Urinary DNA Adductomics for the Assessment of Exposure to Cancer Risk Factors

用于评估癌症危险因素暴露情况的尿液 DNA 加合物组学

• 批准号: 10544501
• 负责人: Marcus Stanley Cooke
• 金额: $ 27.39万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-30 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544501
• 关键词: Achievement; Address; Adopted; Age; Aging; Area; Base Excision Repairs; Basic Science; Benzene; Benzene Exposure; Biological; Biological Assay; Biological Monitoring; Blood; Bone Marrow; Cancer Detection; Cardiovascular Diseases; Cells; Consumption; Coupled; DNA; DNA Adduction; DNA Adducts; DNA Damage; DNA Repair; Data; Deoxyguanosine; Deoxyribonucleosides; Deoxyribonucleotides; Detection; Development; Disease; Environment; Environmental Exposure; Evaluation; Exposure to; Freezing; Generations; Genome; Genomic Instability; Goals; Health; Human; Individual; Institutional Review Boards; Knowledge; Liver; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Measures; Methodology; Methods; Molecular Epidemiology; National Institute of Environmental Health Sciences; Nature; Nerve Degeneration; Neurodegenerative Disorders; Occupational; Occupational Exposure; Organic solvent product; Pathogenesis; Play; Population; Prevention; Process; Public Health; Recommendation; Resolution; Risk; Risk Factors; Role; Route; Sampling; Science; Source; Techniques; Time; Tissues; Transcription-Coupled Repair; Urine; Work; adduct; biobank; cancer prevention; cancer risk; cohort; environmental agent; hazard; human disease; improved; individual variation; innovation; innovative technologies; method development; mouse model; novel; nucleobase; repaired; response; sex; technology development; tool; urinary

PROJECT SUMMARY Exposure to environmental, and endogenous, agents can induce DNA damage, and the consequential genomic instability plays a critical role in the pathogenesis of many major human diseases, such as cancer, neurodegeneration, and cardiovascular disease, together with aging. The emerging technique of DNA adductomics, offers the potential to comprehensively assess the totality of adducts in the genome, but the requirement for significant quantities of tissue DNA limits its application to molecular epidemiology. We are first to demonstrate the ability to perform DNA adductomics in urine. This approach represents an important route to simply, and non-invasively, evaluate the totality of adducts in human populations, which may be applied to assessing cancer risk, or prevention. To date, DNA adductomics has been applied to the study of the adductome in cellular DNA. The requirement to invasively source significant amounts of DNA (and hence cells, or tissue) represents a severe challenge to the application of DNA adductomics to human populations. In contrast, urine is non-invasive, easily collected, transported and stored, with low biological hazard. Furthermore, sample workup is simpler than for DNA. The presence of DNA adducts in urine is a consequence of DNA repair, which includes base excision repair (BER), global genome- and transcriptional coupled- nucleotide excision repair, and sanitization of the 2’-deoxyribonucleotide pools, and results in the generation modified nucleobases and 2’- deoxyribonucleosides. There is a well established precedent for targeted analyses of such adducts (e.g. 8-oxo- 7,8-dihydro-2’-deoxyguanosine, and 1,N6-ethenoadenine) in urine, and their valuable application to biomonitoring and molecular epidemiology. Extending this work to a DNA adductomic approach will massively increase the information obtained, and for which we demonstrate strong pilot data. This achievement exemplifies a strategy recommended to improve exposure science, i.e. incorporating 21st century science into risk based evaluations, and offers the opportunity to apply adductomics to the least invasive matrix, also recommended recently. Our hypothesis is that exogenous and endogenous cancer risk factors act, in part, via the formation of DNA adducts, and that evaluation of these adducts informs on both the nature and size of exposure, and hence cancer risk. Our goal is to develop a non-invasive, DNA adductomic approach in urine, to evaluate exposure, facilitating the assessment of cancer risk, strategies for cancer prevention, and cancer detection, at the individual, and population levels.

项目概要 暴露于环境和内源性物质会引起 DNA 损伤，以及随之而来的基因组损伤 不稳定性在许多主要人类疾病的发病机制中起着至关重要的作用，例如癌症、 神经退行性疾病、心血管疾病，以及新兴的 DNA 技术。 加合物组学，提供了全面评估基因组中加合物总数的潜力，但是 对大量组织 DNA 的要求限制了其在分子流行病学中的应用。 证明在尿液中进行 DNA 加合组学的能力，这种方法代表了一种重要的途径。 简单且非侵入性地评估人群中加合物的总量，这可应用于 评估癌症风险或预防迄今为止，DNA 加合组学已应用于加合组的研究。 细胞 DNA 中需要侵入性获取大量 DNA（以及细胞或组织）。 相比之下，尿液对 DNA 加合组学的应用提出了严峻的挑战。 是非侵入性的，易于采集、运输和储存，并且样品后处理的生物危害性低。 尿液中 DNA 加合物的存在是 DNA 修复的结果，其中包括 DNA 修复。 碱基切除修复 (BER)、全局基因组和转录耦合核苷酸切除修复，以及 2'-脱氧核糖核苷酸库的消毒，并导致生成修饰的核碱基和 2'- 此类加合物（例如 8-氧代-）的靶向分析已有良好的先例。 尿液中的 7,8-二氢-2’-脱氧鸟苷和 1,N6-乙烯腺嘌呤）及其在 生物监测和分子流行病学将这项工作大规模扩展到 DNA 加合组学方法。 增加获得的信息，为此我们展示了强大的试点数据。 建议改进暴露科学的策略，即将 21 世纪科学纳入基于风险的科学 评估，并提供将加合组学应用于侵入性最小的基质的机会，也建议 最近，我们的假设是，外源性和内源性癌症危险因素部分通过形成而发挥作用。 DNA 加合物，对这些加合物的评估可了解暴露的性质和大小，因此 我们的目标是开发一种非侵入性的尿液 DNA 加合方法，以评估暴露情况， 促进癌症风险评估、癌症预防策略和癌症检测 个人和人口水平。