A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications

The development of precision medicine approaches for diffuse large B cell lymphoma (DLBCL) is confounded by its pronounced genetic, phenotypic, and clinical heterogeneity. Recent multiplatform genomic studies revealed the existence of genetic subtypes of DLBCL using clustering methodologies. Here, we describe an algorithm that determines the probability that a patient's lymphoma belongs to one of seven genetic subtypes based on its genetic features. This classification reveals genetic similarities between these DLBCL subtypes and various indolent and extranodal lymphoma types, suggesting a shared pathogenesis. These genetic subtypes also have distinct gene expression profiles, immune microenvironments, and outcomes following immunochemotherapy. Functional analysis of genetic subtype models highlights distinct vulnerabilities to targeted therapy, supporting the use of this classification in precision medicine trials. [Display omitted] •Diffuse large B cell lymphoma (DLBCL) consists of seven genetic subtypes•The LymphGen algorithm classifies a DLBCL biopsy into one or more genetic subtypes•The genetic subtypes have distinct clinical outcomes and pathway dependencies•The genetic subtypes will aid the development of rationally targeted therapy of DLBCL Wright et al. identify seven genetic subtypes of diffuse large B cell lymphoma (DLBCL) with distinct outcomes and therapeutic vulnerabilities. The LymphGen probabilistic classification tool that can classify a DLBCL biopsy into the genetic subtypes is developed, which could be used for precision medicine trials.