UMMS Affiliation

Program in Bioinformatics and Integrative Biology; Division of Infectious Diseases and Immunology, Department of Medicine

Publication Date

2020-08-17

Document Type

Article Postprint

Disciplines

Genetic Phenomena | Genetics and Genomics | Hemic and Lymphatic Diseases | Neoplasms | Pediatrics | Population Biology | Translational Medical Research | Virology | Viruses

Abstract

Endemic Burkitt lymphoma (eBL), the most prevalent pediatric cancer in sub-Saharan Africa, is distinguished by its inclusion of Epstein-Barr virus (EBV). In order to better understand the impact of EBV variation in eBL tumorigenesis, we improved viral DNA enrichment methods and generated a total of 98 new EBV genomes from both eBL cases (n = 58) and healthy controls (n = 40) residing in the same geographic region in Kenya. Using our unbiased methods, we found that EBV type 1 was significantly more prevalent in eBL patients (74.5%) than in healthy children (47.5%) (odds ratio = 3.24, 95% confidence interval = 1.36 to 7.71, P = 0.007), as opposed to similar proportions in both groups. Controlling for EBV type, we also performed a genome-wide association study identifying six nonsynonymous variants in the genes EBNA1, EBNA2, BcLF1, and BARF1 that were enriched in eBL patients. In addition, viruses isolated from plasma of eBL patients were identical to their tumor counterparts consistent with circulating viral DNA originating from the tumor. We also detected three intertypic recombinants carrying type 1 EBNA2 and type 2 EBNA3 regions, as well as one novel genome with a 20-kb deletion, resulting in the loss of multiple lytic and virion genes. Comparing EBV types, viral genes displayed differential variation rates as type 1 appeared to be more divergent, while type 2 demonstrated novel substructures. Overall, our findings highlight the complexities of the EBV population structure and provide new insight into viral variation, potentially deepening our understanding of eBL oncogenesis.

IMPORTANCE Improved viral enrichment methods conclusively demonstrate EBV type 1 to be more prevalent in eBL patients than in geographically matched healthy controls, which previously underrepresented the prevalence of EBV type 2. Genome-wide association analysis between cases and controls identifies six eBL-associated nonsynonymous variants in EBNA1, EBNA2, BcLF1, and BARF1 genes. Analysis of population structure reveals that EBV type 2 exists as two genomic subgroups and was more commonly found in female than in male eBL patients.

Keywords

EBV type 1, EBV type 2, Epstein-Barr virus, endemic Burkitt lymphoma, genetic variation, genome sequencing, UMCCTS funding

Rights and Permissions

Copyright © 2020 American Society for Microbiology. Accepted manuscript posted with a 6-month embargo as allowed by the publisher's copyright transfer license agreement at https://journals.asm.org/content/copyright-transfer-and-supplemental-material-license-agreement-2017.

DOI of Published Version

10.1128/JVI.02007-19

Source

Kaymaz Y, Oduor CI, Aydemir O, Luftig MA, Otieno JA, Ong'echa JM, Bailey JA, Moormann AM. Epstein-Barr Virus Genomes Reveal Population Structure and Type 1 Association with Endemic Burkitt Lymphoma. J Virol. 2020 Aug 17;94(17):e02007-19. doi: 10.1128/JVI.02007-19. PMID: 32581102; PMCID: PMC7431785. Link to article on publisher's site

Journal/Book/Conference Title

Journal of virology

Related Resources

Link to Article in PubMed

PubMed ID

32581102

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