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.

项目总结 环境中的基因毒素暴露导致了80%-90%的癌症风险。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 患者所接触到的环境因素。然而，一些研究表明，许多突变 签名源于内源性的细胞过程。当DNA被修改/损坏时，可能会发生突变 外源性的物理化学物质和内源性的细胞过程(如氧化)。特定于代理的 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， 更常见的是与内源性过程有关的突变，称为衰老特征，即SBS1和 SBS5.了解这些特征的起源，这是更好地理解癌症原因的关键， 需要一个全面的方法来研究加合物。DNA吸引学的目的是描述 基因组中的加合物，它们与癌症的发生有关。我们假设外源因子在 至少部分地通过诱导签名模式或加合物类型，但另外它们也可能影响 内源性突变过程，改变DNA加合物组。内源性的异常变化 尽管有强有力的证据表明，肿瘤中毒剂特异性突变的水平较低，但这一过程将解释 环境因素在癌症发生中的关键作用。为了开始检验这一假设，我们将进行初步研究 为解决以下目标：目标1，评估内源DNA加合物组对 相应的变异景观。在目标2中，评估外源环境暴露的影响 (苯)在内源DNA加合物组上，以及相应的突变景观。三、分析了 突变的景观及其相应的DNA加合物组图谱将开始推进我们对 暴露组、DNA加合物组和突变组之间的关系，从而增强 父R01。进行这一研究将为癌症的识别/评估铺平道路。 风险因素和由外源性/内源性暴露引起的新突变特征的识别。