Genetic Subtypes of DLBCL Uncovered

Four prominent genetic subtypes of diffuse large B-cell lymphoma may provide a conceptual edifice for development of precision therapies

By studying 574 diffuse large B-cell lymphomas (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-centre B-cell–like, and unclassified, according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. In 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 tumour 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 favourable 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 signalling 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 signalling pathways, suggesting testable therapeutic interventions. Defined genetic subtypes may provide a concept for development of precision therapies for DLBCL. 

The study was supported by the Intramural Research Program of the National Institutes of Health, the Center for Cancer Research of the US NCI, and an NCI Strategic Partnering to Evaluate Cancer Signatures grant (5U01CA157581-05). Dr. Schmitz was supported by the Dr. Mildred Scheel Stiftung für Krebsforschung (Deutsche Krebshilfe). Dr. Kasbekar was supported by the NIH Oxford–Cambridge Scholars Program and the Washington University in St. Louis Medical Scientist Training Program. Dr. Hodson was a Kay Kendall Leukaemia Fund intermediate research fellow. 

Drs. Schmitz, Wright, Huang, and Johnson contributed equally to the article. 

Reference 

Schmitz R, Wright GW, Huang DW, et al. Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. N Engl J Med 2018; 378:1396-1407. DOI: 10.1056/NEJMoa1801445