Influence of germline mutations on susceptibility to environmental carcinogens

项目摘要/摘要 我们假设具有肿瘤抑制基因胚系突变的个体是过度易感的。 与基因x环境(GxE)的相互作用，因为暴露在矿物纤维和可能的其他有毒物质中。这 该提案旨在解决我们在内华达州北部人口中的假设，那里的环境是 富含矿物质，包括石棉、砷(As)和其他有毒物质。长而细而持久的吸入 矿物纤维导致恶性间皮瘤(MM)和其他呼吸道疾病。从…摄取砷 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。心脏病、癌症和慢性疾病的累积年龄调整死亡率 下呼吸道疾病在瓦肖县(内华达州北部)的发病率为501.5，全州为416.5，全州为385%。 美国每10万居民。来自内华达州中央癌症登记处的数据显示异常高的发病率 多发性骨髓瘤和肺癌在年轻人中的发病率，可能是由于暴露于自然发生的致癌矿物质纤维。 通过包括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 从三个方面描述GxE的相互作用。在目标1中，我们将量化人群接触矿物的情况 空气中的纤维和水中的纤维，通过识别主要和次要来源并测量 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质对环境的影响 炎症反应和代谢变化与多发性骨髓瘤的发展使用我们的井 与代谢和炎症改变相关的遗传性胚系突变的特征性BAP1模型 对致癌矿物质纤维的反应和增强的细胞转化。因此，我们将测试我们的 环境致癌物诱导细胞转化表型水平降低的假说 BAP1，细胞凋亡受损，主要是由于随后的炎症反应和细胞变化 新陈代谢。这些结果将告诉我们，在接触遗传性纤维时，预期的类似影响。 与BAP1调控的DNA修复和凋亡相似的基因突变。最后，在目标3中，通过 利用健康内华达项目(HNP)，这是一项在内华达州北部进行的大规模人口健康研究，该研究整合了 通过一个全面的电子病历数据库，我们将评估 通过炎性反应和对照的病例/对照研究NV北部人群的基因组变化 癌症。将评估新的全基因组关联，并针对致病突变的基因类型 与癌症风险增加和炎症反应有关的已知相关性将被分析。

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.