Trial Information

Epidemiology of Burkitt Lymphoma in East Africa Children or Minors (EMBLEM)

Burkitt lymphoma (BL) is an aggressive monoclonal B-cell malignancy that is rare (sporadic)
worldwide, but is 100-fold more common (endemic) in equatorial Africa, particularly among
children. Epstein-Barr virus (EBV) and malaria are epidemiologically linked to endemic BL in
epidemiologic studies, but questions remain about role of EBV variants and the evidence for
association with malaria is weak. EBV is ubiquitous, yet only few children develop BL,
possibly because only a few EBV variants are pathogenically relevant. The association of BL
with malaria is based on ecologic and non-comparative clinical studies. Two case-control
studies have reported significant association of high anti-malarial antibodies with BL
(OR=5_ among children in Uganda and in Malawi, but selection bias (cases and controls came
from dissimilar geographical areas) and reverse causality bias were limitations. Three
studies were conducted in the 1960s and 70s to test association of carriage of
malaria-resistance gene with BL, two of which reported a significant or marginal inverse
association. These pioneering studies were small (240 cases all together) and looked at one
polymorphism in one gene (sickle cell gene). Improvements in technologies to characterize
genetic variation allow the EBV and malaria hypotheses to be examined with greater power by
looking at genetic variation across multiple genes.

The Epidemiology of Burkitt lymphoma in East African children and minors (EMBLEM) is a
case-control study of 1500 BL cases and 3000 age-, sex- and residence-frequency matched
controls we are proposing to conduct in East Africa. The study will enroll cases at four
hospitals in four regions in East Africa, where malaria transmission is holoendemic and year
round. The controls will be enrolled from general population attendees at Health Center II
(HC-II) units where the cases originated. The primary study objectives are: 1) to test the
hypothesis that genetic resistance to malaria is associated with a lower risk of BL, and 2)
to use genome-wide association methods to discover genetic variation that may be associated
with decreased or increased risk of BL. Because genetic variation conveys no information on
actual exposure to malaria or EBV, in secondary analyses, we will use empiric
epidemiological questionnaire and laboratory methods: a) to measure exposure to malaria and
its association with BL, and b) to measure EBV variants and their association with BL. To
examine issues related to bias and to obtain data to correct for deviations, we will also
enroll 2250 population controls from 5% of the villages to obtain population distribution of
key exposures variables. This data will be used to reweight the distribution in HC-II
controls back to the general population.