Negative_mutational_selection_reveals_tumor_vulnerabilities_in_murine_skin_photocarcinogenesis

Selection of somatic genome alterations in carcinogenesis may be shaped by multiple factors including by environmental exposures, cell lineage and the host germline. To limit such variation, we examined Skh-1 mice, in which multiple synchronous squamous skin tumors develop in each animal after exposure to UV light. There was strong positive selection of mutant Trp53, Notch1, Notch2 and Fat1 in both tumors and epidermis. Trp53 mutations were predominant in the epidermis and 90% of tumors, the remaining tumors carrying drivers including mutant Kras and Tgfb1. Multiregional sequencing revealed both monoclonal and multiclonal lesions. Mutations of growth factor receptors, including Egfr and epigenetic regulators were negatively selected in the epidermis, but only inactivating Egfr and Rb1 mutants were depleted in tumors. UV driven skin carcinogenesis is convergent in Skh-1 mice and humans. Analysis of negative selection in tumors and paired normal tissue may identify candidate targets for therapy and their potential toxicity.