Mapping the constraints and selection pressures of lung cancer evolution (360G-Wellcome-211179_Z_18_Z)

Lung cancer development is an evolutionary process, involving accumulation of mutations within a given environment. However, although driver alterations and mutational processes in lung cancer evolution have been elucidated, an understanding of the constraints and selection pressures that govern cancer development and their evolution and genomic regulation is unclear. Moreover, while studies have revealed that driver alterations can be present in ‘normal’ tissue, the differences between such somatic genomic evolution and cancer evolution is unclear. I hypothesise that knowledge of the genomic and transcriptomic mechanisms underpinning tumour evolution, coupled with an understanding of constraints and selection pressures that shape tumour development, can inform approaches to tackle cancer. I have previously developed bioinformatics methods to disentangle a cancer’s life history from multi-region sequencing data (e.g. de Bruin and MCGRANAHAN, 2014 SCIENCE; McGRANAHAN et al., 2016 SCIENCE), and developed tools to elucidate immune escape (MCGRANAHAN et al., 2017 CELL). I propose to extend these methods using normal tissue sequencing, public and private data from collaborators, to obtain a pan-cancer database of the evolutionary trajectories of thousands of tumours. Evolutionary maps, including immune micro-environmental and therapeutic selection pressures over space and time, will provide a systems level understanding of cancer evolution.