The core objective of this project is to answer some fundamental human health questions. What causes cancer? Can we predict cancer risk in a tissue? Can we systematically, non-invasively, and economically detect cancer at an early stage? What are the effects of aging on the cell dynamics within our tissues? Currently, and somewhat strikingly, we do not know the answer to these questions. Specifically, we do not know the causes behind a large proportion of cancer cases (~60%). There is also no model for cancer risk prediction based on integrating sequencing, clinical, and tissue-specific data. There are no well-established early detection methodologies for cancer screening based on sequencing cell-free DNA. And the temporal dynamics of the effect of aging on cell division rates in healthy tissues and cancer is not known. Yet the answers to these questions may cause a fundamental paradigm shift in cancer research, with critical consequences for: (a) the direction of future cancer research efforts, (b) public health policies on cancer prevention and screening, and (c) the way cancer is presented to and understood by the general public. This research proposal will yield new critical discoveries on all of these issues, i.e. cancer etiology, cancer risk prediction, cancer early detection, and aging. It will produce publications, presentations, integrated analyses of cancer sequencing data, mathematical modeling of cancer risk, statistical analyses of international cancer incidence data, algorithm development for two novel sequencing methodologies for ovarian/endometrial and bladder screening tests to be licensed to interested companies, and proliferation analyses in human and mice tissues. Also, it will outreach to the most important decision-makers, in both public policy and cancer research, to address the paradigm shift in cancer etiology and prevention.