Research Focus

Professor Wogan's research concerns two major areas: DNA damage and genetic alterations in carcinogenesis; and molecular markers of exposure to environmental carcinogens. The objective of the first area is to elucidate relationships between DNA damage induced by chemical carcinogens and genetic alterations associated with tumor initiation and development. Particular emphasis is placed on studies of carcinogens thought to be of importance as risk factors for human cancers, and the program is structured to include methodologies that can be applied in concurrent parallel studies in appropriate experimental models and in humans known to be exposed to the carcinogens.

Current evidence indicates that DNA damage caused by carcinogens is a critical initiating event in cancer, and investigation of damage induced by environmental carcinogens that are risk factors for human cancers remains a continuing interest. Current projects involve characterization of mutations induced in various experimental systems by nitric oxide and oxygen radicals. These reactive species are of interest because they are produced by cells involved in tissue inflammation, which is in turn an important risk factor for some major forms of cancer, including the stomach and liver. Nitric oxide and reactive oxygen species can induce a wide spectrum of DNA damaging lesions, but which these contribute to cancer initiation is currently unknown. Part of our program concerns characterization of mutations induced by these agents under controlled conditions in well-characterized experimental systems. Mutational spectra induced by reactive derivatives of nitric oxide are being characterized in shuttle vectors after repair and replication in bacterial and human cells. Mutagenesis is also being studied in target cells co-cultured with macrophages induced to produce nitric oxide over prolonged periods of time, as experimental surrogates for cells exposed in vivo to prolonged inflammation. These processes are also being investigated in SJL mice, which spontaneously develop pathologic states involving endogenous production of high levels of nitric oxide.

The second area of research emphasis concerns molecular markers of exposure to environmental carcinogens. Accurate assessment of cancer risks represented by environmental carcinogens and formulation of effective intervention strategies require quantitative data on levels of human exposure to specific carcinogens. Historically, data of this kind have been calculated from measurements of concentrations of the chemicals in food, water or air, coupled with estimates of intake, a procedure of very limited accuracy for quantifying exposures of individuals within populations. Our research program seeks to address this objective through development of molecular markers of exposure that can be applied in determining the significance of carcinogens as risk factors for human cancers. We have characterized the DNA reaction products of aflatoxin B1 and developed analytical procedures of adequate sensitivity to measure DNA adduct levels in tissues and body fluids of humans exposed through dietary contamination. Analogous methods have also been developed for quantification of adducts of the carcinogen with serum albumin. Using these analytical methods, studies of populations known to be exposed to aflatoxin and at high risk of liver cancer in Guangxi Province, PRC and in The Gambia have been conducted in collaboration with cancer epidemiology groups of the University of Southern California, Johns Hopkins University, and the Shanghai Cancer Institute. We have demonstrated that exposure of individuals to the carcinogen can be accurately quantified by this approach, and that such persons are at high risk for development for the cancer, in particular those who are simultaneously infected by the hepatitis B virus. We have recently developed a novel analytical method for detection of DNA adducts of all classes of carcinogens. This methodology is being applied in evaluating the significance of oxidative DNA damage products associated with chronic inflammation as well as specific chemical carcinogens (heterocyclic aromatic amines) in the etiology of other major forms of cancer, including stomach, colon and bladder. Data produced from these studies will be important in the development of preventive and intervention studies to minimize the impacts of these carcinogens as cancer risk factors.

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