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

项目摘要 体细胞突变每天在人体的每个细胞中积累。这些突变来自于 过程由于环境暴露，生活方式的选择，有缺陷的细胞机器，甚至正常的 细胞活动。每一个突变过程都会在基因组上留下一个特征性的突变模式， 体细胞，称为“突变签名”。由于体细胞突变保留在细胞的基因组中， 在它们的后代中，体细胞基因组中突变标记的存在充当了“考古学印记”。 一个人一生中发生的变异过程的活动。最近的事态发展 计算工具的发展使得从癌症的DNA序列中识别出突变特征成为可能 样本和量化不同的突变过程在个别癌症患者的活动。分析 全世界数以千计的癌症患者现在已经显示出近80种不同的突变特征。 重要的是，对于这些患者中的每一个，我们现在都知道了导致他们癌症的突变过程 而且，对于其中许多患者，我们可以确定潜在的策略，以减少环境暴露， 预防癌症。然而，有效和及时的癌症预防需要知道突变的基因。 在健康个体中运行的过程，并在健康个体之前消除或减少这些过程的活动。 这个人就会患上癌症不幸的是，目前还没有方法可以量化 健康个体暴露于环境的突变特征，因此， 个人化的癌症预防措施被忽视了。在这里，我们建议开发一种新的计算方法， 将允许在容易获得的健康人的正常体细胞组织中非侵入性地监测突变特征。 个体我们的方法将从低覆盖率中直接检测体细胞突变特征 单细胞DNA测序数据，而不依赖于体细胞突变的先前鉴定。该办法将 使用来自以下的单细胞DNA测序数据进行优化和验证：（i）暴露于以下的体外细胞系： 环境诱变剂;（ii）消耗被强化学品污染的水的体内小鼠模型 诱变剂;（iii）已确定暴露于已知环境诱变剂的健康个体。总体而言，这 该项目将改变我们监测健康人正常组织中突变过程活动的能力。 这将为个性化癌症预防提供大量机会， 有针对性的干预措施，减少环境因子和生活方式选择的诱变暴露。

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.