.R.G., R.B., G.G.W., G.O., S.J.R., S.M., D.N., M.L., M.P., and L.T. contributed to the analysis and scientific discussions. B.C, C.S., A.D., G.G., and M.A.S. wrote the paper.

Correspondence to Gad Getz or Margaret A. Shipp.

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A correction to this article is available online at https://doi.org/10.1038/s41591-018-0097-4.

A correction to this article is available online at https://doi.org/10.1038/s41591-018-0098-3.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–16 and Supplementary Note

Reporting Summary

Supplementary Table 1

Sample summary

Supplementary Table 2

Patient characteristics

Supplementary Table 3

Significantly mutated genes

Supplementary Table 4

Mutational signature analyses

Supplementary Table 5

Chromosomal rearrangements

Supplementary Table 6

Significant CNAs and correlation to gene expression

Supplementary Table 7

Univariate and multivariate outcome associations

Supplementary Table 8

Gene sample matrix and features of consensus clusters

Supplementary Table 9

Clinical features and features across clusters

Supplementary Table 10

Ordering analyses

Supplementary Table 11

Outcome analyses of clusters

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Chapuy, B., Stewart, C., Dunford, A.J. et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med 24, 679–690 (2018) doi:10.1038/s41591-018-0016-8

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