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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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.).
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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.
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Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–16 and Supplementary Note
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). https://doi.org/10.1038/s41591-018-0016-8
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DOI: https://doi.org/10.1038/s41591-018-0016-8
