Schmitz R, et al. - In view of the phenotypical and genetical heterogeneity of diffuse large B-cell lymphomas (DLBCLs) and identification of subgroups of DLBCL (activated B-cell–like [ABC], germinal-center B-cell–like [GCB], and unclassified), via gene-expression profiling, according to cell of origin that are associated with a differential response to chemotherapy and targeted agents, researchers investigated genetic subtypes of DLBCL based on shared genomic abnormalities and sought to uncover therapeutic vulnerabilities based on tumor genetics. In this study, genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics were uncovered, providing a potential nosology for precision-medicine strategies in DLBCL.

Methods

• In order to identify genes with recurrent aberrations, 574 DLBCL biopsy samples were studied using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes.
• An algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations was developed and implemented.

Results

• Four prominent genetic subtypes were identified in DLBCL: MCD (based on the co-occurrence of MYD88L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations).
• Each genetic subtype was distinguished from other DLBCLs using genetic aberrations in multiple genes.
• Phenotypical differences in these subtypes was suggested by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes.
• In this study, analysis of genetic pathways indicated that MCD and BN2 DLBCLs rely on “chronic active” B-cell receptor signaling that is amenable to therapeutic inhibition.