Burkitt Lymphoma — A paradigm for global cancer research and discovery?
By Mike Miller
Contrary to frequent belief, Burkitt lymphoma is not a disease confined to the African continent. First identified as a distinct form of lymphoma by Irish surgeon Dennis Burkitt in Uganda in 1958, there are well documented cases in the United States, Latin America, and other countries that point to the global aspects of this disease.
A global perspective is one that is clearly desirable in studying cancers, and by comparing and analyzing cancer cases in Africa, Latin America and the U.S., researchers in all countries are benefitting from the cooperation and understanding gleaned from studies carried out by their counterparts and collaborators.
Developing these global perspectives is a key goal of the U.S. National Cancer Institute, particularly in ensuring there is no disconnect between research and care from one nation to another. The recent creation of NCI’s Center for Global Health, which is tasked with leveraging research resources across U.S. government agencies, foreign governments, and numerous commercial companies, is one outgrowth of this goal.
Burkitt lymphoma manifests itself as a very fast growing tumor, often with the appearance of huge tumor masses in the jaw and sometimes the abdomen. The extent of the disease in Africa, where it is more common than in the United States, has not been well characterized due to lack of established cancer registries: only five registries exist on the entire continent and just two in sub-Saharan Africa where the disease predominates. The International Agency for Research in Cancer (IARC) recently called for additional registries and better quality control, and is working on establishing new registries in several African countries. In the meantime statisticians have had to rely on hospital registry data, such as those from one site in Uganda that estimates a prevalence of Burkitt lymphoma that broadly ranges between 5 and 20 cases per 100,000 inhabitants. By comparison, the case rate in the U.S. per NCI’s SEER statistical database for 2001-2009 was 0.4 cases per 100,000.
In the past several years, while the extent of the disease in many parts of the world has not been precisely pinned down, the nature of the disease has come a bit more into focus. Experts now understand that Burkitt lymphoma is decidedly heterogeneous, making pathological confirmation of the disease complex and sometimes difficult, even in the U.S. Because of these pathological challenges, there’s been a call by experts for more studies to help establish a large enough population base in Africa to develop standardized pathology procedures and processes.
There are good models in Africa for establishing statistical, epidemiological and pathological standards and many of them are predicated on HIV/AIDS research supported by USAID and PEPFAR (the President’s Emergency Plan For AIDS Relief, which has committed more than $15 billion dollars to HIV efforts). For example, since 1995 the AIDS malignancy consortium has enrolled nearly 3,000 people into 53 trials in Africa, enabling researchers to engage in many important new areas of HIV science, particularly in the field of vaccine development. Interestingly, according to some experts in Africa, the recent concerted emphasis on HIV control and eradication has sidelined some efforts that were underway in cancer research and they feel efforts that were nascent could now be re-directed back to cancer.
Because Burkitt lymphoma has numerous virological ties or other infectious co-factors, another proposed research model is based on work done in the Americas and Europe on cervical cancer, particularly in the discovery of HPV as the primary causative agent for the disease and the subsequent development of vaccines to prevent viral infection. While a vaccine for Burkitt lymphoma or the viruses associated with it is probably a consideration for the future, HPV vaccine development in the U.S., Costa Rica and other countries is a model that could be emulated in Burkitt lymphoma. Based on the experience of slow HPV vaccine uptake in the adolescent population in the U.S. and the probable need to vaccinate as early as 6 months of age for Burkitt-related viruses, vaccinating for Burkitt lymphoma control could be a daunting goal.
Another potential investigational model is Interlymph, a group of international investigators who conduct research projects that pool data across studies, which now number more than 20 studies. But of the nearly 18,000 cases that comprise these studies, fewer than 300 are Burkitt, pinpointing the need for a new consortium dedicated to this type of lymphoma, or at least incorporation of more Burkitt cases into InterLymph.
Even though much work has yet to be done establishing the extent and nature of the disease in Africa, recent research efforts are helping to elucidate some important cellular and clinical aspects of the disease. Findings published in August 2012 in Nature (see press release) and Cancer Cell based on studies in mice, tumor cell lines, and humans provide a greater understanding of the genetic and molecular underpinnings of the disease. Researchers identified frequent mutations in the genes TCF3, ID3, and CCND3. TCF3 is a master regulator of gene activity in B-cells, the cells of origin of Burkitt lymphoma, and ID3 is a natural inhibitor of TCF3 function. In human studies, the TCF3 and ID3 genes were mutated in almost 70 percent of the Burkitt lymphoma cases, resulting in uninhibited TCF3 action. Consequently, researchers showed that TCF3 maintains the survival of Burkitt lymphoma cells by engaging the PI(3) kinase pathway. Indeed, when examining cell line models, drugs targeting the PI(3) kinase pathway were found to be highly toxic to Burkitt lymphoma cells, suggesting that clinical evaluation of such drugs is warranted in this cancer.
The researchers further showed that CCND3 was mutated in 38 percent of Burkitt lymphoma cases examined. CCND3 encodes a protein named cyclin D3, which in turn interacts with a kinase called CDK6 to promote cell cycle progression. Researchers found that drugs that inhibit CDK6 caused Burkitt lymphoma cells to arrest and die, indicating that CDK6 may also be an important target for the development of therapies.
One of the enduring enigmas related to the biology of Burkitt lymphoma is the role that infectious agents play, particularly in Africa, and perhaps to a lesser extent, Brazil. The disease is typically broken into three clinical subtypes with the sporadic form, which has no obvious infectious co-factors, being the most common type found in the U.S. In Africa, however, two viral subtypes are most common -- one associated with the Epstein-Barr virus (EBV) and the other associated with the human immunodeficiency virus (HIV). Furthermore, the role that malaria plays in both of these subtypes is still an open question as areas with high malaria infection rates, such as Uganda, Tanzania and Ghana, also have high Burkitt lymphoma rates.
The infectious aspects of Burkitt lymphoma probably relate to the fact that the disease is derived from the B-cell, which is the main cell type infected by EBV in most individuals. Although most adults worldwide are infected by EBV sometime during their lives, an immune response to the virus keeps it in check. All infants become susceptible to EBV as soon as maternal antibody protection disappears and in Africa, while early infection is common, most children are asymptomatic, whereas in the U.S. infection often doesn’t occur until adolescence and can lead to mononucleosis in up to half of those infected. However, because EBV can be pathogenic, it has been directly linked not just to Burkitt lymphoma but to Hodgkin and other lymphomas. EBV has been found in 98 percent of endemic Burkitt lymphoma in Africa but the extent of the role that EBV plays in promoting the disease is still unclear. While the etiological link between malaria and Burkitt lymphoma development has not been clearly elucidated, repeated malarial infection has been linked to impaired cellular immunity and also stimulates B-cells non-specifically, perhaps enabling EBV reactivation.
The fact that EBV is so closely linked to Burkitt lymphoma makes the development of vaccines targeting EBV a tempting means of lessening the burden of Burkitt lymphoma. Several researchers, including those working with pharmaceutical companies, are actively developing vaccines that elicit neutralizing antibodies and modulate T-cell response to the virus. While a vaccine might be helpful in preventing endemic Burkitt lymphoma, only 30 percent of sporadic or HIV-related Burkitt cases show evidence of EBV infection.
Many recent basic research advances in Burkitt lymphoma were made possible by tremendous strides in genotyping and other molecular technologies that were developed and refined in the past decade. Even more basic technological advances, such as the adoption of tablet computers (e.g., the iPad) and the increased use of telemedicine (whereby pathology slides or other medical images are transmitted electronically), may help facilitate the sharing of genetic and clinical data from Africa with research counterparts in the U.S. Additionally, in Africa, many physicians are generalists with few assistants who are trained in multiple disciplines; therefore feedback or assistance from experts outside of Africa could provide useful second opinions or insights.
Some of the current barriers identified by experts in Burkitt research fall into three areas: drugs, specimens and communications. In the drug arena, donation of drugs for Burkitt studies may be limited due to low potential return on investment and there have also been some shortages of common drugs used to treat the disease making them less available for clinical trials. For specimen collection, there is a distinct lack in harmonization of requirements and standards between countries, particularly when it comes to specimen verification. And finally, in the communications field, there has often been a failure to articulate needs and goals.
Ultimately, many hope that overcoming barriers in Burkitt research could lead to insights in multiple areas of cancer research, and not just in this disease and other lymphomas. It is often asked why the level of interest and funding for one cancer is higher than for other cancers that actually have greater mortality or incidence rates, and the response is that knowledge gleaned in one area can often translate to other cancers or areas of investigation. While Burkitt lymphoma is a less common disease in the U.S. and not even one of the most common cancers on the African continent, based on the differences in etiology, disease progression, infectious co-factors and many other aspects of the disease, knowledge from this somewhat uncommon disease could be applied to other areas of cancer research fairly readily. The role of infectious agents in promoting cancer is something that applies to about one-quarter of all known cancers and Burkitt lymphoma research shows the potential for leading to tremendous payoffs across all areas of cancer research in the near future.