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

项目总结 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，有500多万人患有癌症 癌症每年的治疗费用估计为81亿美元。退伍军人患皮肤癌的几率 比平民人口高出四倍，并报告更多的阳光暴露，更多 频繁的晒伤，以及较低的防晒使用率。因此，皮肤癌的发病率 预计退伍军人中的人数将继续增加。与其他类型的癌症不同，患者通常会 患上多发性皮肤癌，与皮肤癌相关的死亡中有一半发生在10岁以下的人中 或者更多的皮肤癌。皮肤癌的风险是不同的，但在以下方面进展甚微 确定哪位患者会患上多种皮肤癌。 患有10个或更多皮肤癌的患者有25%的转移风险。学习 多发性皮肤癌高发人群可提供发病机制线索 多发性皮肤癌的发展。器官移植受者(OTR)拥有高达100倍的 皮肤癌的发病率比非牙周炎患者更高。这一增长被认为是由于 免疫抑制剂引起的免疫抑制和DNA修复减少。暴露于 特定的免疫抑制剂与皮肤癌的不同风险有关，尽管它们的 新陈代谢影响皮肤癌的数量尚不清楚。此外，目前还不清楚是否还有其他因素 在移植时的存在可以识别出患多种皮肤癌的高危个体 谁将从积极的初级预防中受益。这项研究将使用芬奇和MVP的数据 要解决如何识别面临10岁或以下疾病风险的退伍军人的关键知识差距 更多的皮肤癌先天减少皮肤癌的发病率和死亡率。 CDA-2的总体目标是推进皮肤的个性化管理 并为更广泛的疾病机制提供线索 退伍军人。我们的长远目标是部署精准医疗管理战略 降低有器官的退伍军人中皮肤癌的发病率、发病率和死亡率 移植和退伍军人的总体情况。在目标1中，我们将确定存在的临床因素的模式 移植的时间与皮肤癌的发生有关。在目标2中，我们将 研究免疫抑制药物新陈代谢的变化如何影响这一数字 患者会患上皮肤癌。在目标3中，我们将研究稀有基因变异的作用 患上10种或更多皮肤癌。 田纳西河谷医疗保健系统，弗吉尼亚州纳什维尔和范德比尔特是理想的选择 支持惠莱斯博士这一提议的环境以及他向独立的 内科科学家。这两家医院都是大容量的移植中心，拥有强大的设施 生物信息学基础设施和专业知识。皮肤科大力支持 惠莱斯博士的职业发展。他的导师Hung博士、Chren和Matheny 在皮肤病学、遗传流行病学和生物信息学方面获得国际认可 成功的辅导记录。这些导师和指导委员会一起， 制定了严格的遗传流行病学和药物基因组学培训计划 和实践学习活动。在强有力的机构支持下，惠莱斯博士将成功 利用他的提议获得功勋基金。

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.