PILOT--SOMATIC ERRORS IN CARCINOGEN METABOLISM

试点——致癌物代谢中的体细胞错误

• 批准号: 6352860
• 负责人: ZOLTAN TRIZNA
• 金额: $ 2.83万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6352860
• 关键词: N acylation; cancer risk; carcinogenesis; clinical research; cytochrome P450; detoxification; environment related neoplasm /cancer; gene environment interaction; genetic polymorphism; glutathione transferase; human subject; neoplasm /cancer epidemiology; neoplasm /cancer genetics; oral pharyngeal neoplasm; squamous cell carcinoma

The genetically determined ability to metabolize carcinogens and procarcinogens is polymorphic. Because of the resulting differences in detoxification of environmental chemicals and/or in activating procarcinogens to carcinogens, these polymorphisms are associated with susceptibility to environmentally-related cancers, such as squamous cell carcinoma of the head and neck. Our hypotheses are that (i) genetic polymorphisms can be detected with regard to glutathione S-transferases mu, theta, pi, and N-acetylation, as well as to components of the cytochrome P450 system (CYP1A1, CYP2E1) in patients with squamous cell carcinoma of the oral cavity and the oropharynx compared to healthy controls, and (ii) these genetic polymorphisms are associated with risk for the development of this type of cancer. In a pilot study of 42 head and neck cancer patients and 42 matched controls we found that the absence of the GSTM1 gene conferred an odds ratio of 3.10 (95% CI=1.24-7.75), and the absence of the GSTT1 gene conferred an odds ratio of 2.18 (95% CI=0.91-5.23) for head and neck cancer. The GSTM1 genotype was absent in 74% of our patients, in contrast to the range of 31-58% published. The absence of the GSTT1 gene was shown in 55% of our patients, in contrast to the published range of 30-40%. A case-control study is proposed, involving 250 patients and 250 healthy individuals (matched by age, gender, race, and smoking status). The genetic status of the study subjects will be determined with regard to glutathione S-transferases mu, theta, and pi, N-acetylation, CYP1A1, and CYP2E1 by PCR-based methodologies, using DNA extracted from peripheral blood lymphocytes (Specific Aim #1). Two approaches will be applied for estimating cancer risk. First, the associations between risk and genetic polymorphisms will be calculated for each polymorphism assayed (Specific Aim #2). Next, this single-factor analysis will be expanded by combining the genotypes into a multifactorial risk model (Specific Aim #3). The study is expected to yield important information about host factors of environmentally-associated carcinogenesis. Testing several genetic polymorphisms simultaneously has the potential to identify individuals with extremely high cancer risk. This has profound implications for prevention: individuals at high risk for cancer can be enrolled into intensive preventive programs not suitable for the general population, including chemopreventive approaches.

基因决定的代谢致癌物质的能力， 前致癌物是多态的。 由于由此产生的差异， 环境化学品的解毒和/或活化 致癌物，这些多态性与 易患环境相关癌症，如鳞状细胞癌 头颈部癌 我们的假设是：（i）遗传多态性可以检测与 关于谷胱甘肽S-转移酶μ、θ、pi和N-乙酰化，如 以及细胞色素P450系统（CYP 1A 1，CYP 2 E1）的组分， 口腔鳞状细胞癌患者， 口咽部与健康对照相比，和（ii）这些遗传 多态性与这种类型的发展风险有关。 癌 在一项对42名头颈癌患者和42名匹配的 我们发现，GSTM 1基因的缺失赋予了 比值为3.10（95%CI =1.24-7.75），GSTT 1基因缺失 头颈部的优势比为2.18（95%CI =0.91-5.23） 癌 GSTM 1基因型在74%的患者中缺失，相反， 31-58%的范围内公布。 GSTT 1基因的缺失显示 我们的患者中有55%，而公布的范围为30- 40%。 本文拟对250例病人和250例健康人进行病例对照研究 个体（按年龄、性别、种族和吸烟状况匹配）。 的 研究受试者的遗传状态将根据以下方面确定： 谷胱甘肽S-转移酶μ、θ和pi、N-乙酰化、CYP 1A 1和 使用从外周血中提取的DNA，通过基于PCR的方法测定CYP 2 E1 血淋巴细胞（特定目标#1）。 将采用两种方法， 估计癌症风险。 首先，风险与遗传之间的联系 将计算每种测定的多态性的多态性（特异性 目标#2）。 接下来，将通过结合 将基因型转化为多因素风险模型（具体目标#3）。 的 这项研究预计将产生关于宿主因素的重要信息， 与环境有关的致癌作用。 检测几种基因 多态性同时具有识别个体的潜力 患癌症的风险极高 这对以下方面有着深远的影响： 预防：癌症高危人群可参加 不适合一般人群的强化预防方案， 包括化学预防方法。