Using Clonal and Non-Clonal UV Signature Mutations to Predict 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 风险因素作为预测个人患癌症或职业病风险的因素。高危人群 然后会经常由专家进行监测。皮肤癌是一个理想的起点，因为它们 众所周知，这种致癌物质通常是紫外线，这种致癌物质几乎是所有其他人类癌症的总和。 (UV)，致癌的DNA光产物是已知的环丁烷嘧啶二聚体(CPD)，即CPD 叶子有紫外线特征的突变，正常暴露在阳光下的组织很容易接触到。现在 项目利用最近的三项技术进步来评估个人风险并回答基本问题 关于使用紫外线诱导突变进行风险预测的问题。 首先，该项目使用了一种基于表面活性物质的无疤痕皮肤活检法(表面活性物质介导的组织 获取分子图谱，STAMP)，以便从单个 这一主题是为了方便招聘。非病变部位比肿瘤更能反映初始紫外线照射。 网站。其次，突变检测的灵敏度通过采用为 液体活组织检查，包括多重基因组靶标和纠错技术，带来了检测 限制在每百万个碱基中有1个突变。第三，该项目利用了最近发现的“基因组” 剂量计“比基因组中典型的CPD靶标对紫外线的敏感性高约100倍。 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 基因组剂量计的突变随着紫外线对正常皮肤的暴露而变化，并最终决定 阳光照射下几种皮肤癌的发病率随基因组剂量计突变水平的不同而不同 正常皮肤，以构建癌症概率指标。结果将建立一条通往Precision的道路 使用紫外线特征突变进行预防。

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 as a factor in predicting that individual'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 known to usually be ultraviolet light (UV), the carcinogenic DNA photoproduct is known to be the cyclobutane pyrimidine dimer (CPD), the CPD leaves telltale UV signature mutations, and normal sun-exposed tissue is readily accessible. The present project takes advantage of three recent technical advances in order to assess individual risk and answer basic questions about using UV-induced mutations for risk prediction. First, the project uses a nonscarring surfactant-based skin biopsy method (Surfactant-mediated Tissue Acquisition for Molecular Profiling, STAMP) in order to sample multiple non-diseased sites from a single subject and to facilitate recruitment. Non-diseased sites reflect the initial UV exposure more closely than tumor sites. Second, mutation detection sensitivity is enhanced by adapting cutting-edge techniques developed for liquid biopsies, including multiplexed genome targets and error-correction techniques that bring the detection limit down to 1 mutation per million bases. Third, the project takes advantage of recently-identified "genomic dosimeters" that are ~100 fold more sensitive to UV than a typical CPD target in the genome. The project begins by adapting these methods to small samples of human skin, then determines how mutations 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 mutation level in sun-exposed normal skin, in order to construct a cancer-probability metric. The results will establish a route to Precision Prevention using UV signature mutations.