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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：
10116194
负责人：
Ludmil B Alexandrov
金额：
$ 70.87万
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/10116194
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.

项目总结