Burkitt's Lymphoma Epidemiology

Burkitt’s lymphoma was first described in Ugandan children by Denis Burkitt in 1958. The rapid clinical course and uneven geographical distribution suggested possible infectious etiology by a vectored pathogen and attracted interest among researchers worldwide. Subsequent research led to many seminal discoveries, including that of Epstein–Barr virus (EBV) which was the first virus to be associated with a human cancer. Chromosomal translocations involving regions on chromosome 8 and 14 have provided clues to the central role of molecular aberrations in the development of cancer. Additionally, dramatic response of these tumors to chemotherapy led to the development of curative treatments for Burkitt’s lymphoma.

Burkitt’s lymphoma occurs as three clinical variants:

The risk factors for endemic Burkitt’s lymphoma are not completely understood. Repeated infection with Plasmodium falciparum malaria and infection at an early age with EBV are widely accepted as risk factors. The role of P. falciparum malaria was first deduced from correlation studies of the geographic distribution of endemic Burkitt’s lymphoma and P. falciparum malaria. Recently, case-control studies conducted in Africa have demonstrated significant associations between high titers of anti-malaria antibodies with increased odds of Burkitt’s lymphoma. However, because these studies measured malaria exposure using an antibody test, which may be influenced by onset of the disease, there is concern that associations may reflect consequences of the disease rather than disease risk (also called reverse causality).

The cumulative impact of malaria on Burkitt’s lymphoma risk in high malaria endemicity areas can be assessed indirectly by measuring functional polymorphisms in malaria-resistant genes (e.g., sickle cell gene). Only three small studies (240 cases), have attempted this approach in studies conducted in the 1960s and 1970s by looking at the sickle cell gene. Two of the studies, conducted in Nigeria and Uganda, reported a significant or marginal decrease in risk for Burkitt’s lymphoma among children with the sickle cell gene, but the third study, conducted in Ghana, did not. With the development of high-throughput genetic sequencing technologies and discovery of many functional genetic variants associated with malaria resistance, it is now possible to use this approach today to include the many genetic markers that have been associated with malaria resistance in different populations. This approach also has the advantage of the exposure measurement being reproducible and not subject to reverse causality bias which has marred interpretation of prior studies.

Epstein Barr Virus (EBV) is widely accepted as contributing to the high incidence of endemic Burkitt’s lymphoma in Africa. EBV is detected in about 95% of endemic Burkitt’s lymphoma cases. However, EBV is ubiquitous and infects virtually all African children by age two, suggesting that only a small fraction of EBV-infected children develop Burkitt’s lymphoma. This disparity in Burkitt’s lymphoma incidence and EBV ubiquity has prompted some researchers to hypothesize that a few EBV genetic variants might be related to the risk for Burkitt’s lymphoma. Thus, the incidence of BL would be higher in populations where causative EBV variants are more prevalent. This hypothesis will be evaluated using novel high throughput EBV variant genotyping assays that are currently being developed through EBV genome sequencing projects.