MOLECULAR BIOMARKERS OF EXPOSURE AND SUSCEPTIBILITY IN HUMAN COLON CANCER

接触环境致癌物质的一个主要途径是通过 节食。流行病学研究表明，20%到50%的 人类的癌症可以归因于饮食原因。频频的 食用动物脂肪、红肉或烤肉/烟熏肉有 与胃肠道癌症风险增加有关 肠道和胰腺。与之形成鲜明对比的是， 黄曲霉毒素和肝癌在本计划的其他项目中描述， 导致许多饮食的特定病原体- 相关的人类癌症尚未确定。两个班级 化学致癌物、多环芳烃(PAHs)和 杂环胺(HAs)，已在烧烤或油炸中识别 肉。这些化学物质会导致多种癌症，包括结肠癌， 在实验动物模型中发现了胃癌、乳腺癌和肝癌。 这个项目的总体目标是调查这些 饮食致癌物质在人类结肠癌发生中的作用 调节新陈代谢的易感因子(效应修饰物) 这些致癌物质最终会增加结肠息肉/癌症的风险。我们的工作 假说是饮食中致癌物质的摄取形成于肉类 在烹饪过程中是形成结肠息肉的一个原因， 发生在人类结肠过程早期的癌前病变 癌症的发展。本项目(目标1和目标2)将审查 儿童尿液HA和PAH代谢物的个体差异 受试者在受控喂养期间摄入油炸或烤肉 学习。相关代谢表型和潜在混杂因素将 接受评估，以调查他们在个人内部和个人之间的角色 不同之处。这些研究应该提供对生物学的洞察力 对摄入的反应的个体间差异的基础 在熟肉中发现的致癌物质。该项目(目标3和目标4)将 也要评估这些生物标志物与暴露和 新陈代谢与结肠息肉发生风险的病例对照和 案例--案例研究。关键代谢和膳食的鉴定 结肠息肉风险的决定因素应导致新的治疗方法 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.