Detecting Mutational Signatures of Environmental Mutagens in Heathy Individuals for Personalized Cancer Prevention

检测健康个体环境诱变剂的突变特征以进行个性化癌症预防

基本信息

批准号：
10331852
负责人：
Ludmil B Alexandrov
金额：
$ 69.87万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-22 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10331852
关键词：
4-Nitroquinoline-1-oxide Aflatoxin B1 Algorithms Archaeology Aristolochic Acids Benchmarking Bioinformatics Blood Blood specimen Cancer Etiology Cancer Patient Cell Line Cells Characteristics Chemicals Chronic Cisplatin Classification Consumption Custom DNA Sequence DNA sequencing Data Detection Development Due Process Environment Environmental Exposure Epidemiologist Event Experimental Models Exposure to Future Genome Goals Human Human body In Vitro Individual Intercept Intervention Lead Leukocytes Life Style Malignant Neoplasms Measurement Measures Methodology Monitor Mutagens Mutation Mutation Detection Normal Cell Normal tissue morphology Outcome Passive Smoking Patients Pattern Persons Platinum Process Research Risk Sampling Somatic Cell Somatic Mutation Source Surveys System Testing Time Tissues Validation Water consumption base cancer genome cancer prevention chemotherapy clinical practice cohort combinatorial computerized tools contaminated water environmental mutagens experimental study imprint in vivo innovation mouse model non-invasive monitor novel novel strategies prevent

项目摘要

PROJECT SUMMARY Somatic mutations accumulate daily in every cell of the human body. These mutations originate from mutational processes due to environmental exposures, lifestyle choices, defective cellular machineries, and even normal cellular activities. Each mutational process imprints a characteristic pattern of mutations on the genome of somatic cells, termed “mutational signature”. Since somatic mutations are retained in the genomes of cells and their progenies, the presence of mutational signatures in a somatic genome serves as an “archaeological imprint” of the activities of the mutational processes that were operative during a person’s lifetime. Recent developments of computational tools have allowed identifying mutational signatures from the DNA sequences of cancer samples and quantifying the activities of different mutational processes in individual cancer patients. Analysis of many thousands of cancer patients across the world has now revealed almost 80 distinct mutational signatures. Importantly, for each of these patients, we now know the mutational processes that have caused their cancers and, for many of these patients, we could identify potential strategies to reduce environmental exposures and prevent their cancers. However, an effective and timely cancer prevention requires knowing the mutational processes operating in a healthy individual and eliminating or reducing the activities of these processes before that individual develops cancer. Unfortunately, currently, there are no approaches that allow quantifying mutational signatures of environmental exposures in a healthy individual and, thus, many opportunities for personalize cancer prevention are missed. Here, we propose to develop a novel computational approach that will allow noninvasive monitoring of mutational signatures in easily accessible normal somatic tissues of healthy individuals. Our approach will perform a direct detection of somatic mutational signatures from low coverage single-cell DNA sequencing data without relying on prior identification of somatic mutations. The approach will be optimized and validated using single-cell DNA sequencing data from: (i) in vitro cell lines exposed to environmental mutagens; (ii) an in vivo mouse model consuming water contaminated with a strong chemical mutagen; (iii) healthy individuals with established exposures to known environmental mutagens. Overall, this project will transform our ability to monitor the activities of the mutational processes in normal tissues of healthy individuals and it will open a plethora of opportunities for personalized cancer prevention through possible targeted interventions that reduce mutagenic exposures from environment agents and lifestyle choices.

项目摘要人体每个细胞中每天都会积累体细胞突变。这些突变起源于突变由于环境暴露，生活方式的选择，缺陷的蜂窝机械甚至正常的过程而引起的过程细胞活动。每个突变过程都印有一个突变的特征模式体细胞，称为“突变特征”。由于体细胞突变保留在细胞的基因组中，它们的后代，体细胞基因组中的突变特征是“考古烙印” 在一个人一生中运行的突变过程的活动。最近的发展计算工具允许从癌症的DNA序列中识别突变特征样品并量化各个癌症患者不同突变过程的活性。分析现在，全球数千名癌症患者揭示了近80个不同的突变特征。重要的是，对于每个患者，我们现在都知道引起癌症的突变过程而且，对于许多患者，我们可以确定潜在的策略来减少环境暴露和防止他们的癌症。但是，有效及时的预防癌症需要知道突变在健康的个人中运作的过程，并消除或减少这些过程的活动那个开发人员癌。不幸的是，目前没有允许量化的方法健康个体中环境暴露的突变签名，因此有许多机会错过了个性化癌症预防。在这里，我们建议开发一种新颖的计算方法将允许在易于获得的正常体细胞组织中对突变特征进行非侵入性监测个人。我们的方法将直接检测到低覆盖范围的躯体突变特征单细胞DNA测序数据，而无需事先识别体细胞突变。方法将使用单细胞DNA测序数据进行优化和验证：（i）暴露于环境诱变剂；（ii）一种消耗强化化学物质污染的水的体内小鼠模型诱变剂；（iii）具有已建立的已知环境诱变剂的健康个体。总体而言，这项目将改变我们在正常健康时机中监视突变过程活动的能力个人，它将通过可能有针对性的干预措施可减少环境代理商和生活方式选择的诱变暴露。