DIETARY HETEROCYCLIC AMINES, GENETIC SUSCEPTIBILITY, AND

描述：（申请人的描述）许多关于分子生物学的研究， 结直肠癌的遗传学研究表明，结直肠癌的突变和缺陷 几种肿瘤相关基因负责肿瘤发生。 中 受影响的基因，K-ras癌基因和p53肿瘤抑制基因突变 被认为在多步骤的过程中起着重要的作用， 肿瘤发生 此外，遗传易感性的作用 最近的研究结果支持结直肠癌，例如， 各种遗传多态性在结直肠癌发生中的作用 正在积极调查中。 杂环胺，环保产品 在高温下烹饪的肉类中含量很高， 已知是强致癌物和诱变剂。 这些物质的新陈代谢 产物在个体之间是不同的，并且已知依赖于基因的多态性。 参与这些底物的活化或解毒的基因。 到 截至2009年12月31日，关于饮食中杂环胺暴露的准确数据如下： 缺乏，由于缺乏饮食工具和分析方法。 在这项研究中，我们建议调查暴露于饮食中的作用， 杂环胺和多态性基因型和表型的风险 腺瘤基因突变和腺瘤复发的两阶段分析 approach. 本研究将在正在进行的III期试验中进行， 熊去氧胆酸对腺瘤复发的影响。 在第一阶段，我们将 利用基因突变对1，200人进行病例系列分析 以K-ras癌基因和p53抑癌基因为终点。 作为 在这一阶段，我们将试验和开发一种自我管理的饮食， 问卷调查，以评估暴露于杂环胺。 在第二 阶段，我们将在试验期间前瞻性地跟踪个人， 以腺瘤复发为终点。 通过这项研究，我们将 有机会评估代谢活化或 杂环胺的解毒与遗传改变有关， 腺瘤或腺瘤复发。 这两个阶段的分析提供了 强有力的方法来解决这些研究问题，并提高我们的 了解与遗传易感性相关的机制 标记。

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.