Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes

Abstract

Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.

Hitting back at lymphoma: How do modern diagnostics identify high‐risk diffuse large B‐cell lymphoma subsets and alter treatment?

“…[19][20][21] These data teach us that the COO in DLBCL may be only the beginning of the story of targeted therapy in DLBCL and that only with further investigation of the molecular substructure within and across COO subsets can we truly enter the era of precision medicine in DLBCL. [19][20][21] These data teach us that the COO in DLBCL may be only the beginning of the story of targeted therapy in DLBCL and that only with further investigation of the molecular substructure within and across COO subsets can we truly enter the era of precision medicine in DLBCL.…”

“…This speaks to additional molecular heterogeneity with COO subsets, which is being increasingly elucidated using integrated genomic analyses. 20,21 These findings suggest that different novel agents warrant exploration in discrete subsets within ABC-like DLBCL: targeting BCR signaling and BCL2 in one subgroup while addressing NOTCH2 and BCL6 in another. 2).…”

“…Dozens of recurrent mutations and copy number variations have been identified within DLBCLs, some of which cluster within COO subgroups, while others occur independent of COO (Fig. 20,21 Although this subset potentially may be targeted with BCL2 inhibitors, epigenetic modifiers, and inhibitors of the BCR/PI3K pathways, an alternate subset of Cancer September 15, 2019 GCB-like DLBCLs was notable for mutations of STAT3 and BRAF, immune evasion molecules, and NF-κB modifiers, which may be targeted better with inhibitors of those relevant pathways. [19][20][21] Within ABC-like DLBCLs, a subgroup can be identified defined by concomitant mutations of CD79B and MYD88 as well as gains of BCL2 and inactivation of PRMD1, whereas a separate cluster within ABC tumors was notable for NOTCH2 mutations and BCL6 translocations as well as mutations of NF-κB family members.…”

Molecular pathogenesis of germinal center‐derived B cell lymphomas

“…92,95,134,[156][157][158] Of over 700 genes that have been found mutated in these tumors, ~150 have been catalogued as significant genetic drivers of the disease based on recurrence and mutation features, with a median of 17 drivers/case in the coding genome. 92,95,134,[156][157][158] Of over 700 genes that have been found mutated in these tumors, ~150 have been catalogued as significant genetic drivers of the disease based on recurrence and mutation features, with a median of 17 drivers/case in the coding genome.…”

“…Supporting this view, initial sequencing studies have uncovered the presence of mutational hotspots in several non-coding regions of the DLBCL genome, with some preference for putative enhancers. 92,95 In the first study, a custom algorithm allowed to assign about half of DLBCL cases to one of four genetic groups, termed based on the most recurrent defining lesions: 92 While additional studies will be necessary to confirm the clinical applicability of these genetic classifications and to possibly integrate them into a unified picture, their clinical relevance is suggested by the association of individual clusters with discrete clinical outcomes following conventional induction chemo-immunotherapy. 160 While some of the identified hits can be found in both transcriptional subtypes of DLBCL, likely reflecting more general mechanisms of malignant transformation, a variety of recurrent oncogenic lesions show preferential distribution in GCB-and ABC-DLBCL (next sections, and recent review).…”