Using Clonal and Non-Clonal UV Signature Mutations to Predict Skin Cancer Risk

使用克隆和非克隆紫外线特征突变来预测皮肤癌风险

• 批准号: 10459459
• 负责人: DOUGLAS E BRASH
• 金额: $ 46.69万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459459
• 关键词: Back; Basal cell carcinoma; Biopsy; Bronchi; Carcinogens; Caring; Cells; Cessation of life; Chemicals; Clinical; Cutaneous; DNA photoproducts; Dermatologist; Diagnostic tests; Environmental Risk Factor; Equilibrium; Exposure to; Fibroblasts; Frequencies; Genome; Genomics; Goals; Health Care Costs; Healthcare; Human; Hypersensitivity; Incidence; Individual; Induced Mutation; Lesion; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Mediating; Methods; Molecular Profiling; Monitor; Morbidity - disease rate; Mucous Membrane; Mutation; Mutation Detection; Occupational Diseases; Persons; Phenotype; Population; Prevention; Prevention program; Prevention strategy; Probability; Pyrimidine Dimers; Reporting; Risk; Risk Factors; Route; Sampling; Site; Skin; Skin Cancer; Specialist; Squamous cell carcinoma; Suggestion; Sun Exposure; Sunlight; Techniques; Time; Tissue Sample; Tissues; UV Radiation Exposure; UV induced; Ultraviolet Rays; base; cancer invasiveness; cancer prevention; cancer risk; carcinogenicity; detection limit; detection sensitivity; follow-up; genome-wide; high risk; individualized prevention; keratinocyte; liquid biopsy; melanocyte; melanoma; mortality; mutant; pollutant; precision medicine; prevent; recruit; risk prediction; screening; surfactant; tumor; whole genome

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.

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保健费用。然而 人口水平的癌症预防计划是昂贵的，难以实施，其效益必须 与过度诊断的风险和与后续护理相关的危害进行权衡。一个新兴的观点是， 预防工作应侧重于风险最高的人群。 在精准医疗时代，精准预防将客观地测量一个人过去接触的 风险因素作为预测个人患癌症或职业病风险的因素。高危个体 然后由专家经常监测。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总和一样频繁，已知致癌物质通常是紫外线 (UV)致癌的DNA光产物是环丁烷嘧啶二聚体（CPD）， 会留下紫外线特征的突变，而正常的暴露在阳光下的组织是很容易接近的。本 该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，该项目使用无瘢痕的基于表面活性剂的皮肤活检方法（表面活性剂介导的组织 用于分子特征分析的采集，STAMP），以便从单个 并促进招聘。非病变部位比肿瘤更能反映初始紫外线暴露 网站.第二，通过采用针对突变检测而开发的尖端技术来增强突变检测灵敏度。 液体活检，包括多重基因组靶点和纠错技术， 每百万个碱基只有一个突变第三，该项目利用最近确定的"基因组"， 这些剂量计对紫外线的敏感性比基因组中典型的CPD靶标高约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 基因组剂量计中的突变随着正常皮肤的紫外线暴露而变化，并最终决定了 几种类型的皮肤癌的发病率随暴露于阳光的皮肤中的基因组剂量计突变水平而变化。 正常皮肤，以构建癌症概率度量。结果将建立一条通往Precision的路线 使用紫外线特征突变进行预防。