AROMATIC AMINES AND COLON CANCER RISK--GENETICS

芳香胺与结肠癌风险——遗传学

• 批准号: 2101742
• 负责人: LOIC LE MARCHAND
• 金额: $ 43.06万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-06-15 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2101742
• 关键词: Japanese; age difference; cancer risk; caucasian American; colon neoplasms; cyclic amine; cytochrome P450; enzyme activity; food processing /preparation; gene expression; gene mutation; high performance liquid chromatography; human subject; interview; neoplasm /cancer genetics; nutrition related neoplasm /cancer; nutrition related tag; polymerase chain reaction; questionnaires; racial /ethnic difference; radionuclides; restriction fragment length polymorphism; transferase; urinalysis

Consumption of fried meat, particularly red meat, has consistently been associated with colorectal cancer in past studies and are frequently consumed by Hawaii Japanese. It has recently been proposed that genetic susceptibilities to heterocyclic aromatic amines (present in these foods), determined by the N-acetyltransferase (NAT) and, possibly, N-oxidation (P4501A2) polymorphisms, may increase the risk of colorectal cancer. Since the susceptible NAT phenotype is twice as common in Japanese as in Caucasians, this could explain the unexpectedly high risk of the Japanese for this disease. It has also been suggested that aromatic amines may activate ras oncogenes, genes that are often found mutated in colorectal tumors. We propose to test these hypotheses in a large population-based case-control study of colorectal cancer among Japanese and Caucasians in Hawaii. A diet history questionnaire will be administered to about 967 cases (574 Japanese and 393 Caucasians) with adenocarcinoma of the large bowel and 967 Japanese and Caucasian population controls, frequency-matched on sex and age, to collect the usual consumption of meat and fish items prepared by high-temperature methods and information on doneness of meats, in addition to estimating the total intake of energy, nutrients, and other dietary components. This study design will provide adequate power to test the associations of various heterocyclic amine-containing foods, fast N- acetylation phenotype/genotype and fast N-oxidation phenotype with cancer at various sites in the large bowel and with specific somatic K-ras mutations. Interactions with race and age will also be tested. Finally, because of its unmatched design, this study will be able to assess the fraction of interethnic risk difference attributable to these dietary and genetic factors. Phenotyping of the subjects will involve the consumption of two cups of coffee and collection of a single urine sample five hours later. These samples will be assayed by HPLC to determine the N-oxidation and N- acetylation phenotypes. A blood sample will also be collected during the same home visit for genetic analyses. The NAT2 genotyping will be performed by polymerase chain reaction (PCR) and restriction fragment length polymorphism analyses of leucocyte DNA. Allele-specific PCR amplification will also be used to identify mutations at codons 12 and 13 of the K-ras gene in tumor tissue from the cases. DNA will be stored for future examination of other germline and somatic mutations.

油炸肉类的消费，特别是红肉，一直是 在过去的研究中与结直肠癌相关， 被夏威夷日本人消费 最近有人提出， 对杂环芳香胺（存在于这些食物中）的敏感性， 通过N-乙酰转移酶（NAT）和可能的N-氧化测定 （P4501 A2）多态性可能增加结直肠癌的风险。 以来 敏感NAT表型在日本人中是在 白种人，这可以解释日本人意外的高风险 治疗这种疾病 也有人提出，芳族胺可 激活ras癌基因，这些基因经常在结直肠癌中发现突变， 肿瘤的 我们建议在一个大规模的基于人口的实验中检验这些假设。 年日本人和高加索人结直肠癌的病例对照研究 夏威夷。 对967例（574 日本人和393名白人）大肠腺癌和967名 日本和高加索人群对照，频率匹配的性别和 年龄，以收集通常食用的肉类和鱼类的项目， 高温的方法和信息熟的肉类，此外， 估计总摄入量的能量，营养素，和其他饮食 件. 本研究设计将提供足够的把握度来检验 各种含杂环胺食物的协会，快速N- 乙酰化表型/基因型和快速N-氧化表型与癌症 在大肠的不同部位， 突变。 还将测试与种族和年龄的相互作用。 最后， 由于其无与伦比的设计，这项研究将能够评估 种族间风险差异的百分比归因于这些饮食和 遗传因素 受试者的表型分析将涉及消耗两杯 咖啡和五小时后收集一份尿样。 这些 将通过HPLC分析样品，以测定N-氧化和N- 乙酰化表型 在此期间还将采集血液样本。 同样的家访做基因分析 NAT 2基因分型将 通过聚合酶链反应（PCR）和限制性片段 白细胞DNA长度多态性分析。 等位基因特异性PCR 扩增也将用于鉴定密码子12和13处的突变 K-ras基因在肿瘤组织中的表达。 DNA将被储存， 其他生殖系和体细胞突变的未来检查。