Influence of germline mutations on susceptibility to environmental carcinogens

项目概要/摘要 我们假设具有抑癌基因种系突变的个体过于易感 暴露于矿物纤维和可能的其他有毒物质与基因 x 环境 (GxE) 的相互作用。这个 该提案旨在解决我们在内华达州北部 (NV) 人口中的假设，那里的环境 富含矿物质，包括石棉，以及砷 (As) 和其他有毒物质。吸入细长且持久 矿物纤维会导致恶性间皮瘤（MM）和其他呼吸道疾病。摄入 As 受污染的地下水还与皮肤病、肺部疾病和心血管疾病有关 如皮肤癌和其他类型的癌症。心脏病、癌症和慢性病的年龄调整累积死亡率 瓦肖县（内华达州北部）的下呼吸道疾病患病率为 501.5，而内华达州全州为 416.5，而内华达州全州为 385。 美国每 10 万居民。内华达州中央癌症登记处的数据显示异常高的发病率 MM 和肺癌在年轻人中的发病率可能是由于接触天然致癌矿物纤维所致。 通过包括来自内华达州和夏威夷高等教育系统的科学家在内的多学科努力，我们将 描述 GxE 互动的三个目标。在目标 1 中，我们将量化人口接触矿物质的情况 通过识别主要和次要来源并测量空气中的纤维和水中的砷 空气和水中存在致癌物质。在目标2中，我们将研究环境致癌物对人类健康的影响。 使用我们的井研究与 MM 发展相关的炎症反应和代谢变化 表征了与代谢和炎症改变相关的遗传种系突变的 BAP1 模型 对致癌矿物纤维的反应和增强的细胞转化。因此，我们将测试我们的 假设环境致癌物会导致细胞中水平降低的表型转化 BAP1 的缺失导致细胞凋亡受损，这主要是因为随后的炎症反应和细胞发生改变 新陈代谢。结果将告诉我们在接触遗传性纤维时预期的类似影响 与 BAP1 调节的 DNA 修复和细胞凋亡相似的基因突变。最后，在《目标 3》中，作者： 利用健康内华达项目 (HNP)，这是一项在内华达州北部开展的大型人口健康研究，其中整合了 通过综合电子病历数据库的基因型，我们将评估患病率 通过炎症反应的病例/对照观察内华达州北部人群的基因组变化 癌症。将评估新的全基因组关联并针对致病突变中的基因型 将分析与癌症风险增加和炎症反应已知的关联。

Project summary/abstract We hypothesize that individuals with germline mutations of tumor suppressor genes, are overly susceptible to gene x environment (GxE) interactions from exposure to mineral fibers and possibly other toxics. This proposal aims at addressing our hypothesis in a population of northern Nevada (NV), where the environment is rich in minerals, including asbestos, and in Arsenic (As) and other toxics. Inhalation of long, thin and persistent mineral fibers causes malignant mesothelioma (MM) and other respiratory diseases. Ingestion of As from contaminated groundwater is associated with skin diseases, pulmonary, and cardiovascular diseases, as well as skin and other types of cancers. Cumulative age-adjusted death rates for heart disease, cancer and chronic lower respiratory disease are 501.5 in Washoe County (northern NV), vs. 416.5 in statewide NV, vs. 385 in the United States per 100,000 inhabitants. Data from the NV Central Cancer Registry reveal abnormally high rates of MM and lung cancer in the young, likely due to exposure to naturally-occurring carcinogenic mineral fibers. By a multidisciplinary effort including scientists from higher education systems in NV and Hawaii, we will characterize GxE interactions in three aims. In Aim 1 we will quantify the population’s exposure to mineral fibers in air and to As in water, by identifying the primary and secondary sources and measuring amounts of carcinogens present in air and water. In Aim 2, we will study the impact of environmental carcinogens on the inflammatory response and the metabolic changes associated with MM development using our well characterized BAP1 model of inherited germline mutations linked to altered metabolic and inflammatory response to carcinogenic mineral fibers and enhanced cellular transformation. Therefore, we will test our hypothesis that the environmental carcinogens induce the transformed phenotype in cells with reduced levels of BAP1, with impaired apoptosis, largely because of the ensuing altered inflammatory response and cell metabolism. The results will inform us on anticipated similar effects upon exposure to fibers of inherited mutations in genes with similarities to BAP1-regulated DNA repair and apoptosis. Finally, In Aim 3, by leveraging the Healthy Nevada Project (HNP), a large population health study in northern NV that integrates genotypes with a comprehensive electronic medical record database, we will evaluate the prevalence of genomic alterations in the population of northern NV via case/controls of the inflammatory response and cancer. Novel genome wide associations will be assessed and targeted genotypes in pathogenic mutations with known associations to increased cancer risk and inflammatory response will be analyzed.