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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZHL1 (F1))
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Szabo, Eva
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Boston University
Internal Medicine/Medicine
Schools of Medicine
United States
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Martinez, Victor D; Enfield, Katey S S; Rowbotham, David A et al. (2016) An atlas of gastric PIWI-interacting RNA transcriptomes and their utility for identifying signatures of gastric cancer recurrence. Gastric Cancer 19:660-665
Firmino, Natalie; Martinez, Victor D; Rowbotham, David A et al. (2016) HPV status is associated with altered PIWI-interacting RNA expression pattern in head and neck cancer. Oral Oncol 55:43-48
Martinez, Victor D; Vucic, Emily A; Thu, Kelsie L et al. (2015) Disruption of KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex components by multiple genetic mechanisms: Association with poor prognosis in head and neck cancer. Head Neck 37:727-34
Hubaux, Roland; Thu, Kelsie L; Vucic, Emily A et al. (2015) Microtubule affinity-regulating kinase 2 is associated with DNA damage response and cisplatin resistance in non-small cell lung cancer. Int J Cancer 137:2072-82
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
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
Martinez, Victor D; Vucic, Emily A; Pikor, Larissa A et al. (2013) Frequent concerted genetic mechanisms disrupt multiple components of the NRF2 inhibitor KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex in thyroid cancer. Mol Cancer 12:124
Hubaux, Roland; Becker-Santos, Daiana D; Enfield, Katey Ss et al. (2013) Molecular features in arsenic-induced lung tumors. Mol Cancer 12:20
Hubaux, Roland; Thu, Kelsie L; Lam, Wan L et al. (2013) In response. J Thorac Oncol 8:e103-4
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

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