Researchers discover four genetic subtypes of diffuse large B-cell lymphomas with potential therapeutic implications

Four prominent subtypes of diffuse large B-cell lymphomas (DLBCLs) have been identified, distinguished by their genetic aberrations. Knowing the genetic subtype could affect the selection of targeted therapies, according to investigators led by Roland Schmitz, PhD, at the Lymphoid Malignancies Branch at the National Cancer Institute, Bethesda, Md.

“The genetic framework for DLBCL that we present here provides a new and evolving understanding of the pathogenesis of DLBCL and the molecular attributes that may influence therapeutic response,” they wrote in New England Journal of Medicine. “Unlike previous genetic investigations that catalogued individual genetic aberrations, our study identified genetic subtypes of DLBCL that differ from one another by many recurrent genetic aberrations.”

Dr. Schmitz and colleagues undertook a multiplatform analysis of structural genomic abnormalities and gene expression in 574 DLBCL biopsy samples, analyzing these samples using exome and transcriptome sequencing and targeted amplicon resequencing of 372 genes. Groups of genetic aberrations that target oncogenic signaling pathways were considered. 

Genes were altered at significantly different frequencies in activated B-cell-like (ABC) and germinal-center-B-cell-like (GCB) subgroups based on cell or origin. NOTCH2 mutations and BCL6 fusions were common genetic features that often co-occurred, and distinguished unclassified from other DLBCLs.

They classified the four genetic subtypes they identified as:

• MCD, with a co-occurrence of MYD88^L265P and CD79B mutations
• BN2, based on BCL6 fusions and NOTCH2 mutations
• N1, based on NOTCH1 mutations
• EZB, based on EZH2 mutations and translocations in BCL2

The MCD and N1 subtypes were dominated by ABC cases, while EZB included mostly GCB cases. BN2 had contributions from these gene-expression subgroups in addition to the unclassified subgroup.

“Overall, we classified 44.8% of our samples into these genetically ‘pure’ subtypes of DLBCL and recognize that non-subtyped cases may share genetic features as well as etiologic factors with the genetic subtypes,” the authors wrote. “On the basis of the gene-expression predictor classifications of MCD, BN2, N1, and EZB cases, we estimate that these genetic subtypes would comprise 46.6% of cases.”

Progression-free survival and overall survival (OS) differed between the four subtypes. The BN2 and EZB subtypes had more favorable outcomes than the MCD and N1 subtypes. The predicted 5-year OS rates for the MCD, N1, BN2, and EZB subtypes were 26%, 36%, 65%, and 68%, respectively.

Within the ABC subgroup, patients with MCD had significantly inferior survival compared with those with BN2, and patients with either MCD or N1 had significantly inferior survival compared with patients with ABC tumors that were not genetically classified.

Within the GCB subgroup, there was a trend toward inferior OS among patients with EZB compared with patients with other GCB tumors (P=0.06).

Analysis of oncogenic pathways suggested that B-cell receptor–dependent NF-κB activation is a recurrent feature of MCD and BN2 tumors.

Based on the findings, the authors propose that targeted agents in DLBCL be evaluated in the context of particular genetic subtypes or genetic aberrations that affect the targeted pathway.

“For example, drugs that target B-cell receptor–dependent NF-κB activation (eg, inhibitors of BTK and protein kinase C beta) could be investigated in BN2 and MCD, given their enrichment for genetic aberrations that should activate or augment this signaling,” they wrote.

Dr. Schmitz and colleagues concluded that genetic subtyping in these patients may confer the ability to choose more targeted, precision therapies in the future.

This study was supported by the Intramural Research Program of the National Institutes of Health, the Center for Cancer Research of the National Cancer Institute (NCI), and an NCI Strategic Partnering to Evaluate Cancer Signatures grant.