MOLECULAR BIOMARKERS

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The overall objectives of this program are to refine and validate molecular biomarkers of human exposures to aromatic and heterocyclic amines, and to utilize the markers to determine the roles of heterocyclic amines on the risk of colon cancer and aromatic amines on the risk of bladder cancer in smokers and nonsmokers in different racial and ethnic groups. In Los Angeles, these will include Latinos, African Americans, Japanese and Whites; defined cohorts will also be studied in Singapore, China and Japan. In Project I, hemoglobin adducts will be used to determine the extent of human exposure to N.hydroxyalkylanilines, as well as the key enzymes regulating their activation. Urinary metabolite excretion will be used to determine metabolic polymorphisms and exposure of different racial and ethnic groups to specific heterocyclic amines, and also determine the relationship between exposure and colon cancer in case- control studies. In project 2, methods for measuring heterocyclic amine- DNA adducts in urine and cellular DNA will be developed and validated as markers of biologically effective exposures. The markers will be used to determine relationships between DNA adduct formation and risk of colon cancer in case control studies and to assess exposure in different racial and ethnic groups. Methodology for measuring the major DNA adduct of 4- aminobiphenyl in urine and cellular DNA will be developed and used to determine relationships between DNA adduct formation and risk of bladder cancer in a case-control study. In addition, methodology will be developed for measurement of total DNA adduct levels in cellular DNA in order to assess possible interactions among diverse carcinogen exposures. Project 3 will determine prevalence of exposure to heterocyclic amines and alkylanilines among different racial and ethnic groups, and also determine dietary and other possible environmental correlates of exposure to these compounds within and between racial-ethnic groups. Additionally, preliminary studies will be conducted to investigate relationships between exposure to heterocyclic amines and colorectal cancer, and between arylamine and alkylaniline exposure and bladder cancer. Interrelationships between different biomarkers and each other and to target tissue levels, as well as relationships to enzymatic genotypes/phenotypes within and between racial/ethnic groups will also be investigated. Together, the individual projects will provide complementary data for assessing the validity of molecular biomarkers in measuring biologically effective exposures, and testing the hypothesis that exposure to aromatic and heterocyclic amines increases risk for bladder and colon and pancreatic cancers.