# Influence of germline mutations on susceptibility to environmental carcinogens

> **NIH NIH R01** · UNIVERSITY OF HAWAII AT MANOA · 2020 · $629,518

## Abstract

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.

## Key facts

- **NIH application ID:** 9993527
- **Project number:** 5R01ES030948-02
- **Recipient organization:** UNIVERSITY OF HAWAII AT MANOA
- **Principal Investigator:** MICHELE CARBONE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $629,518
- **Award type:** 5
- **Project period:** 2019-08-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993527

## Citation

> US National Institutes of Health, RePORTER application 9993527, Influence of germline mutations on susceptibility to environmental carcinogens (5R01ES030948-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9993527. Licensed CC0.

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