) A number of studies on the molecular genetics of colorectal cancer have revealed that mutations and defects of several tumor-related genes are responsible for tumorigenesis. Among the genes affected, mutations in K-ras oncogene and p53 tumor suppressor gene are thought to play an important role in the multistep process of tumorigenesis. In addition, the role of genetic susceptibility to colorectal cancer is supported by results of recent studies, such that the role of a variety of genetic polymorphisms on colorectal carcinogenesis are actively being investigated. Heterocyclic amines, environmental products that are found in high concentrations in meats cooked at high temperatures, are known to be potent carcinogens and mutagens. The metabolism of these products varies among individuals and is known to depend on polymorphisms in genes involved in activation or detoxification of these substrates. To date, accurate data on exposure to heterocyclic amines in the diet are lacking, due to the lack of dietary instruments and analytic methodology. In this study, we propose to investigate the role of exposure to dietary heterocyclic amines and polymorphic genotypes and phenotypes on risk of adenoma genetic mutations and adenoma recurrence in a two-phase analytic approach. This study will be conducted in the on-going phase III trial of ursodeoxycholic acid on adenoma recurrence. In the first phase, we will conduct case-series analyses among 1,200 individuals using genetic mutations in the K-ras oncogene and p53 tumor suppressor gene as the endpoints. As part of this phase, we will pilot and develop a self-administered dietary questionnaire to assess exposure to heterocyclic amines. In the second phase, we will follow individuals prospectively during the trial and focus on adenoma recurrence as the end-point. By conducting this study, we will have the opportunity to assess whether the metabolic activation or detoxification of heterocyclic amines is related to genetic alterations in adenomas or to adenoma recurrence. This two-phase analysis provides a strong approach to address these study questions and enhance our understanding of the mechanisms related to the inherited susceptibility markers.
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