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  • Review Article
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Genetic alterations and their clinical implications in DLBCL

Nature Reviews Clinical Oncology volume 16, pages 634–652 (2019)Cite this article

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Abstract

Diffuse large B cell lymphoma (DLBCL) is a highly heterogeneous lymphoid neoplasm with variations in gene expression profiles and genetic alterations, which lead to substantial variations in clinical course and response to therapy. The advent of high-throughput genome sequencing platforms, and especially whole-exome sequencing, has helped to define the genetic landscape of DLBCL. In the past 10 years, these studies have identified many genetic alterations in DLBCL, some of which are specific to B cell lymphomas, whereas others can also be observed in other types of cancer. These aberrations result in altered activation of a wide range of signalling pathways and other cellular processes, including those involved in B cell differentiation, B cell receptor signalling, activation of the NF-κB pathway, apoptosis and epigenetic regulation. Further elaboration of the genetics of DLBCL will not only improve our understanding of disease pathogenesis but also provide further insight into disease classification, prognostication and therapeutic targets. In this Review, we describe the current understanding of the prevalence and causes of specific genetic alterations in DLBCL and their role in disease development and progression. We also summarize the available clinical data on therapies designed to target the aberrant pathways driven by these alterations.

Key points

  • Application of next-generation sequencing technologies, especially whole-exome sequencing, has helped to define the genomic landscape of diffuse large B cell lymphoma (DLBCL).

  • Characterization of genetic events provides important insights into the pathogenesis of DLBCL.

  • The genetic events identified in DLBCL have prognostic implications and can also enable the molecular classification of DLBCL into specific subtypes.

  • Novel agents have been developed to target the dysregulated signalling pathways caused by genetic events in DLBCL, and some of these agents have achieved promising efficacies.

  • Several genetic biomarkers are predictive of a response to novel targeted agents in patients with DLBCL and could be used in the future to guide patient selection for clinical trials.

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Fig. 1: Genetic aberrations generated by RAG1 and/or RAG2 and AID in DLBCL.
Fig. 2: Disruption of BCL-6.
Fig. 3: Genetic aberrations involving BCR signalling and related pathways.
Fig. 4: Genetic events and aberrations in p53, MYC and apoptotic pathways.
Fig. 5: Genetic events and aberrations in NOTCH signalling and cellular migration pathways.
Fig. 6: Alterations in epigenetic regulation that contribute to the development of lymphoma.
Fig. 7: Genetic alterations related to immune escape.
Fig. 8: Gene expression profiles and genetic subgroups of DLBCL.

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Acknowledgements

K.H.Y. acknowledges support from the US NIH National Cancer Institute (grants R01CA138688, R01CA187415 and 1RC1CA146299), The University of Texas MD Anderson Cancer Center Institutional Research and Development Fund, the Gundersen Lutheran Medical Foundation, the Hagemeister Lymphoma Foundation and the University Cancer Foundation via the Sister Institution Network Fund at The University of Texas MD Anderson Cancer Center. The work of the authors is also partially supported by NIH National Cancer Institute grants P50CA136411 and P50CA142509 and by the MD Anderson Cancer Center Support Grant CA016672.

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Authors and Affiliations

  1. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Yi Miao, L. Jeffrey Medeiros & Ken H. Young

  2. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Yong Li

  3. Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China

    Jianyong Li

  4. Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, TX, USA

    Ken H. Young

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K.H.Y. has received research support from Adaptive Biotechnology, Dai Sanyo, Gilead Sciences, HTG Molecular Diagnostics, Incyte Pharmaceutical, Roche Molecular Systems and Seattle Genetics.

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Miao, Y., Medeiros, L.J., Li, Y. et al. Genetic alterations and their clinical implications in DLBCL. Nat Rev Clin Oncol 16, 634–652 (2019). https://doi.org/10.1038/s41571-019-0225-1

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