Influence of germline mutations on susceptibility to environmental carcinogens

项目总结/文摘

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.