Nucleotide excision repair and lung cancer in Appalachian Kentucky

Persistent DNA damage can result in mutations or chromosomal aberrations that drive carcinogenesis. Cellular repair pathways act to remove DNA damage, thereby minimizing genetic changes and suppressing cancer development. Exposure to tobacco smoke generates DNA damage thought to be causative for development of lung and other cancers; many DNA lesions produced by smoke exposure are targeted specifically by the nucleotide excision repair (NER) pathway. Thus, the efficiency of an individual’s NER system is likely to impact cancer susceptibility, particularly for the relationship of tobacco smoke exposure to lung cancer development, in which lung cells are repeatedly subject to a barrage of DNA damage. Although an overwhelming percentage of lung cancers are related to tobacco smoke exposure, many smokers never develop lung cancer, suggesting the contribution of additional (unknown) factors to smoking-induced lung cancer. Appalachian Kentucky consistently has an extremely high incidence of lung cancer, a statistic that cannot be explained by smoking rates alone. A collaborative group at the University of Kentucky has found that a substantially higher percentage of individuals residing in Appalachian Kentucky have elevated levels of exposure to specific carcinogenic or co-carcinogenic trace metals (arsenic, chromium, and nickel) compared to individuals from metropolitan Louisville. This suggests that exposure to one or more of these metals may contribute to elevated lung cancer susceptibility in Appalachian Kentucky. With this in mind, an epidemiological lung cancer case control study was recently initiated to collect biological and environmental samples and personal data through a detailed questionnaire. As part of this epidemiological study, each subject will be analyzed for exposure to environmental trace metals (measured in toenails) and tobacco smoke (measured in hair nicotine). Separately, our lab has discovered that independent exposures to arsenic and cigarette smoke condensate (a surrogate for whole tobacco smoke) inhibit the efficiency of NER, possibly through a common mechanism. Therefore, we hypothesize that NER is suppressed in individuals (putatively those in Appalachian Kentucky) exposed to tobacco smoke and/or to elevated levels of arsenic and perhaps other trace metals, causing persistence of DNA damage in the lung and resulting in increased mutations and enhancing lung carcinogenesis. To test this hypothesis, here we propose to measure inter-individual differences in NER efficiency in peripheral blood mononuclear cells isolated from subjects of the aforementioned epidemiological lung cancer case-control study of Appalachian Kentucky. For each subject, our NER efficiency measurements will also be directly compared to 1) lung cancer status, 2) levels of exposure to trace metals, and 3) exposure to tobacco smoke and smoking history, to explore potential relationships between NER efficiency and these parameters. Importantly, these studies will determine whether NER efficiency measurements can potentially help identify individuals at risk of developing cancer, particularly in populations in which exposure to environmental agents is likely.