___^__^^_ The observation that HPV-related cancers may be linked to immunosuppression has led us to focus this competitive renewal on a population that is receiving strong immunosuppressive drugs for extended periods of time, i.e., renal and cardiac organ transplant patients (OTR). These patients experience a high incidence of what may be an HPV-associated cancer, squamous cell skin cancer (SCSC). We posit that transplant populations are the best model to study the effect of immunosuppression on HPV infection and the association between HPV and SCSC because transplant patients are now living longer with theirtransplants, the prevalence of SCSC sharply increases with time since transplant, these patients often have multiple and aggressive SCSC tumors, and SCSC will ultimately affect the majority of transplant patients. In this project we propose two complementary but separate population-based studies to investigate the role of HPV in renal and cardiac OTR. The first study we propose is a nested case-control study that will be able to assess 1) if there are high-risk genus beta HPV types that are associated with an increased risk of SCSC;2) whether pre-transplant HPV antibodies predict SCSC;and 3) if patient risk factor data (including history of sun exposure, skin type, eye color, medication use, and other exposures) gathered in an in-person interview and integrated with measures of genus beta HPV types together predict which patients are at increased risk of SCSC. The second study is a longitudinal study designed to explore the kinetics of HPV infection with repeated sample collection over a 2-year period, starting with a pre-transplant sample. All patients transplanted in 2008 and 2009 who are residents of the local area will be invited to participate. In this longitudinal study we will assess 1) whether the number of HPV DNA types, antibody response, or viral persistence increases with time since transplant and 2) the effect of changes in levels of cell-mediated immunity on HPV infection status (as measured by various markers of HPV) over time. Our HPV Program Project group has a long track record of interdisciplinary collaboration, and we plan to develop a new direction for our work that employs recently developed laboratory techniques that are specific to studying genus beta HPV types.. Our studies may contribute to a more complete understanding of the role of genus beta HPV types in SCSC and the role immunosuppression plays in HPV activation. If a strong link between specific HPV types and SCSC can be verified, there may be evidence to suggest clinical trials of HPV vaccines to modify the risk of SCSC in OTR. Lay Summary: This study will examine the risk of squamous cell skin cancer and its relationship to human papillomavirus in a high-risk group. If a clear association can be shown in this study and others like it, future work could explore prevention and treatment of this type of skin cancer in different populations.
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