by Victoria A. McCallum, M.P.H., and Wendy Schneider-Levinson
The investigation of global cancer incidence and mortality patterns can provide clues to cancer etiology and inform the development of cancer control strategies. Among DCEG's many international research activities are its studies in Africa, which stand to contribute significantly to our understanding of cancer and its risk factors.
According to the World Health Organization, Africa's already huge cancer burden will increase in future years—the 681,000 new cases of cancer and 512,000 deaths reported in 2008 are estimated to grow to 1.6 million new cases and 1.2 million deaths annually by 2030.
Contributing to the situation are the large number of infection-related cancers among HIV/AIDS patients and the high costs of cancer treatment, which most African patients cannot afford.
HIV/AIDS has been linked to increased risks of Kaposi sarcoma (KS), non-Hodgkin lymphoma, Hodgkin lymphoma, and cancers of the cervix, anus, liver, and lung. Effects of HIV on cancer incidence, however, appear to vary in magnitude by geographic region. Less is known about the risk of HIV/AIDS-associated cancers in Africa than in the United States, even though Africa is home to more than two-thirds of the nearly 34 million people infected with HIV worldwide. Approximately 30 percent of cancers in Africa are thought to be attributable to infections, including HIV. The incidence of KS has been steadily climbing in parallel with the HIV epidemic in sub-Saharan Africa, and the incidence of lymphomas has increased in several countries, including Nigeria and Uganda.
Scientists in DCEG's Infections and Immunoepidemiology Branch (IIB) have contributed important insights into the origins and mechanisms of HIV/AIDS-related cancers and the role of immunity and inflammation in cancer. One approach has been to link HIV/AIDS registries to cancer registries in both the United States and Africa.
IIB researchers Sam M. Mbulaiteye, M.D., and Eric A. Engels, M.D., M.P.H., implemented the first record-linkage study of AIDS and cancer registries in Africa in Kampala, Uganda. The study provided the first well-characterized data on cancer risk in a defined African HIV-infected population and confirmed the increased risks of AIDS-defining cancers, while also revealing greater risks of some non–AIDS-defining cancers, including Hodgkin lymphoma and conjunctival cancer. The risk of these latter tumors, although they are rare, was subsequently found to be elevated among persons with HIV/AIDs in the United States. "In a few years, we would like to go back to do another record-linkage study in Uganda," Dr. Mbulaiteye said, "to assess the effect of antiretroviral drugs, which have become more available in the region. It is important to see if the impact of treatment is similar in Africa as in other populations."
Another IIB investigator, Charles S. Rabkin, M.D., has studied AIDS-related KS to address unresolved questions on the genomic integrity of KS, specifically whether multiple tumors in individuals arise as clones from a single cell of origin. In Zambia, Dr. Rabkin and colleagues found that all KS tumors in a given patient shared the same inactivated X chromosome, suggesting that KS is a monoclonal cancer that tends to disperse across the body. This work paved the way for additional studies involving KS pathogenesis, including a study in Uganda conducted by Dr. Mbulaiteye that is continuing to examine the clonal properties of KS.
Building upon their research program on HIV/AIDS-related cancer in Africa, DCEG researchers have branched out to study a variety of tumors that are reported to occur more frequently or, in the case of prostate cancer, less frequently in Africa than in western populations.
Burkitt lymphoma (BL) is the most common childhood tumor in Africa, and infections with malaria and Epstein-Barr virus at an early age are widely accepted risk factors for this disease.
Dr. Mbulaiteye, study manager Benjamin Emmanuel, M.P.H. (IIB), and colleagues are conducting a case-control study of BL in Uganda, Tanzania, and Kenya—known as the Epidemiology of Burkitt's Lymphoma in East-African Children and Minors (EMBLEM) study—to explore whether genetic resistance to malaria lowers risk of BL. Some individuals appear to be genetically protected against malaria and have only mild infections, whereas other individuals must receive treatment to survive the disease. "The EMBLEM study is using modern technologies to address questions about malaria and genetics," Dr. Mbulaiteye said. Blood and tissue samples gathered as part of the EMBLEM study will provide a resource for future molecular studies that incorporate technologies such as tumor microarrays.
Less than one year into the study, the investigators are enrolling participants and have introduced activities and protocols in the field. Staff training is an important aspect of a successful epidemiological study, according to Dr. Mbulaiteye. "We have trained local technicians in one country, and they are training local staff from other sites; they really do a wonderful job," he said.
KS is a major public health problem in Africa and was endemic in many sub-Saharan African countries before the AIDS epidemic. Infection with human herpesvirus-8 (HHV8) is necessary for KS to occur, but other factors, such as HIV infection, greatly increase the risk of the disease. HHV8 prevalence varies dramatically across Africa, suggesting that cofactors correlated with geographic or environmental characteristics may influence risk of infection with the virus.
Dr. Mbulaiteye and colleagues are conducting a study in a sickle cell disease clinic in Kampala, Uganda, to explore transmission routes for HHV8. So far, investigators have found that HHV8 transmission in blood is inefficient, but it does occur. They have documented that levels of HHV8 are considerably higher in saliva than in blood, a finding that adds support to a mechanism of salivary transmission from mother to child or from child to child. Further studies are being conducted across Uganda to assess small-area variation of HHV8 and to identify socio-demographic and environmental risk factors for HHV8 and KS.
Esophageal cancer is the sixth leading cause of cancer deaths worldwide, with esophageal squamous cell carcinoma (ESCC) accounting for more than 80 percent of all deaths from this disease.
In Africa, ESCC has a strikingly uneven geographical distribution with higher concentrations in several areas, including western Kenya, a region in which the disease often strikes young people. Christian C. Abnet, Ph.D., M.P.H., Nutritional Epidemiology Branch (NEB), and colleagues have established a pilot study at Tenwek Hospital in Bomet, Kenya, to assess the feasibility of conducting a case-control study with biosamples to explore a wide range of etiologic factors for ESCC in Africa.
Also at Tenwek Hospital, Sanford M. Dawsey, M.D. (NEB), and colleagues are conducting a study to understand the risk factors for (and prevalence of) esophageal squamous dysplasia (ESD), the precursor lesion of ESCC. The study will enroll and endoscope asymptomatic adults in the area to determine the prevalence of ESD. Dr. Dawsey will use the results to guide the design of programs to screen and treat ESD as well as studies that will compare risk factors for ESD and invasive ESCC among Kenyans.
Prostate cancer incidence and mortality have long been thought to be lower among African men than among African American men, despite their similar genetic makeup. However, it was not known if this apparent discrepancy was due to differences in environmental factors or differences in the availability of screening, treatment, or reporting systems.
In 2001, Ann W. Hsing, Ph.D. (IIB), began a study to characterize the burden of prostate cancer in Ghana, a country in West Africa whose men are genetically closely related to African Americans, by using state-of-the-art screening protocols.
The team screened 1,038 randomly selected men for prostate cancer using both a digital rectal exam and the prostate-specific antigen test and then sent for biopsy those who screened positive. The biopsies revealed that 76 of the men had cancer, and those men were provided with treatment. The high prevalence rate suggested that Africans do not have a significantly lower occurrence of prostate cancer than African Americans. Dr. Hsing is continuing her research with a population-based, case-control study conducted in collaboration with the Korle-Bu Teaching Hospital, which is affiliated with the University of Ghana Medical School. Serum, plasma, and tissue samples from cases are being used in genome-wide association and other studies to better understand the genetic and other determinants of prostate cancer.
In Africa, breast cancer rates are rising, with a high frequency of cancers diagnosed at late stage and cancers that are either estrogen receptor negative (ER–) or triple negative (ER–, progesterone negative, and human epidermal growth factor receptor-2 negative). These tumors tend to be aggressive and occur at younger ages. In addition, evidence indicates that inflammatory breast cancer (IBC), a rare, poorly understood, and particularly aggressive form of breast cancer, makes up a larger proportion of breast cancer cases in North Africa than in the United States. In North Africa, Catherine Schairer, Ph.D., Biostatistics Branch, is conducting a case-control study in collaboration with the University of Michigan to investigate the causes of IBC. Study centers in Egypt, Tunisia, and Morocco are currently enrolling participants.
Louise A. Brinton, Ph.D., Chief of the Hormonal and Reproductive Epidemiology Branch (HREB), and Jonine D. Figueroa, Ph.D., M.P.H. (HREB), are conducting a feasibility assessment for a multidisciplinary, case-control study of breast cancer in Ghana to determine why incidence rates of this malignancy are rising in western Africa. Dr. Brinton hopes to coordinate her initiative with ongoing efforts against breast cancer in Ghana and to use various partnerships to build the infrastructure for this study as well as future research activities in this country.
DCEG scientists are helping to build the capacity for cancer research in Africa. Toward this end, it is essential to train African scientists to participate in collaborative research as well as to foster independent research efforts in Africa. DCEG's Africa Working Group was recently established by Drs. Abnet, Dawsey, Hsing, and Mbulaiteye to enhance communication across the Division and Institute and to suggest priorities for future collaborative research that will provide new etiologic insights into cancer in Africa while reducing its burden.