Influence of germline mutations on susceptibility to environmental carcinogens

项目概要/摘要 我们假设，具有肿瘤抑制基因生殖系突变的个体， 基因x环境（GxE）相互作用暴露于矿物纤维和可能的其他有毒物质。这 一项提案旨在解决我们在北方内华达州（NV）人口中的假设，那里的环境是 富含矿物质，包括石棉，砷和其他有毒物质。吸入长、细且持久 矿物纤维引起恶性间皮瘤（MM）和其它呼吸道疾病。摄入As 受污染的地下水也与皮肤病、肺病和心血管疾病有关 如皮肤癌和其他类型的癌症。按年龄调整的心脏病、癌症和慢性 下呼吸道疾病在瓦肖县（北方NV）为501.5，在全州NV为416.5，在 每100，000名居民的美国人口。NV中央癌症登记处的数据显示， MM和肺癌的年轻人，可能是由于暴露于自然发生的致癌矿物纤维。 通过包括内华达州和夏威夷高等教育系统科学家在内的多学科努力，我们将 在三个目标中表征GxE相互作用。在目标1中，我们将量化人口对矿物质的暴露 空气中的纤维和水中的砷，通过确定主要和次要来源和测量量的 空气和水中的致癌物质。在目标2中，我们将研究环境致癌物对 炎症反应和与MM发展相关的代谢变化， 与代谢和炎症改变相关的遗传性种系突变的特征性BAP 1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 假设环境致癌物在细胞中诱导转化表型， BAP 1的表达，细胞凋亡受损，主要是因为随之而来的炎症反应和细胞凋亡的改变。 新陈代谢.这些结果将告诉我们，在暴露于遗传性神经纤维后， 与BAP 1调节的DNA修复和凋亡相似的基因突变。在Aim 3中， 利用健康内华达州项目（HNP），这是一项在北方内华达州进行的大型人群健康研究， 基因型与一个全面的电子病历数据库，我们将评估患病率 通过炎症反应的病例/对照，观察北方NV人群的基因组改变， 癌将评估新的全基因组关联，并靶向致病突变中的基因型 与癌症风险增加和炎症反应的已知关联将被分析。

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.