AROMATIC AMINES AND COLON CANCER RISK--GENETICS

油炸肉类，特别是红肉的消费量一直保持在 在过去的研究中与结直肠癌有关，并经常 被夏威夷的日本人吃掉。最近有人提出，基因 对杂环芳胺的易感性(存在于这些食品中)， 由N-乙酰转移酶(NAT)和可能的N-氧化决定 (P4501A2)基因多态性，可能会增加患结直肠癌的风险。自.以来 易感NAT表型在日本是在日本的两倍 高加索人，这可以解释日本人出人意料的高风险 治疗这种疾病。还有人提出，芳香胺可能 激活ras癌基因，这是在结直肠中经常发现的突变基因 肿瘤。我们建议在大规模人口调查中检验这些假设。 年日本人和高加索人结直肠癌病例对照研究 夏威夷。 将对约967名患者(574名)进行饮食历史问卷调查 日本人和393名高加索人)患有结肠腺癌，967人 日本和高加索人口控制，性别和性别频率匹配 年龄，收集日常消费的肉类和鱼类项目准备 关于肉类的高温方法和信息，此外 估计能量、营养素和其他饮食的总摄入量 组件。这项研究设计将提供足够的功率来测试 各种杂环胺类食物的相关性，快N- 乙酰化表型/基因型和快速N-氧化表型与癌症 在大肠的不同部位和特定的体细胞K-ras 突变。还将测试与种族和年龄的互动。最后， 由于其无与伦比的设计，这项研究将能够评估 种族间风险差异可归因于这些饮食和 遗传因素。 受试者的表型鉴定将涉及消费两杯 咖啡和五小时后采集的单一尿样。这些 样品将通过高效液相色谱法进行检测，以确定N-氧化和N- 乙酰化表型。期间还将采集血样。 同样的家访进行基因分析。Nat2基因分型将是 通过聚合酶链式反应(PCR)和限制性内切酶片段 白细胞DNA长度多态分析。等位基因特异性聚合酶链式反应 扩增还将用于识别密码子12和13的突变 这些病例肿瘤组织中的K-ras基因。DNA将被储存起来用于 未来对其他种系和体细胞突变的检查。

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.