The genomic landscape and molecular features of lung adenocarcinoma in patients who formerly smoked and never smoked

Lung cancer is the leading cause of cancer deaths worldwide and understanding the pathogenesis of different subpopulations of this lethal disease is critical to improve clinical outcomes. The mechanisms involved in lung cancer heterogeneity among patients who have formerly smoked (FS) and the processes through which air pollution contributes to lung cancer in patients who have never smoked (LCNS) remain incompletely understood. The objective of this thesis was to use an integrated bioinformatics approach to characterize biological impact of smoking and air pollution in FS and LCNS, respectively. To study FS, I derived a gene signature to stratify patients by their levels of smoking-related gene expression. These subgroups of FS were then assessed for associations with different molecular features and clinical outcomes. In LCNS, I established a long-term in vitro fine particulate matter (PM2.5) exposure model to evaluate the transformation potential and define mutational signatures associated with PM2.5. A whole exome sequencing cohort of LCNS was also generated to correlate PM2.5 exposure with various molecular features and clinical demographic variables. I found that FS are a diverse patient population with distinct genomic and transcriptomic differences as well as clinical outcomes based on their smoking-related gene expression profiles, which were not captured by clinical or demographic variables alone. I also demonstrated that PM2.5 possesses transformation potential in vitro, inducing changes in cell morphology, colony formation, and mutational burden compared to the negative control. LCNS with high PM2.5 exposures were correlated with unique mutational patterns including trending towards greater levels of SBS40a, a signature also detected from in vitro sequencing of PM2.5-exposed cells, suggesting a distinct mutational signature profile may be driven by PM2.5. Together, this thesis advances our understanding of how a patient’s history of exposure to cigarette smoke and air pollution shapes lung cancer tumour biology.