DIETARY HETEROCYCLIC AMINES, GENETIC SUSCEPTIBILITY, AND

描述：(申请人的描述)一些关于分子的研究 结直肠癌的遗传学研究表明，基因突变和缺陷 几个与肿瘤相关的基因与肿瘤的发生有关。在这些人中 受影响的基因，K-ras癌基因和p53抑癌基因的突变 都被认为在多步骤的过程中发挥着重要作用 肿瘤发生学。此外，遗传易感性对 最近的研究结果支持结直肠癌，比如 多种基因多态在结直肠癌发生中的作用 正在积极接受调查。杂环胺，环保产品 在高温烹调的肉类中发现的高浓度物质， 都是已知的强效致癌物质和致突变物质。它们的新陈代谢 产品因个体而异，已知依赖于 参与这些底物的激活或解毒的基因。至 关于饮食中暴露于杂环胺的准确数据是 缺乏，这是由于缺乏膳食仪器和分析方法。 在这项研究中，我们建议调查饮食暴露的作用 杂环胺和多态基因和表型对高血压风险的影响 腺瘤基因突变与腺瘤复发的两阶段分析 接近。这项研究将在正在进行的第三阶段试验中进行 熊去氧胆酸对腺瘤复发的治疗作用。在第一阶段，我们将 利用基因突变对1200名个体进行病例系列分析 以K-ras癌基因和P53抑癌基因为终点。AS 作为这一阶段的一部分，我们将试点并开发一种自我管理的饮食 评估接触杂环胺的调查表。在第二个 阶段，我们将在试验和重点关注期间前瞻性地跟踪个体 以腺瘤复发为终点。通过进行这项研究，我们将 有机会评估代谢激活或 杂环胺的解毒作用与基因改变有关。 腺瘤或以至腺瘤复发。此两阶段分析提供了 解决这些研究问题的强有力的方法并加强我们的 对遗传性易感性相关机制的理解 记号笔。

DESCRIPTION: (Applicant's Description) 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.