Abstract
Epstein–Barr virus (EBV)-associated diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) constitute a distinct clinicopathological entity in the current World Health Organization (WHO) classification. However, its genomic features remain sparsely characterized. Here, we combine whole-genome sequencing (WGS), targeted amplicon sequencing (tNGS), and fluorescence in situ hybridization (FISH) from 47 EBV + DLBCL (NOS) cases to delineate the genomic landscape of this rare disease. Integrated WGS and tNGS analysis clearly distinguished this tumor type from EBV-negative DLBCL due to frequent mutations in ARID1A (45%), KMT2A/KMT2D (32/30%), ANKRD11 (32%), or NOTCH2 (32%). WGS uncovered structural aberrations including 6q deletions (5/8 patients), which were subsequently validated by FISH (14/32 cases). Expanding on previous reports, we identified recurrent alterations in CCR6 (15%), DAPK1 (15%), TNFRSF21 (13%), CCR7 (11%), and YY1 (6%). Lastly, functional annotation of the mutational landscape by sequential gene set enrichment and network propagation predicted an effect on the nuclear factor κB (NFκB) pathway (CSNK2A2, CARD10), IL6/JAK/STAT (SOCS1/3, STAT3), and WNT signaling (FRAT1, SFRP5) alongside aberrations in immunological processes, such as interferon response. This first comprehensive description of EBV + DLBCL (NOS) tumors substantiates the evidence of its pathobiological independence and helps stratify the molecular taxonomy of aggressive lymphomas in the effort for future therapeutic strategies.
Highlights
Introduction EpsteinBarr virus-positive (EBV + ) diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) was first described in a pivotal study by Oyama et al in 2003, whichGebauer et al Blood Cancer Journal (2021)11:102 observations led to an adapted definition of the entity in the 2016 revision of the World Health Organization (WHO) classification[4,5].While Epstein–Barr virus (EBV)-positive patients account for 8–10% of DLBCL cases in the East Asian population, data on the incidence in the western hemisphere is scarce, yet suggests similar to slightly lower numbers
Case selection and clinicopathological characteristics In a retrospective approach, we reviewed our institutional database to identify EBV + DLBCL (NOS) patients whose primary diagnostic biopsy specimen had been referred to the Reference center for Hematopathology at University Hospital Schleswig Holstein Campus Lübeck and Hämatopathologie Lübeck for centralized histopathological panel evaluation between 2008 and April 2018
An underlying HIV infection had to be clinically excluded prior to recruitment in all cases and EBV + DLBCL (NOS) tumor cells were shown to express EBER in >50% of large cell infiltrates in accordance with the current WHO definition of the entity
Summary
Introduction EpsteinBarr virus-positive (EBV + ) diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) was first described in a pivotal study by Oyama et al in 2003, whichGebauer et al Blood Cancer Journal (2021)11:102 observations led to an adapted definition of the entity in the 2016 revision of the WHO classification[4,5].While EBV-positive patients account for 8–10% of DLBCL cases in the East Asian population, data on the incidence in the western hemisphere is scarce, yet suggests similar to slightly lower numbers. Recent observations relativized EBV as an independent risk factor, several studies found EBV + DLBCL (NOS) patients to be significantly enriched for adverse confounding clinical factors, such as stage, impaired performance status, advanced age, and significant canonical and alternative nuclear factor κB (NFκB)-pathway activation[10]. This resulted in a high number of cases with non-germinal center B-cell-like immunophenotype[2,7,11,12,13,14].
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