Biography

Dr. Rabkin earned an Sc.B. and M.D. from Brown University and an M.Sc. in epidemiology from the London School of Hygiene and Tropical Medicine. He received postgraduate training at the University of Colorado and the Centers for Disease Control and Prevention (CDC), and is board certified in internal medicine and preventive medicine. Before coming to the NCI, Dr. Rabkin was an Epidemic Intelligence Service Officer and a medical epidemiologist at the CDC. He joined the NCI as a medical epidemiologist in 1989, and has been the Branch's HIV-Cancer Coordinator since 1992. Dr. Rabkin received PHS Commendation and Unit Commendation Medals for studies of non-Hodgkin's lymphoma and Kaposi's sarcoma and the Outstanding Service Medal for the molecular epidemiology of Helicobacter pylori and HIV-related malignancies.

Research Interests

With improvement in the treatment and prevention of opportunistic infections, malignancy is emerging as an important cause of HIV-related morbidity and mortality. Our studies focus on the molecular mechanisms of HIV-related KaposiÆs sarcoma and non-HodgkinÆs lymphoma, and cancers associated with other chronic infections.

HIV-associated malignancies

The neoplastic or hyperplastic nature of Kaposi's sarcoma has long been debated on clinical, pathologic, and experimental grounds. Using the HUMARA polymerase chain reaction assay of X-inactivation, we have shown that individual Kaposi's sarcoma lesions are clonal proliferations. To improve the specificity of the HUMARA assay, we combined it with microdissection to analyze spindle cells from multiple lesions in the same individual. With this refinement, most Kaposi's sarcoma tumors demonstrate skewed HUMARA inactivation, indicative of clonality, and all skewed tumors shared the same inactivated allele. These data are inconsistent with independent clonal transformations and indicate that Kaposi's sarcoma arises at multiple sites as a disseminated monoclonal malignancy. We are following up these observations with examinations of other markers of clonality, including virus and host cell characteristics.

HHV-8 is an important factor in the pathogenesis of Kaposi's sarcoma. However, the prevalence of this herpesvirus in non-diseased populations is controversial because of great variation in reported seropositivity rates. We conducted a blinded comparison of assay results from leading U.S. and European laboratories to examine the correspondence of the various serotests for HHV-8. While many of the tests distinguished high- risk (e.g., Kaposi's sarcoma patients) and low-risk (e.g., blood donors) sera on a group level, the individual concordance between tests was low. Thus, current HHV-8 antibody tests are of uncertain accuracy in diagnosing asymptomatic HHV-8 infection.

AIDS-associated non-Hodgkin's lymphomas frequently have the t(8;14) translocation of c-myc characteristic of Burkitt's lymphomas. We have detected this same translocation in circulating lymphocytes from individuals without lymphoma in our prospective cohort study of HIV-infected homosexual men. In some instances, translocated clones have been persistently detectable for many years without development of frank lymphoma. The prevalence of recombined clones increased with duration of HIV infection, in parallel with the increase in lymphoma risk. Interestingly, no increase in the frequency of circulating cells with the t(14;18) translocation of bcl-2 characteristic of follicular lymphoma was found, which is consistent with the lack of an HIV association with this histologic subtype.

The Epstein-Barr virus (EBV) is an important co-factor in a fraction of AIDS-associated lymphomas. We are currently assessing EBV viral loads in two cohort studies of HIV infected adults and children, to determine relationships with risk of lymphoma and other complicating conditions. In preliminary analyses, subjects with lymphoma had higher median and mean EBV levels than controls. Notably, the highest levels were seen in HodgkinÆs rather than non-HodgkinÆs lymphoma. Humoral and cell-mediated immunity to EBV also being assessed, to determine whether host response to EBV is also an intermediate marker of these malignancies.

Gastrointestinal malignancies

Helicobacter pylori is a common gastric infection that causes variable inflammation of the stomach mucosa. Gastritis confined to the antrum is associated with excessive acid secretion and high risk of duodenal ulcer disease, whereas widespread gastritis leads to gastric atrophy and hypochlorhydria, precursor conditions for gastric cancer. We are examining host genetic factors that control the immune and inflammatory response to H. pylori as potential determinants of these dichotomous outcomes. We recently showed that genetic polymorphisms in interleukin-1 beta, an important mediator of inflammation and potent inhibitor of gastric acid secretion, are strongly associated with increased risk of both hypochlorhydria and gastric cancer. We are currently examining variations in other pro- and anti-inflammatory cytokines for their associations with these diseases.

Hepatitis C virus (HCV) infection is associated with some cases of liver cancer, but the absolute risk is unknown. We obtained follow-up information on the 17 (0.2%) HCV seropositive individuals among 8568 Korean War era military recruits with banked sera originally collected between 1948 and 1954. During the 45-year follow-up, 2 (12%) of the 17 were diagnosed with liver disease but none had liver cancer, which suggests that healthy HCV-positive persons may be at less risk for progressive liver disease than is currently thought. These studies are being extended with a cohort study of injection drug users recruited in the 1970s.

Selected Publications

• El-Omar EM, et al. "OMIM Interleukin-1 polymorphisms associated with increased risk of gastric cancer." Nature 2000, 404:398-402.
• Rabkin CS, et al. "Chemokine and chemokine receptor gene variants and risk of non-Hodgkin's lymphoma in human immunodeficiency virus-1-infected individuals." Blood 1999;93:1838-42.
• Rabkin CS, et al. "Kaposi's sarcoma and non-Hodgkin's lymphoma incidence trends in AIDS Clinical Trial Group study participants." J Acquir Immune Defic Syndr 1999;21:S31-3.
• Seeff LB, et al. "45-year follow-up of hepatitis C virus infection in healthy young adults." Ann Intern Med 2000;132:105-11.