MOLECULAR BIOMARKERS OF EXPOSURE AND SUSCEPTIBILITY IN HUMAN COLON CANCER

暴露于环境致癌物的一个主要途径是通过 饮食. 流行病学研究表明， 人类癌症可归因于饮食原因。 频繁 食用动物脂肪、红肉或烧烤/熏制肉类 与胃肠道癌症风险增加有关 胰管和胰腺。 与两者之间的强烈关联相反 黄曲霉毒素和肝癌在本项目的其他项目中描述， 导致许多饮食的特定病原体- 相关的人类癌症尚未确定。 两类 化学致癌物，多环芳烃（PAH）， 杂环胺（Has），已确定在烤或油炸 肉。 这些化学物质会导致多种癌症，包括结肠癌， 胃癌、乳腺癌和肝癌的实验动物模型。 本项目的总体目标是调查这些因素的作用， 饮食致癌物在结肠癌的人类，并确定 敏感性因子（效应调节剂），调节 这些致癌物质，最终，结肠息肉/癌症的风险。 我们的工作 一种假说是，摄入肉类中形成的膳食致癌物 在烹饪过程中是结肠息肉形成的一个致病因素， 癌前病变发生在人类结肠癌的早期过程中， 癌症发展 本项目（目标1和2）将审查国际间的 尿HA和PAH代谢产物谱的个体差异 受试者在控制喂养期间进食油炸或烧烤的肉类 问题研究 相关代谢表型和潜在混杂因素将 被评估以调查他们在个体内和个体间的作用 差异 这些研究应该提供深入了解生物学 个体间对摄入的反应差异的基础 在熟肉中发现的致癌物质。 本项目（目标3和4）将 还评估了这些暴露生物标志物的相关性， 代谢与结肠息肉发展风险的病例对照研究， 个案研究 关键代谢和饮食的识别 结肠息肉风险的决定因素应该导致新的方法， 预防结肠息肉和癌症。

A major route of exposure to environmental carcinogens is through the diet. Epidemiological studies indicate the 20 to 50 percent of all human cancers can be attributed to dietary causes. The frequent consumption of animal fat, red meats, or grilled/smoked meats has been associated with increased risk for cancers of the gastrointestinal tract and pancreas. In contrast to the strong association between aflatoxin and liver cancer described in other projects in this program, the specific etiologic agents responsible for causing many diet- associated human cancers have yet to be determined. Two classes of chemical carcinogens, polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (Has), have been indentified in grilled or fried meats. These chemicals produce a variety of cancers, including colon, stomach, breast, and liver cancers, in experimental animal models. The overall goals of this project are to investigate the role of these dietary carcinogens in colon carcinogenesis in humans, and to identify susceptibility factors (effect modifiers) that modulate the metabolism of these carcinogens and, ultimately, colon polyp/cancer risk. Our work hypothesis is that ingestion of dietary carcinogens formed in meat during cooking is a causative factor in the formation of colon polys, preneoplastic lesions that occur early in the process of human colon cancer development. This project (Aim 1 and 2) will examine inter- individual differences in urinary HA and PAH metabolite profiles in subjects ingesting fried or broiled meat during controlled feeding studies. Relevant metabolic phenotypes and potential confounders will be assessed to investigate their role in intra-and inter-individual differences. These studies should provide insight into the biological basis for inter-individual variation in response to ingestion of carcinogens found in cooked meats. This project ( Aim 3 and 4) will also evaluate the association of these biomarkers of exposure and metabolism with risk of colon polyp development in a case-control and a case-case study. The identification of critical metabolic and dietary determinants of colon polyp risk should lead to new approaches for prevention of colon polyps and cancer.