GENETIC SUSCEPTIBILITY TO VINYL CHLORIDE INDUCED CANCER

对氯乙烯诱发癌症的遗传易感性

• 批准号: 2378004
• 负责人: Roland Valdes
• 金额: $ 22.67万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2378004
• 关键词: N glycosidase; angiosarcoma; biomarker; chemical carcinogen; chemical related neoplasm /cancer; clinical research; cytochrome P450; disease /disorder proneness /risk; gene environment interaction; genetic polymorphism; genetic promoter element; glutathione transferase; human genetic material tag; human subject; liver neoplasms; methylpurine; neoplasm /cancer genetics; nucleic acid sequence; phenotype; polymerase chain reaction; polyvinyls; single strand conformation polymorphism

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.

描述（改编自研究者的摘要）：长期 这项研究的目的是开发基于基因的生物标志物检测 用于识别因接触而导致健康风险增加的个人 致癌物质。 具体目标是确定遗传决定因素 氯乙烯代谢和 DNA 损伤修复用作生物标志物 评估对氯乙烯诱发的肝癌的先验易感性 人类。 肝脏血管肉瘤（ASL）将用作工作模型。 ASL 是一种毁灭性的疾病，死亡率为 100%。 有一个 ASL 与职业接触氯乙烯之间存在密切关联 （VC）。 ASL 在各种氯乙烯中以恒定速率发生 （VC）暴露，表明人类存在高风险表型。 VC 的致突变潜力由三个过程控制： 1) 细胞色素 P4502E1 (CYP2E1) 介导的生物活化增加，2) 通过谷胱甘肽 S-转移酶 (GST) 介导的缀合而减少 代谢为谷胱甘肽，并且，3) 通过甲基嘌呤-DNA 减少 糖基化酶 (MPG) 引发乙烯-DNA 加合物的去除。 模型是 定义明确，因为它包括： 暴露于的主题的独特来源 VC，来自 ASL 受试者的肝组织样本，是一种经过充分表征的 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。 研究人员假设 VC 诱发的肝脏血管肉瘤的易感性与 具有异常 CYP2E1、GST 和/或 MPG 表型的遗传决定因素。 到 评估这个假设，他们将：1）筛查患有 ASL 的个体 CYP2E1 和 MPG 基因的特定突变可能导致高风险 表型； 2）开发方法来筛查人群 ASL 受试者中发现的 CYP2E1 和 MPG 突变等位基因的流行率，以及 3)确定CYP2E1、GST和/或中多态性之间的关系 MPG 与人群中肝癌的易感性 接触氯乙烯。 这项研究有望提供一种机制 快速有效地识别当前在该公司工作的个人 乙烯基单体行业可能面临获得 VC 引起的 ASL 的高风险。 它还将提供一个工作模型来评估 CYP2E1、GST、 和 MPG 与暴露相关的健康结果。 结果将提供一个 基于遗传的模型可用于处理引起的各种其他疾病 来自环境暴露于异生物质。