Precision Medicine in DLBCL Improved via New Genetic Subtyping

A recent study identified genetic subtypes of diffuse large B-cell lymphoma (DLBCL) based on shared genomic alterations that may offer new precision medicine strategies for the disease.

DLBCLs are phenotypically and genetically heterogenous, and gene-expression profiling has helped identify subgroups of the disease (ie, activated B-cell-like, germinal-center B-cell-like, and unclassified) according to cell of origin that are linked to a differential response to chemotherapy as well as targeted agents.

Roland Schmitz, PhD, National Cancer Institute (Bethesda, MD), and colleagues conducted a study to further these findings by identifying genetic subtypes of DLBCL through shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. A total of 574 DLBCL biopsy samples were studies through exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify those with recurrent aberrations.

An algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations was developed.

Researchers found four prominent genetic subtypes in DLBCL: MCD (based on the co-occurrence of MYD88L265P), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB ( based on EZH2 mutations and BCL2 translocations).

Genetic alterations in multiple genes helped distinguish each genetic subtype. Each subtype differed phenotypically, according to differences in gene-expression signatures and responses to immunochemotherapy. Survival was found to be favorable in the BN2 and EZB subtypes, while inferior outcomes were observed in the MCD and N1 subtypes.

Additionally, researchers reported that MCD and BN2 DLBCLs rely on chronic active B-cell receptor signaling that is responsive to therapeutic inhibition.

These findings “may provide a conceptual edifice on which to develop precision therapies for these aggressive cancers,” Dr Schmitz and colleagues concluded. Furthermore, genetically subtyping DLBCL has the potential to guide patients into appropriate clinical trials, they added.—Zachary Bessette