Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Lung cancer (LC) is the most common cause of cancer death worldwide, killing over 1.2 million people yearly. Half of newly diagnosed LC patients are former smokers (FS), who remain at elevated risk of LC years after smoking cessation. In Canada, FS account for over 7.5 million people. Recent evidence suggests that LC patients harbour distinct molecular profiles based on smoking status, and that these alterations explain response to current LC therapeutics. Understanding why FS develop LC is crucial to development of early detection, prevention and treatment strategies for this fast growing population at elevated LC risk. Effects of cigarette smoke are widespread and are associated with modifications to DNA, altering control of gene expression. One of these modifications, DNA methylation, is a gene regulatory event highly altered in cells lining airways of smokers and also a frequent, early event in LC. Differences in DNA methylation between FS with and without LC may explain why some FS develop LC while others do not despite similar lifestyle changes. I hypothesize that altered DNA methylation found in airway cells of FS with LC that are absent in FS without LC, highlight early events in LC development. Also, additional genetic disruptions further deregulating these genes could be found at these genetic locations in tumors of FS. In this study, I will determine differentially methylated (DM) regions in airway cells of FS with and without LC and examine the DNA sequence of these regions in lung tumors of FS. Genes altered at these levels will be further assessed to identify pathways involved in LC development. Furthering the understanding of mechanisms of tumorigenesis in FS provides an opportunity to improve risk assessment and treatment design in a high risk population and therefore has broad clinical applications. As methylation is a reversible DNA modification, this knowledge may facilitate development of new chemopreventative agents.