Investigating the dynamics of proliferation rate and replication timing changes in cancer evolution (360G-Wellcome-225491_Z_22_Z)

Each tumour consists of multiple distinct subpopulations of cancer cells which evolve over time. In addition to DNA changes, distinct cancer cells are also characterised by other differences, including alterations in the timing of DNA replication during cell duplication. In fact, normal cells duplicate their DNA in a highly preserved order, but this is thought to be altered in cancer cells. Recent studies suggest that these alterations may allow cancer cells to improve proliferation and evade treatments, leading to poor outcomes for patients. In this project, I aim to characterise alterations in DNA replication timing and effects on proliferation using large cohorts of multi- region and longitudinal DNA sequencing data from lung and breast cancer patients. To achieve this goal, I propose to develop novel computational methods to identify alterations of DNA replication timing from cancer DNA sequencing data and to measure their fitness advantage in cancer evolution. We hope this will allow us to discover the role of DNA replication timing alterations in cancer evolution, helping us to better understand cancer progression and hopefully leading us towards better outcomes for cancer patients.