Our vision is to determine the earliest events in the evolution of malignancy and use this knowledge to design efficacious precision strategies for cancer early detection, intervention and prevention. We will build on our pioneering work delineating the initial events driving the development of common cancers focussing on lung, colon, prostate, breast, oesophagus and the hematopoietic system. Charting the molecular changes in the first evolutionary steps towards cancer are likely to both provide realistic biomarker candidates for cancer detection, and potential targets for cancer chemoprevention and treatment of pre-cancer. We will combine our extensive research in basic biology (exemplified by Themes 1-3) to determine the cellular dynamics and molecular drivers of the evolutionary process underlying progression from healthy tissue to invasive cancer with our unique experience in population approaches leveraging the diverse and large population serviced by our affiliated NHS Trusts, and our track record in running large-scale prevention and early detection clinical trials. We will focus initially on our unique cohorts of patients with early disease and banked tissue samples of early lesions and then explore the feasibility of using novel signatures and molecules to serve as early detection markers in non-invasive samples such as blood, urine and saliva.