PILOT: Center for Appalcahian Research in Envrionmental Sciences: Interactions Between Epigenetics and Exposure to Environmental Particulates in Lung Cancer in Appalachian KY Residents

Data from the Kentucky Cancer Registry (KCR) reveal the age-adjusted incidence rate for lung cancer in Appalachian Kentucky (App KY) was 109.1 per 100,000 residents from 2010-2014, compared to 53.1 per 100,000 nationally. Other areas of the Commonwealth have similar smoking rates, but significantly lower lung cancer incidence thus supporting the finding that smoking alone cannot explain the higher incidences of the lung cancer in App KY. Several hypotheses have emerged to explain the extremely high occurrence of lung cancer in App KY, including exposure to environmental contaminants, genetic/epigenetic susceptibility of the population, and exposure to indoor air pollutants. The hypothesis that exposure to contaminants in airborne particulates helps to explain excess rates of lung cancer in App KY has yet to be tested. Several studies have shown that lung tumor tissue has higher trace-element concentrations relative to surrounding normal tissue, and this has been related to inhalation exposure to particulates. It has also been hypothesized that there are population-specific genetic and epigenetic factors involved in this increased lung cancer-incidence in App KY. However, epigenetic changes have not been examined in the residents from this region. Epigenetic changes, such as in histone modifications at specific histone methylation marks play a critical role in gene expression and have been shown to be associated with different cancers including lung cancer. Depending on the sites of the histone modifications, the regulation of the gene expression can be affected by the exposure to various environmental stressors, including trace-elements. The association between histone methylation and exposure to trace-elements has been previously shown, thus justifying the study of epigenetic changes and trace-element exposure in App KY. Our specific aimfor this pilot proposal is to determine if changes in histone methylation and in expression of the genes responsible for these epigenetic modifications are greater in the App KY than in general KY population and if there is a correlation between these epigenetic changes and concentrations of trace-elements in the lung tumor tissues. The objectives for this specific aim are: 1) determine if non-small cell lung cancer (NSCLC) tumor tissue from App KY residents has a greater degree of epigenetic modifications in histone methylation at H3K4me3 and H3K9me2 marks relative to surrounding non-tumor tissue when compared to the general KY population 2) determine if NSCLC tumor tissue from App KY has higher concentrations of certain trace-elements (an indicator of inhalation exposure to particulates) relative to the general population and 3) determine if there is difference between epigenetic modifications and elemental composition of NSCLC tumor tissue from App KY and the general KY population. This project will be among the first to examine interaction between epigenetic changes and inhalation exposure to environmental particulates in App KY. Samples from already collected and available frozen tissues from Biospecimen Procurement and Translational Pathology Shared Resource Facility at the Markey Cancer will be used for this pilot project.