Genetic Subtypes of DLBCL Uncovered

Findings from a study recently published in the New England Journal of Medicine uncovered genetic subtypes of diffuse large B-cell lymphomas (DLBCLs) with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies.

The study, “Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma,” was conducted by Roland Schmitz, Ph.D., of the National Cancer Institute (NCI), and colleagues, and supported by the Intramural Research Program of the National Institutes of Health (NIH), the Center for Cancer Research of the National Cancer Institute (NCI), and an NCI Strategic Partnering to Evaluate Cancer Signatures grant.¹

It sought to extend historical findings of DLCBCL by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics.

DLBCLs are phenotypically and genetically heterogeneous, and gene-expression profiling has identified subgroups of DLBCL according to cell of origin that are associated with a differential response to chemotherapy and targeted agents.

To classify genes with recurrent aberrations, Schmitz and his team of researchers studied 574 DLBCL biopsy samples via exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 different genes. An algorithm was developed and implemented to uncover genetic subtypes based on the co-occurrence of genetic alterations.

Four prominent genetic subtypes in DLBCL were identified and labeled. The terms given to the subtypes included: 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 via the genetic aberrations in multiple genes. The subtypes differed phenotypically, as assessed by differences in gene-expression signatures and responses to immunochemotherapy, with promising survival in the BN2 and EZB subtypes and lesser outcomes in the MCD and N1 subtypes.

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

“The results of our studies suggest that, in clinical trials, targeted agents in DLBCL could be evaluated in the context of particular genetic subtypes or genetic aberrations that affect the targeted pathway,” it was stated in the article. “For example, drugs that target B-cell receptor—dependent NF-κB activation (e.g., 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.”

“Clinical trials evaluating inhibitors of B-cell receptor proximal signaling (e.g., spleen tyrosine kinase [SYK] inhibitors) or the downstream PI3 kinase pathway could investigate whether response is correlated with lesions that alter negative regulators of B-cell receptor signaling or the B-cell receptor subunits CD79A and CD79B. Differential BCL2 expression could be considered in the assessment of response to BCL2 inhibitors. Finally, immune-checkpoint inhibitors could be studied in the N1 subtype, given its prominent T-cell gene-expression signature and poor response to R-CHOP.”

The multiplatform genomic analysis strengthens the gene-expression classification of DLBCL by adding a genetic nosology that can suggest DLBCL pathogenesis. The analysis exposed an interrelationship between this genetic nosology and oncogenic signaling pathways, proposing evaluable therapeutic interventions.

While the study authors do not suggest selecting treatment for DLBCL based on individual genetic alterations, the identification of these genetic subtypes could potentially provide a conceptual structure for future development of precision therapies for those affected by the aggressive cancers.

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References:

1. Schmitz R, Wright GW, Huang DW, et al. Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. New England Journal of Medicine. 2018; 378:1396-1407 DOI: 10.1056/NEJMoa1801445.