DIETARY HETEROCYCLIC AMINES, GENETIC SUSCEPTIBILITY, AND

膳食杂环胺、遗传易感性和

• 批准号: 2896698
• 负责人: MARIA ELENA MARTINEZ
• 金额: $ 10.42万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2896698
• 关键词: acyltransferase; adenomatous polyps; clinical research; cytochrome P450; dietary constituent; enzyme activity; gene environment interaction; gene induction /repression; gene mutation; genetic susceptibility; heterocyclic compounds; human genetic material tag; human subject; neoplasm /cancer chemotherapy; neoplasm /cancer epidemiology; neoplasm /cancer genetics; neoplasm /cancer relapse /recurrence; nutrition related neoplasm /cancer; nutrition related tag; p53 gene /protein; protooncogene; sulfotransferase; tumor suppressor genes; ursodeoxycholate

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.

描述：（申请人的描述）许多有关分子的研究 结直肠癌的遗传学表明，突变和缺陷 几个与肿瘤相关的基因负责肿瘤发生。 在 受影响的基因，K-RAS癌基因和p53肿瘤基因的突变 被认为在多步过程中起着重要作用 肿瘤发生。 另外，遗传易感性的作用 最近研究的结果支持结直肠癌，以便 多种遗传多态性在结直肠癌发生上的作用是 积极调查。 杂环胺，环境产品 在高温下煮熟的肉中发现的， 已知是有效的致癌物和诱变剂。 这些新陈代谢 产品之间的产品各不相同，众所周知取决于多态性 这些底物激活或解毒的基因。 到 日期，饮食中有关杂环胺暴露的准确数据是 由于缺乏饮食仪器和分析方法，缺乏。 在这项研究中，我们建议研究暴露于饮食的作用 杂环胺和多态性基因型和表型 腺瘤遗传突变和两相分析中的腺瘤复发 方法。 这项研究将在正在进行的III期试验中进行 ursoxyoxycholic在腺瘤复发上。 在第一阶段，我们将 使用基因突变进行1,200个个体之间的病例序列分析 在K-RAS癌基因和p53肿瘤抑制基因中作为终点。 作为 这一阶段的一部分，我们将试行并发展自我管理的饮食 评估暴露于杂环胺的问卷。 在第二个 阶段，我们将在试验期间前瞻性地关注个人，并关注 在腺瘤复发中作为终点。 通过进行这项研究，我们将 有机会评估代谢激活还是 杂环胺的排毒与遗传改变有关 腺瘤或腺瘤复发。 这种两相分析提供了 解决这些研究问题并增强我们的强大方法 了解与遗传易感性有关的机制 标记。