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

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.