Abstract
Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in regions of equatorial Africa where P. falciparum malaria is holoendemic. The tumor is consistently associated with Epstein-Barr virus (EBV). Screening for EBV DNA in plasma in a high-risk population in Hong Kong has been shown to be useful in facilitating the early diagnosis of nasopharyngeal carcinoma, another EBV-associated tumor. Here, we investigate plasma EBV as a diagnostic marker for eBL in children in Uganda. We studied plasma specimens from 25 children with eBL and 25 controls matched for age (<3-16 years), gender and geography, including many with asymptomatic P. falciparum infection. These specimens were previously collected under the auspices of the EMBLEM (Epidemiology of Burkitt lymphoma in East African children and minors) study. After cell-free DNA isolation, plasma EBV DNA was measured using a quantitative PCR assay that amplifies the large internal repeats of the EBV genome. All children with eBL had measurable plasma EBV, as compared to 84% of control children. The median plasma EBV DNA level was 5.23 log10 copies/mL (interquartile range 3.54-6.08 log10 copies/mL) in children with eBL. In contrast, the median plasma EBV DNA level was 0.37 log10 copies/mL (interquartile range 0.18-1.05 log10 copies/mL) in children without lymphoma. An EBV threshold of 2.52 log10 copies/mL yielded a sensitivity of.88 and a specificity of 1. The estimated AUC was 0.936 (95% CI: 0.8496 – 1.00) for the corresponding ROC curve. Plasma EBV copy number did not depend on age, gender, or malaria screening status. However, two control children with asymptomatic P. falciparum infection and parasitemia also had high plasma EBV copy number. Our analysis suggests that measurements of EBV copy number in plasma may be useful in identifying children with eBL versus control children. A promising area for future research is the differentiation of high copy number associated with tumor versus high copy number associated with asymptomatic parasitemia.
Highlights
Epstein-Barr virus (EBV) was first discovered in cell lines established from Burkitt lymphoma (BL) tumors from Uganda [1, 2]
It appeared that the distribution of the tumor might correspond to the distribution of the virus, but it was appreciated that the tumor occurs relatively commonly (~5/ 100,000) in children in certain regions of equatorial Africa where it is described as endemic Burkitt Lymphoma, and sporadically elsewhere (~0.1/100,000) [3]
We studied 25 children with endemic Burkitt Lymphoma (eBL) and 25 children without lymphoma ranging in age from less than three years of age up to 16 years of age
Summary
Epstein-Barr virus (EBV) was first discovered in cell lines established from Burkitt lymphoma (BL) tumors from Uganda [1, 2]. At first, it appeared that the distribution of the tumor might correspond to the distribution of the virus, but it was appreciated that the tumor occurs relatively commonly (~5/ 100,000) in children in certain regions of equatorial Africa where it is described as endemic Burkitt Lymphoma (eBL), and sporadically elsewhere (~0.1/100,000) [3]. Unlike BL, the EBV association is very strong in both high and low incidence regions Given this strong association, plasma EBV DNA has been extensively studied as a diagnostic marker for NPC. A large study in Hong Kong screened approximately 20,000 men at high risk for NPC by PCR for EBV DNA in plasma [9], and found more than 300 cases of NPC, most of which represented early-stage disease that could be treated with radiation to achieve long term survival
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