Applying Genomic Dosimeters of UV Damage to Predicting Skin Cancer Risk

应用紫外线损伤基因组剂量计预测皮肤癌风险

• 批准号: 10113619
• 负责人: DOUGLAS E BRASH
• 金额: $ 56.88万
• 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: 2019-05-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10113619
• 关键词: Back; Basic Science; Behavioral Sciences; Biopsy; Bronchi; Cancer Etiology; Carcinogens; Caring; Cessation of life; Clinical; Cutaneous; DNA; DNA Adducts; Dermatologist; Diagnostic tests; Environmental Exposure; Environmental Risk Factor; Equilibrium; Exposure to; Fibroblasts; Genome; Genomics; German population; Goals; Health Care Costs; Human; Incidence; Individual; Lesion; Malignant Neoplasms; Measures; Mediating; Methods; Molecular Profiling; Monitor; Morbidity - disease rate; Mucous Membrane; Nature; Occupational Diseases; Persons; Population; Prevalence; Prevention; Prevention program; Prevention strategy; Probability; Pyrimidine Dimers; Reporting; Risk; Risk Factors; Route; Sampling; Screening for Skin Cancer; Screening for cancer; Site; Skin; Skin Cancer; Specialist; Suggestion; Sun Exposure; Time; Tissue Sample; Tissues; UV Radiation Exposure; Ultraviolet Rays; adduct; base; cancer invasiveness; cancer prevention; cancer risk; carcinogenicity; economic impact; follow-up; genome-wide; high risk; individualized prevention; innovation; keratinocyte; melanocyte; melanoma; mortality; precision medicine; prevent; recruit; risk prediction; screening; stem; surfactant; tumor; ultraviolet damage; 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 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.

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，以预测该人患癌症或职业病的风险。高风险人群将 然后由专家进行频繁监测。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，致癌物质通常是紫外线（UV）， 致癌的DNA加合物已知是环丁烷嘧啶二聚体（CPD），并且组织容易 容易接近本项目利用最近的两项技术进步，以评估个人 风险和回答有关使用DNA内收组学进行风险预测的基本问题。 首先，该项目使用全基因组基因组学来识别“基因组剂量计”，即皮肤中的基因组区域， 对紫外线的敏感性比全基因组平均值高出1041倍。其次，它使用了 无瘢痕的基于表面活性剂的皮肤活检方法（用于分子生物学的表面活性剂介导的组织获取） 分析，STAMP），以增加人体研究的招募率，并允许对多个非 单个受试者的患病部位;非患病部位比肿瘤部位更能反映初始暴露 网站做。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随着对正常皮肤的UV暴露而变化，并最终决定了发病率如何 几种类型的皮肤癌的变化与基因组剂量计CPD水平在阳光照射的正常皮肤， 来构建一个癌症概率度量研究结果将建立一条通往精确预防的路线， 内收神经切断术