PROJECT 1 − SUMMARY/ABSTRACT A subset of human papillomaviruses (HPVs) cause 5% of human cancers including the majority of cervical cancers. Over the current funding period, we discovered that interactions between the cervical epithelium and its stromal tumor environment are key to cervical carcinogenesis. We will test specific hypotheses for how the tumor microenvironment contributes to cervical carcinogenesis. We will also evaluate the role of mutations in cellular genes in cervical carcinogenesis based upon insights gained from The Cancer Genome Atlas initiative, and identify mutations in cancer related genes that cause cervical cancers arising in FA patients to become HPV-independent. In the second aim we will continue utilizing the recently discovered mouse papillomavirus MmuPV1 to investigate the role of high risk cutaneous HPVs in neoplastic skin disease, as seen in patients with epidermodysplasia verrucoformis, using powerful new mouse models for that disease developed in our labs. We will also study the importance of immunosuppression and epithelial progenitor cells in papillomavirus induced skin disease.