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

项目摘要 自1999年以来，全国9%的退伍军人被诊断出患有皮肤癌。皮肤 癌症是美国最常见的恶性肿瘤， 每年治疗癌症的费用估计为81亿美元。退伍军人患皮肤癌的几率 比平民高出四倍，并报告更多的阳光照射， 经常被晒伤，防晒使用率较低。因此，皮肤癌发病率 预计将继续增加退伍军人。与其他癌症类型不同，患者通常 患有多种皮肤癌，一半的皮肤癌相关死亡发生在10岁以上的人中， 或更多的皮肤癌。皮肤癌的风险是异质的，但在这方面几乎没有进展。 决定哪个病人会患上多种皮肤癌。 患有10种或更多皮肤癌的患者有25%的转移风险。研究 具有多种皮肤癌高患病率的人群可以提供线索， 多发性皮肤癌器官移植受者（OTR）有高达100倍的 皮肤癌的发病率高于非OTR。这一增长被认为是由于两个 免疫抑制和免疫抑制剂引起的DNA修复减少。暴露于 特定的免疫抑制剂与不同的皮肤癌风险有关，尽管它们的 新陈代谢影响皮肤癌的数量是未知的。此外，尚不清楚其他因素是否 在移植时存在可以识别出患有多种皮肤癌的高风险个体 积极的一级预防会让他们受益本研究将使用芬奇和MVP数据 解决如何识别退伍军人在发展10或 更多的皮肤癌先验，以减少他们的皮肤癌发病率和死亡率。 该CDA-2的总体目标是推进皮肤的个性化管理 器官移植受者的癌症，并提供更广泛的疾病机制的线索， 退伍军人我们的长期目标是部署精准医疗管理战略 降低皮肤癌的发病率，发病率和死亡率，在两个退伍军人与器官 移植和退伍军人整体。在目标1中，我们将确定存在于 移植的时间与皮肤癌的发展有关。在目标2中，我们 研究免疫抑制药物代谢的变化如何影响 皮肤癌的发病率在目标3中，我们将研究罕见遗传变异的作用 患上10种或更多的皮肤癌。 田纳西流域医疗保健系统纳什维尔弗吉尼亚州和范德比尔特是一个理想的 环境支持博士Wheless为这一建议和他的过渡到独立 医学科学家两家医院都是大容量移植中心， 生物信息学基础设施和专业知识。皮肤科大力支持 博士Wheless的职业发展。他的导师，洪博士，Chren和Matheny，是 国际公认的皮肤病学，遗传流行病学和生物信息学， 成功的指导跟踪记录。这些导师，沿着指导委员会， 制定了严格的遗传流行病学和药物基因组学培训计划， 和动手学习活动。在强大的机构支持下，Wheless博士将成功地 利用他的提案来获得优异奖的资助

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.