A population-based case-control study of lung cancer in Appalachian Kentucky: The role of environmental carcinogens

A. Background Appalachian Kentucky has one of the highest incidence rates of lung cancer in the United States (115.2 per 100,000 compared to 61.6 per 100,000 nationally). The disproportionately high incidence is not explained by tobacco alone; environmental carcinogens in the form of trace elements are known to promote carcinogenesis by several mechanisms, including increased oxidative stress, inflammation, DNA damage, and reduced DNA repair efficiency. Studies of environmental exposure in this Appalachian region are incomplete; however, preliminary analysis of trace element content in toenail samples reveals higher levels of arsenic, chromium and nickel in Appalachian Kentucky residents compared with other Kentuckians. These findings justify further investigation of the role that trace elements play in the development of lung cancer in this region. Appalachian Kentucky is the ideal setting for this study because of its high lung cancer burden, low population migration rate and disproportionately high level of environmental toxins. B. Objective/Hypothesis We hypothesize that the unexpectedly high rate of lung cancer in Appalachian Kentucky is associated with exposure to environmental carcinogens that increase oxidative stress and DNA damage. C. Specific Aims 1. Specific Aim 1: Conduct a case-control study of lung cancer and matched controls in the 5th Congressional District of Kentucky to compare rates of moderate to high arsenic in lung cancer cases and controls (primary endpoint). This will be accomplished by the following: a. Implementation of a rapid case ascertainment system in Appalachian Kentucky to identify all incidence lung cancer cases and matched controls (1:2 ratio). b. Collection of epidemiologic data, biospecimens and geocoding of residences by lay health workers. c. Analysis of toenail samples for trace element content as a marker of long-term environmental exposure in all subjects. 2. Specific Aim 2: Create a biospecimen repository by collecting, annotating and archiving biologic and environmental samples from these subjects or their residences for analysis of DNA repair markers and, in the future, markers of oxidative stress and inflammation. 3. Specific Aim 3: Fund four pilot projects which will utilize collected data from Aim 1 to develop a cadre of investigators focused on lung cancer research in this study population and to ensure the generation of preliminary data that will lead to independent funding. D. Study Design This is a population-based, case-control study encompassing the 5th Congressional District of Kentucky. Persons with an incident diagnosis of lung cancer and matched controls will be identified; lay health workers will visit their homes and collect epidemiologic information, in addition to biologic and environmental samples and global positioning system (GPS) coordinates to allow for spatial analysis. E. Relevance This proposal is the first of its kind to be performed in Appalachian Kentucky, an area known to have high levels of environmental carcinogens. The shared database and repository generated by this study will provide resources needed to identify additional risk factors in this region and allow for study of mechanisms that contribute to cancer development. This translational research will fundamentally improve our understanding of the causes of the disproportionately high incidence of lung cancer in Appalachian Kentucky, foster collaboration among scientists dedicated to the study of lung cancer and provide a permanent resource to be used for future research.