Grant: CIHR Fellowship

Lung cancer results from mutations in tumour suppressor genes and oncogenes. DNA sequencing of patient tumours indicates that cancer-causing mutations arise with defined sequential orders, where specific mutations mostly occur early during tumour development, while other mutations tend to occur later. Why mutations follow these defined orders is unknown, and their impacts on tumour behaviour have not been explored. To better understand the role of mutation order in lung tumour development, I will combine an innovative DNA barcoding approach with mouse models that closely represent human lung cancer. This approach labels each tumour and its associated genetic mutation with a unique DNA barcode, allowing the growth of thousands of tumours with different mutations to be tracked and measured simultaneously. To understand the effect of mutation timing, genes that suppress tumour growth will be inactivated at different time points after tumors start growing. This will reveal the impact each genetic mutation has on tumour growth at different time points along a tumour's developmental trajectory. Next, I will introduce cancer-causing mutations sequentially into normal lung cells. By analyzing the impact each mutation has on normal cells' growth, I will uncover mutations capable of initiating lung tumours. To gain insights into the molecular mechanism of mutation order on tumour development, I will determine the effect of mutation order on gene accessibility using single-cell sequencing. Overall, this study will provide a better understanding of how mutation order and timing drive cancer which could inform prevention, detection, and early intervention strategies.