Abstract:
Endemic Burkitt lymphoma (eBL) is primarily found in children in equatorial regions and rep-
resents the first historical example of a virus-associated human malignancy. Although
Epstein-Barr virus (EBV) infection and MYC translocations are hallmarks of the disease, it is
unclear whether other factors may contribute to its development. We performed RNA-Seq
on 20 eBL cases from Uganda and showed that the mutational and viral landscape of
eBL is more complex than previously reported. First, we found the presence of other her-
pesviridae family members in 8 cases (40%), in particular human herpesvirus 5 and human
herpesvirus 8 and confirmed their presence by immunohistochemistry in the adjacent non-
neoplastic tissue. Second, we identified a distinct latency program in EBV involving lytic
genes in association with TCF3 activity. Third, by comparing the eBL mutational landscape
with published data on sporadic Burkitt lymphoma (sBL), we detected lower frequencies of
mutations in MYC, ID3, TCF3 and TP53, and a higher frequency of mutation in ARID1A in
eBL samples. Recurrent mutations in two genes not previously associated with eBL were
identified in 20% of tumors: RHOA and cyclin F (CCNF). We also observed that polyviral
samples showed lower numbers of somatic mutations in common altered genes in compari-
son to sBL specimens, suggesting dual mechanisms of transformation, mutation versus
virus driven in sBL and eBL respectively.
