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: 10740573
• 负责人: Marcus Stanley Cooke
• 金额: $ 1.45万
• 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/10740573
• 关键词: Address; Aging; Benzene; Cancer Etiology; Cell physiology; DNA; DNA Damage; Disease; Environment; Environmental Carcinogens; Environmental Exposure; Evaluation of Cancer Risk Factors; Exposure to; Genome; Health; Human; Investigation; Knowledge; Lead; Malignant Neoplasms; Maps; Mutagens; Mutation; Mutation Analysis; Parents; Pathologic Mutagenesis; Patients; Pattern; Pilot Projects; Process; Risk; Risk Factors; Role; Route; Testing; adduct; cancer risk; carcinogenesis; environmental agent; genome sequencing; novel; oxidation; tumor; urinary; whole genome

PROJECT SUMMARY Environmental genotoxin exposure is responsible for 80-90% of the risk of developing cancer. Indeed, Whole Genome Sequencing studies show that human cancers carry mutational signatures reflective of the environmental agents to which the patients were exposed. However, some studies suggest that many mutational signatures arise from endogenous cellular processes. Mutations can arise when DNA is modified/damaged by exogenous physicochemical agents and endogenous cellular processes (e.g., oxidation). Agent-specific mutational signatures of environmental carcinogens reveal similarities to those found in human tumors. However, more common are the mutations related to endogenous processes known as ageing signatures i.e., SBS1 and SBS5. Understanding the origins of these signatures, which is key to a better understanding of cancer causes, requires a comprehensive approach to studying adducts. DNA adductomics aims to describe the totality of adducts in the genome, which are implicated in carcinogenesis. We hypothesize that exogenous agents act, at least in part, via the induction of signature patterns or types of adducts, but additionally they may also influence endogenous mutagenic processes, altering the DNA adductome. The aberrant alteration of endogenous processes would account for the low level of agent-specific mutations in tumors despite strong evidence for the key role of environmental agents in carcinogenesis. To begin to test this hypothesis, we will perform pilot studies to address the following aims: Aim 1, evaluate the impact of the endogenous DNA adductome upon the corresponding mutational landscape. In Aim 2, evaluate the impact of an exogenous environmental exposure (benzene) upon the endogenous DNA adductome, and corresponding mutational landscape. Analysis of the mutational landscapes, and their corresponding DNA adductome maps, will begin to advance our understanding of the relationships between the exposome, DNA adductome and mutatome, and hence enhance the results of the parent R01. Pursuing this route of investigation will pave the way for the identification/evaluation of cancer risk factors and the identification of novel mutational signatures caused by exogenous/endogenous exposures.

项目摘要 环境遗传毒素暴露是导致80-90%的癌症风险的原因。事实上，整个 基因组测序研究表明，人类癌症携带的突变特征反映了癌症的发生。 患者接触的环境因素。然而，一些研究表明，许多突变 信号来源于内源性细胞过程。当DNA被修饰/损坏时， 外源性物理化学试剂和内源性细胞过程（例如，氧化）。制剂特异 环境致癌物的突变特征揭示了与人类肿瘤中发现的相似之处。然而，在这方面， 更常见的是与称为老化标记的内源性过程相关的突变即，SBS 1和 SBS5.了解这些特征的起源是更好地了解癌症原因的关键， 需要一个全面的方法来研究加合物。DNA内收体学旨在描述 基因组中的加合物，这与致癌作用有关。我们假设，外源性药物的作用，在 至少部分地，通过加合物的特征模式或类型的诱导，但另外，它们也可能影响 内源性诱变过程，改变DNA内收体。内源性的异常改变 尽管有强有力的证据表明，这些过程可以解释肿瘤中药物特异性突变水平较低的原因。 环境因素在致癌作用中的关键作用。为了开始检验这一假设，我们将进行试点研究 为了实现以下目标：目标1，评估内源性DNA内收组对细胞的影响 对应的突变景观在目标2中，评估外源性环境暴露的影响 （苯）对内源性DNA内收体的影响，以及相应的突变景观。分析 突变景观和它们相应的DNA内收组图谱将开始推进我们的理解 的关系，DNA内收体和mutatome，从而提高结果， 父R 01。遵循这一研究路线将为癌症的识别/评估铺平道路。 风险因素和识别由外源性/内源性暴露引起的新突变特征。