GENETICALLY DISTINCT PATHOGENESIS OF EPSTEIN‐BARR VIRUS (EBV)‐POSITIVE VERSUS EBV‐NEGATIVE CLASSICAL HODGKIN (CHL) LYMPHOMA

Introduction: Latent EBV infection of the cHL clone is more frequent in mixed-cellularity (MC) histological subtype, early childhood and older adulthood, developing countries. Based on these other epidemiologic features, EBV+ has been hypothesized to have distinct etiology pathogenesis compared EBV− cHL. However, landscape genetic lesions genome incompletely defined. Methods: We studied 57 cases (10–83 year-old; 41 EBV−, 16 EBV+) by whole-exome sequencing/WES (n = 56 cases; 34 from Tiacci et al. Blood 2018; 18 Wienand Adv 2019; 4 newly added) and/or whole-genome sequencing/WGS (32 processed, including 31 also subjected WES). Tumor normal cells were purified frozen samples microdissection 39; 9 EBV+, 30 EBV−) or flow cytometry 18; 7 11 EBV−). EBV- sequenced at identical median depths (WGS 44X; WES 146X) same bioinformatics pipelines. Results: Clonal nonsynonymous somatic mutations much fewer versus (median 4.5 vs. 57; p 0.0013), was observed for total genome-wide 112 6826; < 0.0001). In contrast, within cHL, MC 6) non-MC 33) had similar mutation load (p 0.56), indicating a link with viral status rather than subtype. AID-associated mutational signatures stronger both (SBS9, q 0.069; SBS85, 0.023) target region 126 genes known undergo AID-driven aberrant hypermutation 0 mutations/Mb; 0.045). Compared copy number alterations ≥1 multiple pathways that drive can be activated latent proteins (possibly surrogating cellular lesions). particular (Figure A): (i) JAK-STAT signaling STAT6, SOCS1, CSF2RB JAK2 mutated 85% 47% 0.0057); (ii) PI3K-AKT GNA13 ITPKB 34% 7% 0.047); (iii) NF-κB TNFAIP3, NFKBIE REL 0.0057). MHC-I B2M HLA-A/B/C (56% 20% 0.0032; Figure A), possibly prevent presentation tumor neo-antigens generated higher burden. contrast B), showed germline homozygosity HLA-I often (53% 19%; 0.05), particularly HLA-C (33% 2%; 0.0039), which may predispose development through reduced diversity alleles available antigen presentation. Encore Abstract - previously submitted EHA 2023 Keywords: genomics, epigenomics, other-omics, Hodgkin lymphoma, biology heterogeneity No conflicts interests pertinent abstract. * K. Gomez G. Schiavoni are co-first authors. ^ R. Rabadan co-last