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.

项目概要 80-90% 的癌症风险与环境基因毒素暴露有关。确实，整体 基因组测序研究表明，人类癌症携带反映了 患者所接触的环境因素。然而，一些研究表明，许多突变 特征源自内源性细胞过程。当 DNA 被修改/损坏时，就会发生突变 外源性理化因子和内源性细胞过程（例如氧化）。特定代理 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， 更常见的是与称为衰老特征的内源过程相关的突变，即 SBS1 和 SBS5。了解这些特征的起源是更好地了解癌症原因的关键， 需要一种全面的方法来研究加合物。 DNA 加合组学旨在描述 DNA 加合组学的总体 基因组中的加合物，与致癌作用有关。我们假设外源性因素作用于 至少部分是通过特征模式或加合物类型的诱导，但此外它们也可能影响 内源性诱变过程，改变 DNA 加合物。内源性异常改变 尽管有强有力的证据表明肿瘤中药物特异性突变的水平较低， 环境因素在致癌过程中的关键作用。为了开始检验这个假设，我们将进行试点研究 实现以下目标： 目标 1，评估内源 DNA 加合物组对 相应的突变景观。在目标 2 中，评估外源环境暴露的影响 （苯）在内源性 DNA 加合物上的作用，以及相应的突变景观。分析 突变景观及其相应的 DNA 加合组图谱将开始增进我们的理解 暴露体、DNA加合物和突变体之间的关系，从而增强结果 父 R01。遵循这一研究途径将为癌症的识别/评估铺平道路 风险因素和识别由外源/内源暴露引起的新突变特征。