Epstein–Barr virus (EBV)-associated diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) constitutes a distinct clinicopathological entity in the current World Health Organization (WHO) classification, yet its genomic features remain sparsely characterized. Combining whole-genome sequencing (WGS), targeted amplicon sequencing (tNGS) and fluorescence in-situ hybridization (FISH) of tumours from 47 cases of EBV+ DLBCL we delineate the genomic landscape of this rare disease. Interrogating WGS data by sequential gene-set enrichment and network-diffusion we describe an accumulation of mutations affecting the nuclear factor κB (NFκB) pathway (CSNK2A2, CARD10), IL-6/JAK/STAT (SOCS1/3, STAT3) and WNT signalling (FRAT1, SFRP5) alongside aberrations in immunological processes like interferon-response. Further, WGS uncovered structural aberrations including 6q deletions (5/8 patients), which were subsequently validated by FISH (14/32 cases). Integrated WGS and tNGS analysis emphasized a profile distinct from EBV-negative DLBCL enriched for mutations in ARID1A (45%), KMT2A/D ... (Show More)

Epstein–Barr virus (EBV)-associated diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) constitutes a distinct clinicopathological entity in the current World Health Organization (WHO) classification, yet its genomic features remain sparsely characterized. Combining whole-genome sequencing (WGS), targeted amplicon sequencing (tNGS) and fluorescence in-situ hybridization (FISH) of tumours from 47 cases of EBV+ DLBCL we delineate the genomic landscape of this rare disease. Interrogating WGS data by sequential gene-set enrichment and network-diffusion we describe an accumulation of mutations affecting the nuclear factor κB (NFκB) pathway (CSNK2A2, CARD10), IL-6/JAK/STAT (SOCS1/3, STAT3) and WNT signalling (FRAT1, SFRP5) alongside aberrations in immunological processes like interferon-response. Further, WGS uncovered structural aberrations including 6q deletions (5/8 patients), which were subsequently validated by FISH (14/32 cases). Integrated WGS and tNGS analysis emphasized a profile distinct from EBV-negative DLBCL enriched for mutations in ARID1A (45%), KMT2A/D (32/30%), ANKRD11 (32%), NOTCH2 (32%). Expanding on previous reports, we identified recurrent alterations in CCR6 (15%), DAPK1 (15%), TNFRSF21 (13%), CCR7 (11%) and YY1 (6%). Our comprehensive description of the mutational landscape in EBV+ DLBCL substantiates the evidence of its pathobiological independence. Further, these observations aid in the refinement of the molecular taxonomy for aggressive lymphomas and guides future therapeutic strategies.

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