Chronic Obstructive Pulmonary Disease (COPD) and lung cancer 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. This proposed project will use normal bronchial epithelial cell (NBEC) and blood samples collected through funding from CA148572 from a cohort of 600 non-lung cancer subjects over age 50, with more than 20 pack-years smoking history, and a separate cohort of 150 lung cancer subjects. The objective here 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 subjects compared to matched controls. In addition, inherited DNA variation causes variation in transcript regulation of genes comprised by the LCRT. We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following two specific aims:
Aim 1. Determine whether key antioxidant and DNA repair genes have increased dispersion of transcript abundance in Normal Bronchial Epithelial Cells of COPD cases and whether a multi-gene test comprising a subset of these genes is an accurate test for COPD prevalence.
Aim 2. Identify DNA variants that contribute to increased transcript abundance dispersion of genes associated with COPD and/or Lung Cancer Prevalence. We expect that Aim 1 will produce evidence that higher transcript abundance dispersion of key antioxidant, DNA repair, and transcription factor genes is associated with risk for COPD, as it is for lung cancer and will produce a candidate biomarker for increased COPD risk.
Aim 2 will provide identification of DNA variants associated with increased transcript abundance dispersion in key genes with high prior likelihood of involvement in the pathogenesis of COPD and lung cancer. This research is relevant to public health because it will lead to development of biomarkers for selection into 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.
This proposed project is relevant to the mission of NCI and NHLBI because the results are expected to 1) lead to development of biomarkers for closer surveillance and selection for screening and/or chemoprevention trials for individuals at risk for COPD and lung cancer,2) provide evidence for an inherited genetic basis for COPD and lung cancer risk, and 3) provide drug targets for development of chemo-preventative and therapeutic pharmaceuticals for COPD and lung cancer. In addition, the proposed studies will provide further characterization of normal bronchial epithelial cells from a cohort of 600 non-lung cancer subjects at risk for COPD and lung cancer and this will support studies by other COPD and lung cancer investigators, including those participating in this HL-11-002 mechanism. The approach that is proposed is innovative and it is likely that the proposed methods will enable more rapid progress in discovery of hereditary genetic risk factors for COPD and lung cancer.
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