Genetic alterations and their clinical implications in DLBCL

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. Approximately 50% of patients with diffuse large B cell lymphoma (DLBCL) are cured with chemotherapy. However, patients with relapsed and/or refractory DLBCL have few other treatment options. In this Review, the authors describe emerging data on genetically targeted therapies for patients with DLBCL and how these might improve patient outcomes. 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 tri