Identifying clinical and genetic factors for risk of multiple skin cancers in organ transplant recipients

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PROJECT SUMMARY Since 1999, 9% of all Veterans nationwide have been diagnosed with skin cancer. Skin cancer is the most common malignancy in the United States with more than 5 million individual cancers costing an estimated $8.1 billion to treat annually. Veterans have skin cancer rates as much as four times higher than the civilian population and report greater sun exposures, more frequent sunburns, and lower use of sun protection. Skin cancer incidence is therefore anticipated to continue increasing among Veterans. Unlike other cancer types, patients will often develop multiple skin cancers, and half of skin cancer-related deaths occur among those with 10 or more skin cancers. Skin cancer risk is heterogeneous, but little progress has been made in determining which patient will develop numerous skin cancers. Patients with 10 or more skin cancers have a 25% risk of metastasis. Studying populations with a high prevalence of multiple skin cancers can provide clues to mechanisms of multiple skin cancer development. Organ transplant recipients (OTR) have up to 100-fold greater rates of skin cancer than non-OTR. This increase is believed to be due to both immunosuppression and decreased DNA repair caused by immunosuppressants. Exposure to specific immunosuppressants is associated with varying risks of skin cancer, although how their metabolism affects the number of skin cancers is unknown. Further, it is unclear if other factors present at the time of transplant can identify individuals at high risk for multiple skin cancers who would benefit from aggressive primary prevention. This study will use VINCI and MVP data to address the critical knowledge gap of how to identify Veterans at risk of developing 10 or more skin cancers a priori to reduce their skin cancer morbidity and mortality. The overall goal of this CDA-2 is to advance the personalized management of skin cancer in organ transplant recipients and provide clues to mechanisms of disease in the broader Veteran population. Our long-term goal is to deploy precision medicine management strategies to reduce skin cancer incidence, morbidity, and mortality among both Veterans with organ transplants and Veterans overall. In Aim 1, we will identify patterns of clinical factors present at the time of transplant that are associated with skin cancer development. In Aim 2, we will investigate how variation in metabolism of immunosuppressant medications impacts the number of skin cancers a patient will develop. In Aim 3, we will examine the role of rare genetic variants in developing 10 or more skin cancers. The Tennessee Valley Healthcare System Nashville VA and Vanderbilt are an ideal environment to support Dr. Wheless for this proposal and his transition to an independent physician scientist. Both hospitals are high-volume transplant centers and house strong bioinformatics infrastructure and expertise. The Department of Dermatology strongly supports Dr. Wheless’s career development. His mentors, Drs. Hung, Chren, and Matheny, are internationally recognized in dermatology, genetic epidemiology, and bioinformatics with successful mentoring track records. These mentors, along with the mentoring committee, have developed a rigorous training plan in genetic epidemiology and pharmacogenomics with didactic and hands-on learning activities. With strong institutional support, Dr. Wheless will successfully leverage his proposal to obtain Merit funding.