Precision disease prevention via somatic mutagenesis enumeration (PREDICTION)

摘要 为了实现精准医疗的承诺，需要更好的生物标志物来指导临床决策。 需要新的标志物来预测处于发展疾病风险中的个体，从而可以从 特别干预。考虑到突变是基因突变的关键因素， 所有遗传变异的最终来源，突变基因驱动许多重要的致病过程， 例如癌症。然而，缺乏关键要素来评估诱变与疾病风险的关系。 缺乏具有高质量暴露数据的大规模、特征良好的队列; 使用统一协议收集和储存的样本;以及稳健监测 人体突变我们通过临床医生之间的协同合作克服了这些问题， 基础，计算，生物统计和人口科学家，利用一个非常敏感的下一个 代测序（NGS）为基础的突变测定，我们最近开发的;及其应用， 来自临床试验和具有里程碑意义的妇女健康倡议的最高质量的生物样本 (WHI)study.我们的首要目标是为实现精确预防的承诺作出贡献 通过完成以下具体目标：1）监测诱变和选择的动力学， 人类基因组，以确定强大的突变目标; 2）检查体细胞突变诱导的效用， 一种诱变暴露的生物标志物及其对患肺癌的吸烟者与患肺癌的吸烟者进行分层的潜力 3）测试监测体细胞突变率作为易感性/风险生物标志物的效用， 确定哪些人会患上癌症。总的来说，我们的建议在技术方面是创新的。 使用及其应用于高度策划的人类样本。该项目将突出的潜在效用 监测体内突变诱导以分层癌症风险，为指导医学干预提供基础， 生活方式改变（即限制诱变剂暴露）、早期诊断和/或化学预防的应用 这些措施有可能最终挽救生命。

ABSTRACT In order to realize the promise of precision medicine, better biomarkers are needed to guide clinical decisions. New markers are needed to predict individuals at risk for developing a disease and thus may benefit from a particular intervention. Focusing on markers of mutagenesis is a promising strategy given that mutation is the ultimate source of all genetic variation, and mutated genes drive a number of important pathogenic processes, such as cancer. However, key elements are missing for evaluating mutagenesis in relation to disease risk. Absent are large-scale, well-characterized cohorts with high quality exposure data; populations with serial samples that have been collected and stored using uniform protocols; and the ability to robustly monitor somatic mutation in humans. We overcome these issues through a synergistic collaboration among clinicians, basic, computational, biostatistical, and population scientists that leverages an exceptionally sensitive next generation sequencing (NGS)-based mutational assay, which we recently developed; and its application to biological samples of the highest quality from both a clinical trial and the landmark Women’s Health Initiative (WHI) study. Our overarching goal is to contribute to the realization of the promise of precision prevention through completion of the following specific aims: 1) Monitor the kinetics of mutagenesis and selection across the human genome to identify robust mutational targets; 2) Examine the utility of somatic mutation induction as a biomarker of mutagenic exposure and its potential to stratify smokers that develop lung cancer versus those that do not; and 3) Test the utility of monitoring somatic mutation rate as a susceptibility/risk biomarker to identify individuals who will develop cancer. Overall, our proposal is innovative with respect to the technology used and its application to highly curated human samples. This project will highlight the potential utility of monitoring in vivo mutation induction to stratify cancer risk, providing a basis for directing medical intervention, lifestyle changes (i.e. limiting mutagen exposure), early diagnosis, and/or the application of chemopreventive measures with the potential to ultimately save lives.