Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type–Specific Differences

Abstract

e most common pedi atric cancer in malaria-endemic equatorial Africa and nearly always contains Epstein–Barr virus (EBV), unlike sporadic Burkitt lymphoma (sBL) that occurs with a lower incidence in developed countries. Given these differences and the variable clinical pre sentation and outcomes, we sought to further understand path ogenesis by investigating transcriptomes using RNA sequencing (RNAseq) from multiple primary eBL tumors compared with sBL tumors. Within eBL tumors, minimal expression differences were found based on: anatomical presentation site, in-hospital survival rates, and EBV genome type, suggesting that eBL tumors are homogeneous without marked subtypes. The outstanding differ ence detected using surrogate variable analysis was the signifi cantly decreased expression of key genes in the immunoprotea some complex (PSMB9/b1i, PSMB10/b2i, PSMB8/b5i, and PSME2/PA28b) in eBL tumors carrying type 2 EBV compared with type 1 EBV. Second, in comparison with previously pub lished pediatric sBL specimens, the majority of the expression and pathway differences was related to the PTEN/PI3K/mTOR sig naling pathway and was correlated most strongly with EBV status rather than geographic designation. Third, common mutations were observed significantly less frequently in eBL tumors harboring EBV type 1, with mutation frequencies sim ilar between tumors with EBV type 2 and without EBV. In addition to the previously reported genes, a set of new genes mutated in BL, including TFAP4, MSH6, PRRC2C, BCL7A, FOXO1, PLCG2, PRKDC, RAD50, and RPRD2, were identified. Overall, these data establish that EBV, particularly EBV type 1, supports BL oncogenesis, alleviating the need for certain driver mutations in the human genome. Implications: Genomic and mutational analyses of Burkitt lym phoma tumors identify key differences based on viral content and clinical outcomes suggesting new avenues for the development of prognostic molecular biomarkers and therapeutic interventions. Mol Cancer Res; 15(5); 563–76. 2017 AACR.