Radon and Tobacco Smoke Exposure Biomarkers of Lung Cancer Risk

Lung cancer is the second most commonly diagnosed cancer and has the highest mortality rate of all cancers.1 Smoking is the leading cause of lung cancer, followed by radon2 and secondhand smoke (SHS) exposure.3 Kentucky has the highest rates of lung cancer incidence and mortality in the nation. While high rates of tobacco use and smoke exposure are undoubtedly primary drivers for most lung cancers, most of Kentucky is also located in high to moderate radon potential zones, suggesting that radon exposure, alone and in combination with tobacco smoke exposure, also contributes significantly to these grim statistics. Importantly, combined exposure to radon and tobacco smoke has apparent synergistic effects on lung cancer susceptibility.2,4 Early stage (stage I) non small cell lung cancer is resectable and the 5 year survival rate is >60% compared with advanced stage cancer which has a survival rate of < 10%. Unfortunately, early stage lung cancer is asymptomatic and difficult to diagnose. Large scale screening by spiral CT is expensive and difficult in rural communities. Ideally a robust, low cost technology is needed that can accurately determine susceptibility in individuals, who can then be monitored closely for development of the disease. Our application will build upon Dr. Hahn’s ongoing epidemiological and behavioral studies to recruit a cohort of Kentucky residents with (or without) exposure to tobacco smoke (mainstream or SHS) and/or radon. Participants between 50-70 years of age will be recruited from Hahn’s subject pool. Tobacco smoke exposure history will be assessed and participants will test for residential radon. Based on the current subject pool recruited as part of Dr. Hahn’s ongoing NIEHS-funded study of in-home radon and SHS exposure, we anticipate that about 46% will have at least one high exposure value, and 15% will have high radon and high tobacco smoke (TS) exposure levels. After radon testing and based on TS exposure history, participants will be enrolled into four exposure groups: (1) high radon/high TS; (2) low radon/high TS; (3) high radon/low TS; and (4) low radon/low TS, and asked to provide blood, urine and hair samples to confirm TS exposure and assess biomarkers of lung cancer risk. Specific biomarkers assessed will be: (1) chromosomal aberration frequency as a marker of ongoing genetic changes; (2) F2-isoprostane levels as markers of systemic inflammation;5,6 and (3) lipid profiles of plasma exosomes to determine markers of likelihood to progress to cancer or very early stage tumors. Biomarker measurements will be correlated with each other and with the environmental exposures to establish a set of discriminators that robustly associate environmental exposure with risk of progression to detectable lung cancer. The effects of combined tobacco smoke and radon exposure on biomarker distributions will be scrutinized to determine potential molecular and cellular causes for their apparent synergistic effects on lung cancer susceptibility. Our overarching goal is to better predict which individuals will develop lung cancer so that these high risk individuals can be monitored and the disease can be detected early, allowing for more effective medical treatment and survival. Along with exposure measurements, our biomarker data on F2-isoprostanes and chromosomal aberration frequency, alone or in combination, may reveal which individuals harbor more inflammatory processes and genetic changes, respectively, two known drivers of carcinogenesis. Furthermore, co-I Dr. Fan’s research has already noted a marked association between the presence of specific lipids in plasma exosomes and the presence of early stage lung cancer (unpublished data). Our study would reveal whether different lipid patterns might be detected in individuals not yet diagnosed with cancer, but who are at high risk due to tobacco smoke and/or radon exposure, and whether these patterns might be associated with elevation of biomarkers of genetic change or inflammation. Our findings will support future examination of these and other biomarkers in this cohort and in individuals being screened for lung cancer as well as the potential to track future development of lung and other cancers using banked blood samples from Hahn and Orren’s current CCSG-funded research.