Molecular profiling of EBV associated diffuse large B-cell lymphoma

Abstract

Epstein-Barr virus (EBV) associated diffuse large B-cell lymphoma (DLBCL) represents a rare aggressive B-cell lymphoma subtype characterized by an adverse clinical outcome. EBV infection of lymphoma cells has been associated with different lymphoma subtypes while the precise role of EBV in lymphomagenesis and specific molecular characteristics of these lymphomas remain elusive. To further unravel the biology of EBV associated DLBCL, we present a comprehensive molecular analysis of overall 60 primary EBV positive (EBV+) DLBCLs using targeted sequencing of cancer candidate genes (CCGs) and genome-wide determination of recurrent somatic copy number alterations (SCNAs) in 46 cases, respectively. Applying the LymphGen classifier 2.0, we found that less than 20% of primary EBV + DLBCLs correspond to one of the established molecular DLBCL subtypes underscoring the unique biology of this entity. We have identified recurrent mutations activating the oncogenic JAK-STAT and NOTCH pathways as well as frequent amplifications of 9p24.1 contributing to immune escape by PD-L1 overexpression. Our findings enable further functional preclinical and clinical studies exploring the therapeutic potential of targeting these aberrations in patients with EBV + DLBCL to improve outcome.

Epstein–Barr Virus and the Pathogenesis of Diffuse Large B-Cell Lymphoma

“…Additionally, the profiles could be applied to nearly 60% tumours of various DLBCL subtypes, including nodal and extranodal tumours [ 102 ]. However, when this algorithm was applied to EBV+ DLBCL, over 80% of tumours could not be attributed to a genetic subtype [ 103 ]. This provides further evidence of the unique genetic profile of EBV+ DLBCL compared to its EBV-negative counterpart [ 103 ].…”

“…However, when this algorithm was applied to EBV+ DLBCL, over 80% of tumours could not be attributed to a genetic subtype [ 103 ]. This provides further evidence of the unique genetic profile of EBV+ DLBCL compared to its EBV-negative counterpart [ 103 ].…”

“…EBV is only rarely found in association with DHL/THL; a recent study examining a cohort of 846 DHL/THL found that 16 cases were EBV+, 13 of which were of the GCB type [ 115 ]. Another study by Frontzek et all (2023) found that 4% of tumours carried translocations of MYC and BCL6 , but no cases of MYC/BCL2 double hit [ 103 ]. Nonetheless, whether synergistic effects between EBV and MYC/BCL2/BCL6 aberrations contribute to the pathogenesis of this subset of tumours remains to be established.…”

Epstein–Barr virus‐associated lymphomas decoded

“…89,90 The percentage of positive EBER-ISH cells required for the diagnosis of EBV-associated DLBCL-NOS is not clearly defined, with levels varying between 20% and 90% described. 89,90,92 The WHO 2016 criteria set the level at 80%, and this is currently endorsed by the ICC. 93 However, a 50% cut-off is utilised by some studies, and it is likely that EBV-positive levels below arbitrary thresholds still play a significant part in the pathogenesis of the disease.…”

“…93 However, a 50% cut-off is utilised by some studies, and it is likely that EBV-positive levels below arbitrary thresholds still play a significant part in the pathogenesis of the disease. 92,94 Histologically, it can occur in a polymorphic form not dissimilar to cHL, with the remaining cases presenting as a monomorphic form resembling de-novo DLBCL. 90 Perhaps uniquely in EBV-associated DLBCL-NOS, almost all cases demonstrate malignant cell CD30 and PD-L1 positivity.…”