Subgrouping of Burkitt lymphoma variants by DNA methylation is driven by an EBV‐associated epigenotype

Introduction: Burkitt lymphoma (BL) is an aggressive mature B-cell lymphoma, which traditionally has been separated into three epidemiologic variants: endemic (eBL), sporadic (sBL) and immunodeficiency-associated BL (iBL). This subgrouping strongly confounded by EBV-infection. Indeed, there evidence from molecular studies that subtyping of based on EBV status might better reflect the pathogenetic heterogeneity than epidemiology. As known to influence epigenetic regulation, we here aimed at a comparative DNA methylation (DNAme) profiling variants with respect their geographic origin status. Methods: We collected DNAme profiles (Infinium HumanMethylation450 Infinium MethylationEPIC BeadChip) 116 patients (80 sBL: 7 EBV+; 29 eBL: 27 iBL: 4 EBV+), 17 cell lines 6 EBV-transformed LCLs. For group determination unsupervised clustering algorithms (K-means, PGMRA, UMAP) were applied. To investigate potential consequences EBV-associated performed protein-protein interaction network analysis genes within EBV-specific pattern. Moreover, mined gene expression values RNAseq in 21 EBV- sBL 5 germinal-center populations. Results: Unsupervised revealed two distinct phenotypes, differentiate EBV+ 1,266 CpGs. separation accompanied characteristic hypermethylation BLs. Additionally, identified subgroup similar pattern like LCLs, possibly indicating latency phase differences Investigation UBC as key interactor, importance ubiquitin-proteasome system (UPS) EBV-induced lymphomagenesis. Among differentially methylated between BL, 19 have reported recurrently mutated BL. All except 3 these are expressed B-cells. significantly hypermethylated regulatory regions BLs (σ/σmax = 0.4, q ≤ 0.01), including lower mutational frequency versus Conclusion: The findings this study show be associated subgroups supporting rather origin. suggest silencing deregulated ubiquitination means alternative mutation involved pathogenesis Keywords: Aggressive non-Hodgkin Genomics, Epigenomics, Other -Omics, Pathology Classification Lymphomas No conflicts interests pertinent abstract.