Frequency of EBV LMP-1 Promoter and Coding Variations in Burkitt Lymphoma Samples in Africa and South America and Peripheral Blood in Uganda.

Hsiao-Mei Liao,Marina Gutierrez,Sidnei Epelman,Robert Biggar,Kishor Bhatia,Shyh-Ching Lo,Francis Nkrumah,Bingjie Li,Martin Ogwang,Pei-Ju Chin,Sam Mbulaiteye,Hebing Liu,Janet Neequaye,Shien Tsai,Heiyan Lei,Steven Reynolds

doi:10.3390/cancers10060177

Abstract

Epstein-Barr virus (EBV) is linked to several cancers, including endemic Burkitt lymphoma (eBL), but causal variants are unknown. We recently reported novel sequence variants in the LMP-1 gene and promoter in EBV genomes sequenced from 13 of 14 BL biopsies. Alignments of the novel sequence variants for 114 published EBV genomes, including 27 from BL cases, revealed four LMP-1 variant patterns, designated A to D. Pattern A variant was found in 48% of BL EBV genomes. Here, we used PCR-Sanger sequencing to evaluate 50 additional BL biopsies from Ghana, Brazil, and Argentina, and peripheral blood samples from 113 eBL cases and 115 controls in Uganda. Pattern A was found in 60.9% of 64 BL biopsies evaluated. Compared to PCR-negative subjects in Uganda, detection of Pattern A in peripheral blood was associated with eBL case status (odds ratio [OR] 31.7, 95% confidence interval: 6.8–149), controlling for relevant confounders. Variant Pattern A and Pattern D were associated with eBL case status, but with lower ORs (9.7 and 13.6, respectively). Our results support the hypothesis that EBV LMP-1 Pattern A may be associated with eBL, but it is not the sole associated variant. Further research is needed to replicate and elucidate our findings.

Highlights

Epstein-Barr virus (EBV) is a gammaherpesvirus that is causally associated with multiple cancers [1,2,3,4,5,6], including endemic Burkitt lymphoma, an aggressive pediatric cancer that occurs with high incidence in African countries with high malaria endemicity [7]
We recently reported novel sequence variants in the latent membrane protein 1 (LMP-1) gene and promoter in EBV genomes sequenced by high throughput sequencing (HTS) from 13 of 14 BL biopsies from Ghana, Brazil, and Argentina [18]
Because we have previously shown that the Lei Patterns A to D identify unique genetic variants that cluster together in phylogenetic trees based on the entire EBV genome sequence, on the sequence from EBNA1, or LMP-1 genes (Figure 1 in [18])

Summary

Introduction

Epstein-Barr virus (EBV) is a gammaherpesvirus that is causally associated with multiple cancers [1,2,3,4,5,6], including endemic Burkitt lymphoma (eBL), an aggressive pediatric cancer that occurs with high incidence in African countries with high malaria endemicity [7]. The small proportion of EBV-infected people who progress to cancer could be due to the effects of high-risk variants with greater propensity for carcinogenicity [10]. North African, stand in marked contrast to the ubiquitous distribution of EBV [11]. These regional distributions may be interpreted as epidemiological clues about the regional distribution of high-risk. EBV tumor-specific variants that play a role in the pathogenesis of eBL and NPC [10,12]. The nature of high-risk EBV variants is currently unknown. EBV type 2 appears to be over-represented in samples collected in Africa [14], but recent studies conducted in the United

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Discussion

Conclusion