By studying 574 diffuse large B-cell lymphoma (DLBCL) biopsy samples, the researchers from US National Cancer Institute (NCI) uncovered four prominent genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision medicine strategies. The findings are published in The New England Journal of Medicine.

The authors wrote in study background that DLBCLs are phenotypically and genetically heterogeneous. Gene-expression profiling has identified 3 subgroups of DLBCL: activated B-cell–like, germinal-center B-cell–like, and unclassified, according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. In the current study, they sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics.

The study team undertook a multiplatform analysis of structural genomic abnormalities and gene expression in DLBCL biopsy samples. In particular, fresh-frozen DLBCL biopsy samples were analyzed by means of exome and transcriptome sequencing, deep amplicon resequencing of 372 genes, and DNA copy-number analysis. The investigators developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations.

Four prominent genetic subtypes have been identified, namely 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.

Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs.

The subtypes differed phenotypically, as judged 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.

Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on “chronic-active” B-cell receptor signaling that is amenable to therapeutic inhibition.

This multiplatform genomic analysis builds on the gene-expression classification of DLBCL. The analysis uncovered a relationship between genetic nosology and oncogenic signaling pathways, suggesting testable therapeutic interventions. Defined genetic subtypes may provide a concept for development of precision therapies for DLBCL.