Molecular Background of Double Protein Expressor B-Cell Lymphomas

Introduction: Concomitant deregulation of MYC and BCL2, whether at the genomic or protein level, comprises clinically a significant biological high-risk feature in aggressive B-cell lymphomas. Yet, the molecular background of these lymphomas is not fully understood. We sought to comprehensively characterize BCL2 and MYC aberrations and to identify clinically feasible determinants of the recent genomic subtypes and clinical outcome in diffuse large B-cell lymphoma (DLBCL).

Patients and Methods: We analyzed BCL2, BCL6 and MYC rearrangements and corresponding protein expression in the context of somatic exome-wide driver gene alterations, copy number annotations, transcriptome and clinical data in 181 patients with primary DLBCL.

Results: We found that germinal center B-cell (GCB) and activated B-cell (ABC)-like DLBCLs utilized different mechanisms to deregulate MYC and BCL2 expression. While the structural variations of BCL2 were subtype-specific and specifically increased antiapoptotic BCL2 expression, MYC deregulation was associated with gene expression signatures including biosynthetic pathways and telomerase activity and depletion of JAK-STAT, cytokine and immune cell signatures. Genomic dissection of MYC translocations and protein overexpression revealed associations with other lymphoma drivers, of which we highlight a novel interplay between MYC deregulation and TP53 alterations.

Double protein expression (DPE) arose from different 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. Importantly, we recognized more GCB lymphomas with double hit -like clinical behavior when BCL2 copy number alterations were considered. In the non-GCB DLBCLs in turn, concurrent alterations were rare and clinical behavior of DPE was dependent on the molecular context. Interestingly, BN2/C1 -like non-GCB lymphomas with BCL6 translocations had excellent outcomes regardless of the DPE status. Overall, 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.

Conclusion: Our findings elucidate the pathogenesis and modern biological determinants of high-risk DLBCL and reveal subtype-specific and clinically feasible improvements to risk-stratification and predictors of outcome.