GENETIC SUSCEPTIBILITY TO VINYL CHLORIDE INDUCED CANCER

对氯乙烯诱发癌症的遗传易感性

• 批准号: 6043507
• 负责人: Roland Valdes
• 金额: $ 21.84万
• 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 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6043507
• 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（改编自研究者摘要）：长期 本研究的目的是开发基于遗传学的生物标志物检测方法 用于识别暴露于以下物质的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损伤修复作为生物标志物， 评估氯乙烯诱发肝癌的先验易感性， 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与氯乙烯职业暴露之间的强相关性 （VC）。 ASL在很宽的氯乙烯范围内以恒定的速率发生 (VC)暴露，表明人类存在高风险表型。 VC的致突变潜力受三个过程控制：1） 细胞色素P4502 E1（CYP 2 E1）介导的生物活化增加，2）它是 通过谷胱甘肽S-转移酶（GST）介导的 代谢产物谷胱甘肽，和，3）它是减少通过甲基嘌呤-DNA 糖基化酶（MPG）引发的乙烯基-DNA加合物的去除。 该模型 定义明确，因为它包括：一个独特的受试者来源， VC，来自ASL受试者的肝组织样本， VC相关肿瘤细胞系，致病因子（VC及其代谢产物）， 和遗传易感性的可能性。 调查人员假设 对VC诱导的肝脏血管肉瘤的易感性与 具有异常CYP 2 E1、GST和/或MPG表型的遗传决定因素。 到 为了评估这一假设，他们将：1）筛选ASL患者， CYP 2 E1和MPG基因的特定突变可能导致高风险 表型; 2）开发筛选人类群体的方法， ASL受试者中确定的CYP 2 E1和MPG突变等位基因的患病率，以及， 3)确定CYP 2 E1、GST和/或 MPG与个体人群肝癌易感性 暴露在氯乙烯中 这项研究有望提供一种机制， 迅速有效地查明目前在 乙烯基单体行业，他们可能处于获得VC诱导ASL的高风险中。 它还将为评估CYP 2 E1，GST， 和MPG在与糖尿病相关的健康结果中的作用。 结果将提供一个 基于遗传学的模型，可用于处理各种其他疾病引起的 从环境暴露到异生物质。