Applying Genomic Dosimeters of UV Damage to Predicting Skin Cancer Risk

项目摘要 癌症预防计划可以减少癌症发病率、癌症相关死亡和医疗成本。还没有 人口层面的癌症预防计划既昂贵又难以实施，它们的好处必须 要权衡过度诊断的风险和与后续护理相关的危害。一种新的观点是 预防工作应侧重于风险最高的人群。 在精准医学的时代，精密预防将客观地衡量一个人过去接触 风险因素，以预测此人患癌症或职业病的风险。高危人群会 然后经常由专家进行监测。皮肤癌是一个理想的起点，因为它们几乎 与所有其他人类癌症的发病率总和一样，致癌物质通常是紫外线(UV)，即 致癌的DNA加合物是已知的环丁烷嘧啶二聚体(CPD)，组织很容易 无障碍。本项目利用最近的两项技术进步来评估个人 并回答有关使用DNA加合物进行风险预测的基本问题。 首先，该项目使用全基因组学来识别“基因组剂量计”，即皮肤中的基因组区域 对紫外线的敏感度比全基因组平均预期高出1041倍。其次，它使用一个 无瘢痕表面活性物质皮肤活检法(表面活性物质介导的分子组织采集 分析、盖章)，以提高人体研究的招聘率并允许对多种非 单个受试者的病变部位；非病变部位比肿瘤更能反映最初的暴露 网站就是这样。该项目首先将这些方法应用于人类皮肤的小样本，然后确定如何 基因组剂量计中的CPD随着紫外线对正常皮肤的暴露而变化，并最终决定如何发生 在暴露在阳光下的正常皮肤中，几种类型的皮肤癌的风险因基因组剂量计的CPD水平而异 以构建一个癌症概率指标。结果将建立一条通往精密预防的途径 内收术。

Project Summary Cancer prevention programs can reduce cancer incidence, cancer-related deaths, and healthcare costs. Yet population-level cancer prevention programs are expensive and difficult to implement, and their benefit must be weighed against the risk of overdiagnosis and harms associated with followup care. An emerging view is that prevention efforts ought to be focused on the populations at highest risk. In an era of precision medicine, Precision Prevention would objectively measure a person's past exposure to a risk factor in order to predict that person's risk of cancer or occupational disease. High-risk individuals would then be monitored frequently by a specialist. Skin cancers are an ideal starting point because they are nearly as frequent as all other human cancers combined, the carcinogen is typically ultraviolet light (UV), the carcinogenic DNA adduct is known to be the cyclobutane pyrimidine dimer (CPD), and the tissue is readily accessible. The present project takes advantage of two recent technical advances in order to assess individual risk and answer basic questions about using DNA adductomics for risk prediction. First, the project uses whole-genome genomics to identify "genomic dosimeters", genome regions in skin that are up to 1041 fold more sensitive to UV than expected from the genome-wide average. Second, it uses a nonscarring surfactant-based skin biopsy method (Surfactant-mediated Tissue Acquisition for Molecular Profiling, STAMP) in order to increase recruitment rates for human studies and allow sampling of multiple non- diseased sites from a single subject; non-diseased sites reflect the initial exposure more closely than tumor sites do. The project begins by adapting these methods to small samples of human skin, then determines how CPDs in genomic dosimeters vary with UV exposure to normal skin, and finally determines how the incidence of several types of skin cancer varies with the genomic dosimeter CPD level in sun-exposed normal skin, in order to construct a cancer-probability metric. The results will establish a route to Precision Prevention using adductomics.