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Distinct subtypes of diffuse large B-cell lymphoma defined by hypermutated genes


Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease whose personalized clinical management requires robust molecular stratification. Here, we show that somatic hypermutation (SHM) patterns constitute a marker for DLBCL molecular classification. The activity of SHM mutational processes delineated the cell of origin (COO) in DLBCL. Expression of the herein identified 36 SHM target genes stratified DLBCL into four novel SHM subtypes. In a meta-analysis of patients with DLBCL treated with immunochemotherapy, the SHM subtypes were significantly associated with overall survival (1642 patients) and progression-free survival (795 patients). Multivariate analysis of survival indicated that the prognostic impact of the SHM subtypes is independent from the COO classification and the International Prognostic Index. Furthermore, the SHM subtypes had a distinct clinical outcome within each of the COO subtypes, and strikingly, even within unclassified DLBCL. The genetic landscape of the four SHM subtypes indicated unique associations with driver alterations and oncogenic signaling in DLBCL, which suggests a possibility for therapeutic exploitation. These findings provide a biologically driven classification system in DLBCL with potential clinical applications.

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This work was supported financially by the Academy of Finland (SH, SL), the Sigrid Jusélius Foundation (SH, SL), Finnish Cancer Foundations (SH, SL), Helsinki University Hospital (SL), the Biomedicum Helsinki Foundation (AA) and the University of Helsinki graduate program (AA). The results published here are in part based upon data generated by the Cancer Genome Characterization Initiative (Non-Hodgkin Lymphoma project), and data generated by the Genomic Variation in Diffuse Large B Cell Lymphoma study, which was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Both datasets have been accessed through the NIH database for Genotypes and Phenotypes (dbGAP) with accession numbers phs000532 and phs001444. Information about CGCI projects can be found at The authors thank Dr. Ryan D Morin and Dr. Sandeep Dave for providing gene expression data. The international DLBCL consortia whose data we have used in this study are gratefully acknowledged. The authors thank professors Ville Mustonen and Jussi Taipale for critical review of the article. Computing resources from CSC – IT Center for Science Ltd. and technical assistance from Anne Aarnio and Marika Tuukkanen are gratefully acknowledged.

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AA conceptualized the study together with R Lehtonen, SL, and SH; AA designed the methodology, performed the analyses, made the figures and wrote the paper; AA, AC, KZ, and R Louhimo processed sequencing data; AP, SKL, LM, HH, and SL provided resources and materials for the in-house samples and participated in scientific discussions; SH, SL, and R Lehtonen supervised the study; SH and SL acquired funding; all authors read and edited the paper.

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Correspondence to Sampsa Hautaniemi.

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Alkodsi, A., Cervera, A., Zhang, K. et al. Distinct subtypes of diffuse large B-cell lymphoma defined by hypermutated genes. Leukemia 33, 2662–2672 (2019).

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