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

项目总结 暴露在环境和内源性因素下会导致DNA损伤，从而导致基因组 不稳定在人类许多重大疾病的发病机制中起着关键作用，例如癌症， 神经退行性变，心血管疾病，以及衰老。新兴的DNA技术 加合物，提供了全面评估基因组中加合物的整体的可能性，但 对大量组织DNA的要求限制了其在分子流行病学中的应用。我们是第一个 以证明在尿液中进行DNA加合运算的能力。此方法是实现以下目标的重要途径 简单地、非侵入性地评估人类群体中加合物的总数，这可以应用于 评估癌症风险或预防。到目前为止，dna加合物组学已被应用于加合物组的研究。 在细胞DNA中。对大量DNA(细胞或组织)进行侵入性来源的要求 这对DNA加合物在人类群体中的应用是一个严峻的挑战。相比之下，尿液 非侵入性，易于收集、运输和储存，生物危害低。此外，样本检查 比DNA简单。尿液中DNA加合物的存在是DNA修复的结果，包括 碱基切除修复(BER)，全球基因组和转录偶联核苷酸切除修复，以及 对2‘-脱氧核糖核酸库进行消毒，并产生修饰的碱基和2’-脱氧核糖核酸库。 脱氧核糖核苷。对这种加合物进行有针对性的分析(例如8-氧代-8-氧- 7，8-二氢-2‘-脱氧鸟苷和1，N6-乙基腺嘌呤)，以及它们在尿中的应用价值。 生物监测和分子流行病学。将这项工作扩展到DNA内收切除法将大量 增加获得的信息，我们为这些信息展示了强大的试点数据。这一成就证明了 建议改进暴露科学的战略，即将21世纪的科学纳入基于风险的科学 评估，并提供将内收术应用于侵入性最小的矩阵的机会，还建议 最近。我们的假设是，外源性和内源性癌症风险因素在一定程度上通过形成 DNA加合物，而对这些加合物评价既可告知暴露的性质和大小，也可因此 癌症风险。我们的目标是开发一种非侵入性的，DNA内收摘除尿液的方法，以评估接触， 促进癌症风险评估、癌症预防战略和癌症检测， 个人和人口水平。

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.