MOLECULAR BIOMARKERS FOR HUMAN LIVER CANCER

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Molecular Biomarkers for Human Liver Cancer Hepatocellular carcinoma is one of the most common cancers in parts of China and sub-Saharan Africa and the poor prognosis of this tumor results in it being one of the three leading causes of cancer deaths world-wide with at least 250,000 deaths per year. Human epidemiology and experimental data have provided the statistical association and biological information necessary to implicate aflatoxins and chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) as major risk factors for this cancer in these high-risk areas. The degree that aflatoxins and HBV/HCV contribute to the causation of this disease may be affected by a number of factors including; the level of carcinogen exposure, intrinsic cytochrome P-450 and glutathione-S-transferase activation/detoxification pathways for aflatoxins, and the nutritional status of the person. Primary prevention measures by vaccination against HBV and food safety techniques to lower aflatoxin exposure could significantly lower liver cancer rates. HBV vacccination should be an effective contributor to prevention if people can be inoculated prior to infection, which generaly occurs before age two in Asia and Africa. Unfortunately, a vaccine has yet to be developed for HCV. For aflatoxins a similar targeted intervention could be envisaged, but for this to be effective requires determination of the relative roles and mechanisms of action of aflatoxin and HBV/HCV in the etiopathogenesis of liver cancer. Our hypothesis is that levels of formation and persistence of aflatoxin biomarkers reflect intrinsic risk of disease development from aflatoxin exposures. Briefly, the aims of this project are: a) To define the precise temporal relationships between dietary exposure to afltoxins and the formation and persistence of its serum albumin adducts and the kinetics of formation and removal of urinary metabolites of aflatoxin exposures including the DNA adducts and oxidative metabolites such as aflatoxin M1, Q1, P1 and the mercapturic acids as modulated by HBV and/or HCV infection, nutriture and metabolic polymorphism status. The relation between exposure and marker levels will be examined in two populations at high risk for liver cancer in West Africa and Qidong County, P.R.C. b) To determine the impact of primary prevention strategies in Guinea (West Africa) using a targeted contamination reduction strategy in community settings towards the reduction of aflatoxin biomarkers levels, and c) To continue to follow- up a prospective cohort in rural China to examine the relation and interaction between aflatoxin biomarker levels, intrinsic risk factors and disease outcome.