Browsing by Author "Meriranta, Leo"

Concomitant deregulation of MYC and BCL2, whether at the genomic or protein level, comprises a clinically significant poorly characterized biological high-risk feature in diffuse large B-cell lymphoma (DLBCL). To interrogate these lymphomas, we comprehensively characterized genomic alterations and protein expression of BCL2, BCL6 and MYC in the context of comprehensive mutational, transcriptomic and clinical data in 181 patients with primary DLBCL. While the structural variations of BCL2 were subtype-specific and specifically increased BCL2 expression, molecular dissection of MYC deregulation revealed associations with other lymphoma drivers, of which we highlight concurrent TP53 alterations. Double protein expression (DPE) arose from heterogeneous molecular backgrounds in a subtype-dependent manner. In GCB DLBCL, concurrent alterations of MYC and BCL2 loci gave rise to the majority of DPE DLBCLs, whereas in the ABC DLBCLs, concurrent alterations were infrequent. Clinically, DPE DLBCL defined a prognostic entity, which was independent of International Prognostic Index (IPI) and cell-of-origin, and together with TP53 alterations had synergistic dismal impact on survival. Importantly, BCL6 translocations identified non-GCB lymphomas with favorable BN2/C1 -like outcomes independent of IPI and concurrent DPE status. Our findings elucidate the pathogenesis and biological determinants of high-risk DLBCL and reveal subtype-specific and clinically feasible predictors of subtype and outcome.