The multi-omic characterization of pediatric and adult Burkitt lymphoma

Burkitt lymphoma (BL) is the most prevalent pediatric non-Hodgkin lymphoma (NHL) and while infrequent within the adult setting it is associated with greater lethality. Much of the prevailing understanding of the molecular etiology of BL stems from pediatric research, resulting in an ambiguous relationship between pediatric (pBL) and adult BL (aBL) and other B-NHLs. Recent findings highlighting variations associated with Epstein-Barr virus (EBV) status imply a potentially underappreciated complexity of the role of EBV in BL pathogenesis. Furthermore, despite the growing comprehension of genetic features associated with BL, insights into the methylation landscape and its contribution to pathogenesis are still underexplored. Thus, we aimed to comprehensively identify somatic alterations driving lymphomagenesis across aBL and pBL and to discern molecular characteristics correlated with clinical disparities. Additionally, we sought to identify consistent DNA methylation changes and their interplay between BL pathogenesis and other features such EBV status and somatic mutations. Using comprehensive whole-genome sequencing (WGS) of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumours we revealed additional significantly mutated genes (SMGs) in BL and identified distinct subgroupings within BL, namely DGG-BL (DDX3X, GNA13 and GNAI2), IC-BL (ID3, CCND3), and Q53-BL (quiet TP53). These subgroups are defined by combinations of driver and non-coding mutations resulting from aberrant somatic hypermutation (aSHM). Notably, IC-BL and DGG-BL exhibit unique biological and gene expression profiles, with associations to patient outcomes differing between aBL and pBL. Utilizing an integrative approach combining CpG methylation profiling, WGS, and gene expression data, we determined that the BL methylome displays global hypomethylation relative to normal centroblasts, accompanied by localized hypermethylation of tumour suppressor genes. EBV-positive BL methylomes presented with localized hypermethylation enriched within enhancer regions. Furthermore, we identified two distinct epitypes, HyperBL and HypoBL. HyperBL is characterized by localized promoter hypermethylation, increased mutation rates, and inferior survival outcomes. Both pBL and aBL patients were equally distributed across these epitypes, with a notable predominance of EBV-positive tumours in HyperBL. These findings underscore the shared pathogenesis between aBL and pBL, delineate tumours with unique molecular features, and emphasize the potential of targeting molecular and epigenetic alterations through novel therapeutics.