The goals of this Project are to develop and validate biomarkers of biologically effective dose and risk induced by environmental carcinogens. It is now axiomatic in human cancer that ambient exposures to multiple environmental carcinogens are significant factors in the development and progression of many cancer types. Thus, an understanding of the dose-response relationships between exposure and outcomes in critical targets such as DNA may characterize disease potential. While Dr. Tannenbaum's Project has a major focus on the development of novel, sensitive methods for the detection of DNA and protein adducts, this Project extends these strategies into risk-biomarker analysis. Since there are critical genetic targets in cells, such as tumor suppressor genes, for environmental carcinogens, then it is possible that these targets might prove to be useful biomarkers for risk analysis. Co-occurring environmental exposures and genetic susceptibility may modify the above dose-response effects and consequently these parameters will also be considered. The linkage between carcinogen-induced DNA damage and heritable change in genetic targets is a cornerstone of this Program Project's paradigm. Recently, the discovery that DNA from cells undergoing apoptosis and other turnover processes is found in the blood has resulted in the ability to noninvasively measure mutations in targets such as p53 offering the potential to quantify early biological effects in risk individuals. Therefore, a combined use of biologically effective dose biomarkers, susceptibility biomarkers and genetic biomarkers might reveal the subset of high risk people within a population who will benefit from targeted interventions, which is the outcome of studies proposed in Project 3. It is the hypothesis that levels of biomarkers of biologically effective dose in combination with gene mutations are predictive of disease outcome characterizing risk in individuals. Thus, specific aim 1 is to determine the power of p53 mutations and other genetic alterations in sera using the Short Oligonucleotide Mass Analysis (SOMA) methodology combined with aflatoxin-DNA adducts in urine to predict cancer outcome and disease risk in cohorts in rural China and West Africa.
Specific aim 2 is designed to extend the investigators' observations on the high level of aflatoxin biomarkers in West African children in order to assess the impact on growth and immune status, including susceptibility to hepatitis B virus (HBV) infection. West African children, unlike adults, have elevated aflatoxin biomarker levels when infected with HBV.
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