While cigarette smoke exposure is the leading cause of lung cancer and chronic obstructive pulmonary disease (COPD) in both men and women, gender disparities in disease risk and phenotype independent of exposure level have been observed. Moreover, lung cancer incidence, survival, cell-type, and molecular defects differ in a sex-specific manner. Similarly, the degree of lung function impairment, extent of emphysema, and expression of proteins in bronchoalveolar lavage fluid differ in women with COPD compared to men with this disease. These observations suggest that sex-related molecular processes influence the development of lung cancer and COPD. This administrative supplement aims to describe sex-specific alterations of gene expression in lung tissue and the bronchial airway epithelium that influence lung carcinogenesis in a COPD-related or COPD-independent manner. The proposed studies leverage transcriptomic data generated as part of parent grant NCI 1R01CA16483-02, and transcriptomic profiling of additional samples from the same cohorts in order to achieve adequate power to detect sex-specific differences in gene expression that contribute to lung carcinogenesis. Building upon our prior work demonstrating smoking-associated, lung cancer-associated, and COPD-associated gene expression changes in the airway epithelial "field of injury", this proposal further aims to describe sex-specific influences on lung carcinogenesis that extend to the more proximal and easily-obtainable bronchial airway. These studies will further our understanding of the influence of sex-related processes on the development of lung cancer and COPD, and will ultimately allow the development of improved diagnostic biomarkers, targeted therapy, and chemoprevention strategies that may be especially beneficial for managing these diseases in women.
Both lung cancer and chronic obstructive pulmonary disease (COPD) are caused by cigarette smoking, and represent significant causes of morbidity and mortality worldwide. The incidence of lung cancer and COPD differ between men and women, suggesting that gender influences the disease processes underlying lung cancer development. The proposed studies will identify how gender influences the development of lung cancer and COPD. This will ultimately lead the way for less-invasive early diagnostic strategies and personalized therapy and chemoprevention for lung cancer that may be especially beneficial for detecting and treating this disease in women.
|Vucic, Emily A; Chari, Raj; Thu, Kelsie L et al. (2014) DNA methylation is globally disrupted and associated with expression changes in chronic obstructive pulmonary disease small airways. Am J Respir Cell Mol Biol 50:912-22|
|Hubaux, Roland; Becker-Santos, Daiana D; Enfield, Katey Ss et al. (2013) Molecular features in arsenic-induced lung tumors. Mol Cancer 12:20|
|Martinez, Victor D; Thu, Kelsie L; Vucic, Emily A et al. (2013) Whole-genome sequencing analysis identifies a distinctive mutational spectrum in an arsenic-related lung tumor. J Thorac Oncol 8:1451-5|
|Hubaux, Roland; Thu, Kelsie L; Coe, Bradley P et al. (2013) EZH2 promotes E2F-driven SCLC tumorigenesis through modulation of apoptosis and cell-cycle regulation. J Thorac Oncol 8:1102-6|