Lung cancer and Chronic Obstructive Pulmonary Disease (COPD) are leading causes of morbidity and mortality both in the United States and worldwide. Inhalation of cigarette smoke is the primary known and preventable cause but only 10-15% of heavy smokers develop these diseases. This suggests that cigarette smoke exposure interacts with inherited susceptibility factors to determine risk. While some susceptibility genes are known, they account for less than 5% of risk for either disease. There is urgent need to identify additional heritable susceptibility factors for these diseases that explain the majority of COPD and lung cancer risk. For example, the National Lung Screening Trial (NLST) recently reported a 20% reduction in mortality from lung cancer. Because there are over 50 million individuals in the US who meet the criteria for the NLST, at a cost of $400/CT scan, the yearly cost of screening could be $20 billion. The objective in this study is to determine the role of inter-individual variation in antioxidant and DNA repair gene transcript regulation in conferring risk for both COPD and lung cancer. The central hypothesis is that inherited DNA variants are associated with increased risk for both COPD and lung cancer and that many of these manifest as increased transcript abundance dispersion in key antioxidant, DNA repair, and transcription factor genes. In support of our hypothesis, we recently identified a lung cancer risk test (LCRT) that comprises transcript abundance values of 14 genes, including nine anti-oxidant, three DNA repair, and two transcription factor genes. For each of these genes, transcript abundance values were dispersed over a greater range in lung cancer compared to matched controls (Blomquist et al, 2009). In addition, inherited DNA variation causes variation in transcript regulation of genes comprised by the LCRT (Crawford et al, 2007;Blomquist et al, 2010). Here we report that in a small number of non-lung cancer cases studied thus far N=13), a subject with positive LCRT value has a 6.7-fold increased likelihood of having COPD (defined by FEV1/FVC<0.7). Development of biomarkers for lung cancer and/or COPD risk will enable prioritization for screening and/or chemoprevention trials and provide drug targets for development of chemo-preventative and therapeutic pharmaceuticals. These developments are expected to reduce mortality and health care costs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3168. doi:10.1158/1538-7445.AM2011-3168