"Integration of large scale genetic and epigenetic analysis needs to be coupled with well defined biological hypotheses that can be experimentally tested. This project is aimed at developing a novel integrated approach to understand genetic and epigenetic predisposition to cancer with skin as model system.The Caucasian (West European) and Asian (East Asian) populations differ substantially in their predisposition to skin cancer, specifically Squamous Cell Carcinoma (SCC). The underlying mechanisms are poorly understood. As in other organs, skin SCC results from changes in both epithelial and mesenchymal compartments. We will be focusing on two key gene regulatory networks of cells of the two compartments (keratinocytes and dermal fibroblasts), with a key role in skin SCC. The ""keratinocyte network"" has Notch/p53/p63 as key nodes, while the ""dermal fibroblast network"" had Notch and AP1 family members. We will pursue two main goals :1) We will test the hypothesis that a linkage can be established between specific genetic and epigenetic marks in the Caucasian versus Asian populations and differences in expression and function of ""keratinocyte and/or dermal fibroblast network genes"".2) We will test the hypothesis that keratinocytes and/or dermal fibroblasts of Caucasian versus Asian individuals differ in their tumor yielding capability, and that these differences in cancer forming capability are due to differences in either ""keratinocyte or dermal fibroblast network genes"".The applicant is a world leader in epithelial signaling and cancer biology, and is heading interdisciplinary research efforts that bridge the basic and clinical sciences. Together with his bioinformatician and clinician collaborators, he is in an excellent position to attain the high goals of the proposal. The approach has not been attempted before, is only possible within the frame of an advanced ERC grant, and has substantial basic as well as translational/clinical implications."