GENETIC SUSCEPTIBILITY TO VINYL CHLORIDE INDUCED CANCER

描述(改编自《调查者摘要》)：长期 这项研究的目的是发展基于遗传的生物标记物分析。 用于识别因接触以下物质而增加健康风险的个人 致癌物质。具体的目标是确定遗传决定因素 氯乙烯-用作生物标志物的代谢和DNA损伤修复 评估氯乙烯诱发的肝癌的先验易感性 人类。肝血管肉瘤(ASL)将被用作工作模型。 ASL是一种致命的疾病，死亡率为100%。有一个 ASL与职业性氯乙烯接触密切相关 (VC)。ASL在广泛的氯乙烯范围内以恒定的速度发生 (VC)暴露，表明人类存在高危表型。 VC的诱变潜力受三个过程控制：1)它是 由细胞色素P4502E1(细胞色素P4502E1)介导的生物激活而增加，2) 通过谷胱甘肽S转移酶介导的结合降低 代谢产物为谷胱甘肽，以及，3)它通过甲基嘌呤-DNA还原。 糖基酶(MPG)启动的亚乙基DNA加合物的去除。该模型是 定义良好，因为它包括：接触到的对象的独特来源 Vc，ASL受试者的肝组织样本，具有良好的特征性 VC相关肿瘤细胞系，病原体(VC及其代谢物)， 以及遗传易感性的可能性。调查人员的假设是 对VC诱导的肝脏血管肉瘤的易感性与 具有异常的CYP2E1、GST和/或MPG表型的遗传决定因素。至 评估这一假设，他们将：1)筛查ASL患者 可能导致高危的CYP2E1和MPG基因的特定突变 表型；2)开发方法对人群进行筛查 在ASL患者中发现的CYP2E1和MPG突变等位基因的患病率，以及， 3)确定CYP2E1、GST基因多态与/或 个人群体中的MPG与肝癌易感性 暴露在氯乙烯中。这项研究有望提供一种机制 要快速有效地识别目前在 乙烯基单体行业可能是感染VC诱导的ASL的高危人群。 它还将提供一个工作模型，用于评估CYP2E1、GST、 和MPG在暴露相关的健康结果中。结果将提供一个 基于遗传的模型，可用于研究各种其他引起的疾病 从环境暴露到外源生物。

DESCRIPTION (Adapted from the Investigator's Abstract): The long-term objective of this research is to develop genetically-based biomarker assays for identifying individuals with increased health-risk from exposure to carcinogens. The specific objective is to identify genetic determinants of vinyl chloride-metabolism and DNA lesion repair for use as biomarkers to assess a priori susceptibility to vinyl chloride-induced liver cancer in humans. Angiosarcoma of the liver (ASL) will be used as a working model. ASL is a devastating disease with a 100% rate of mortality. There is a strong association between ASL and occupational exposure to vinyl chloride (VC). ASL occurs at a constant rate over a broad range of vinyl chloride (VC) exposure, suggesting the existence of a high risk phenotype in humans. The mutagenic potential of VC is controlled by three processes: 1) It is increased by cytochrome P4502E1 (CYP2E1)-mediated bioactivation, 2) it is decreased through glutathione S-transferase (GST)-mediated conjugation of metabolites to glutathione, and, 3) it is decreased through methylpurine-DNA glycosylase (MPG)-initiated removal of etheno-DNA adducts. The model is well defined because it includes: a unique source of subjects exposed to VC, liver tissue samples from subjects with ASL, a well characterized VC-associated tumor cell line, the causative agent (VC and its metabolite), and the likelihood of genetic susceptibility. The investigators hypothesize that susceptibility to VC-induced angiosarcoma of the liver is associated with genetic determinants of aberrant CYP2E1, GST and/or MPG phenotypes. To evaluate this hypothesis, they will: 1) screen individuals with ASL for specific mutations of the CYP2E1 and MPG genes which may lead to a high risk phenotype; 2) develop methods to screen a human population for the prevalence of CYP2E1 and MPG mutant alleles identified in ASL subjects, and, 3) determine the relationship between polymorphism in CYP2E1, GST, and/or MPG and susceptibility to liver cancer in a population of individuals exposed to vinyl chloride. This research is expected to provide a mechanism to rapidly and effectively identify individuals currently working in the vinyl monomer industry who may be at high risk for acquiring VC-induced ASL. It will also provide a working model for assessing the role of CYP2E1, GST, and MPG in exposure-linked health outcome. The results will provide a genetic-based model useful in approaching a variety of other diseases caused from environmental exposure to xenobiotics.