Mutational landscape of high-grade B-cell lymphoma with <i>MYC-</i>, <i>BCL2</i> and/or <i>BCL6</i> rearrangements characterized by whole-exome sequencing

Abstract

High-grade B-cell lymphoma accompanied with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) poses a cytogenetically-defined provisional entity among aggressive B-cell lymphomas that is traditionally associated with unfavorable prognosis. To better understand the mutational and molecular landscape of HGBL-DH/TH we here performed whole-exome-sequencing and deep panel next-generation-sequencing (NGS) of 47 clinically annotated cases. Oncogenic drivers, mutational signatures and perturbed pathways were compared with data from follicular lymphoma (FL), diffuse large-B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We find an accumulation of oncogenic mutations in NOTCH, IL6/JAK/STAT and NFκB signaling pathways and delineate the mutational relationship within the continuum between FL/DLBCL, HGBL-DH/TH and BL. Further, we provide evidence of a molecular divergence between BCL2 and BCL6 rearranged HGBL-DH. Beyond a significant congruency with the C3/EZB DLBCL cluster in BCL2 rearranged cases on an exome-wide level, we observe an enrichment of the SBS6 mutation signature in BCL6 rearranged cases. Differential gene set enrichment and subsequent network propagation analysis according to cytogenetically defined subgroups revealed an impairment of TP53 and MYC pathway signaling in BCL2 rearranged cases, whereas BCL6 rearranged cases lacked this enrichment, but instead showed impairment of E2F targets. Intriguingly, HGBL-TH displayed intermediate mutational features in all three aspects. This study elucidates a recurrent pattern of mutational events driving FL into MYC-driven BCL2 rearranged HGBL, unveiling the mutational pathogenesis of this provisional entity. Through this refinement of the molecular taxonomy for aggressive, germinal-center derived B-cell lymphomas, this calls into question the current WHO-classification system, especially regarding the status of MYC/BCL6 rearranged HGBL.

Induction treatment in high-grade B-cell lymphoma with a concurrent MYC and BCL2 and/or BCL6 rearrangement: a systematic review and meta-analysis

“…However, the present meta-analysis did demonstrate an improved 2y-PFS using intensified regimens over R-CHOP (-like) (HR=0.66; p=0.045). Interestingly, one study included in this meta-analysis showed improved 2y-PFS with R-CHOP(-like) protocols (26). This is possibly explained by selection bias as these patients were older (median age 73 vs. 60 years), had less frequently advanced stage disease (47.6% vs. 92.3%), and less often concomitant BCL2 translocation (52.4% vs. 76.9%), signifying an enrichment in the pathogenetically and clinically divergent MYC/ BCL6 rearranged subgroup.…”

“…The flowchart of the reviews shows the detailed process of selection (Figure 1). Finally, 11 relevant studies, comprising a total of 891 HGBCL-DH/TH patients, were included (6,7,18,(25)(26)(27)(28)(29)(30)(31)(32). We identified no prospective, randomized controlled trials (RCT); all studies included in the meta-analysis were of retrospective design.…”

“…A significant heterogeneity between the results of the individual studies (I 2 = 66.7%; p=0.02) was noticed. The study by Kuenstner et al was shown to be the key contributor to this between-study heterogeneity after performing the so-called leave- one-out sensitivity analysis (26). Following exclusion of this study, the combined effect size for the impact of intensified treatment on 2y-PFS was found to be stronger (HR=0.57 [95% CI 0.45-0.7]; p<0.01) and there was no longer heterogeneity among studies (I 2 = 0%; p=0.60) (Supplementary Table S3).…”

A comparison of the International Consensus and 5th World Health Organization classifications of mature B-cell lymphomas

“…As compared to DLBCL or HGBCL with MYC and BCL2 rearrangements, it shows GCB immunophenotype less often, is more likely to be CD10(−)/IRF4/MUM1(+), infrequently expresses BCL2 and is cytogenetically less complex [ 144 ]. Moreover, it does not show the impairment of TP53 and MYC signaling pathway typically observed in DLBCL or HGBCL with MYC and BCL2 rearrangements, whereas it exhibits impairment of E2F targets [ 148 ]. Because of its less distinctive biological features [ 141 ], HGBCL with MYC and BCL6 rearrangements, regarded as a provisional entity in ICC, is considered in the WHO-HAEM5 as a genetic subtypes of DLBCL, NOS and HGBCL, NOS, respectively.…”

Cytological Diagnosis of Aggressive Small-Cell Lymphomas

“…In MCL, concurrent TP53 and CDKN2A gene aberrations correlate with chemoresistance [50]. In BL, we already assessed the prognostic role of MYC insertions or concomitant BCL2 and BCL6 mutations [46,51]. In B-ALL/LBL and HGBL with MYC and BCL2 and/or BCL6 rearrangements, NGS sequencing has shown recurrent variants of genes coding for transcription factors (MYC, FOXO1), epigenetic modulators (KMT2D, EZH2, and CREBBP), and antiapoptotic proteins (BCL2) [51,52].…”