Distinct Viral and Mutational Spectrum of Endemic Burkitt Lymphoma

Abstract

Endemic Burkitt lymphoma (eBL) is primarily found in children in equatorial regions and represents 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 herpesviridae 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 comparison to sBL specimens, suggesting dual mechanisms of transformation, mutation versus virus driven in sBL and eBL respectively.

Epstein‐Barr virus lytic cycle involvement in diffuse large B cell lymphoma

“…Furthermore, lytic antigen expression was confirmed by immunohistochemical staining for BMRF1 early lytic protein, a DNA polymerase factor essential for lytic virus replication, observed in 9/13 (70%) of our EBV+ DLBCL cases (Figure ). This was in agreement with similar observations found in other B‐cell lymphomas, where it was proposed that lytically infected B‐cells secrete factors that may promote tumourigenesis, including growth and angiogenesis factors and immunosuppressive cytokines.…”

“…Even though latency programs predominate in EBV‐driven tumours, recent evidence suggests that lytic EBV replication has certain pathogenic role, at least in the early phases of cell transformation . Abate et al observed RNAseq in an endemic BL cohort, the expression of lytic genes suggesting a noncanonical latency program of the virus with a subset of viral episomes initiating lytic reactivation . Particularly, in DLBCL, the EBV lytic cycle is by and large unexplored, but recently, Morishima et al described higher IgG antibody titres against lytic antigens, which were considered as a marker of EBV reactivation, in a series of 13 EBV+ DLBCL patients older than 50 years .…”

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

“…These genes also implicate DNA repair in terms of oncogenesis where we identify 3 previously undescribed genes ( MSH6, RAD50 , and PRKDC ) involved in double strand repair and nonhomologous end joining. The analysis presented here of BL patients from Kisumu, Kenya was underway when a similar study was published involving 20 Ugandan patients (24). Therefore, we reevaluated our analysis to determine if we could validate their findings.…”

“…Even though deregulated expression and subsequent mutations of MYC gene severely alter the DNA binding efficiency of this transcription factor, these do not appear to be sufficient for tumorigenesis (20). The search for additional driver mutations in sBL has yielded several candidate tumor suppressors and oncogenes (21–23), however; eBL primary tumor biopsies have not been studied at a genome-wide level until recently with limited numbers of cases (24). The most common driver mutations in coding regions appear to occur in the transcription factor TCF3 (E2A) and its inhibitor ID3 .…”

High-throughput sequencing of the B-cell receptor in African Burkitt lymphoma reveals clues to pathogenesis

“…No significant differences, however, were seen in the expression of BCR signaling pathway genes in tumors with and without a dominant, productive IGH rearrangement. RNAseq variant analysis revealed sequence variants in genes previously reported to be mutated in BL, including ID3, TP53, SMARCA4, ZNF587, and FOXO1, 24,25,[28][29][30] as well as 14 genes that are mutated in other cancers, including NOTCH1, PAX5, and TFAP4 ( Figure 1D; supplemental Table 2). Two tumors with a polyclonal IGH repertoire and a clonal IGK/IGL rearrangement by HTS of gDNA carried mutations in several genes mutated in other BL tumors, including TP53, POMC, COL6A3, and BSCL2, supporting the diagnosis of BL in these cases.…”