Precision disease prevention via somatic mutagenesis enumeration (PREDICTION)

摘要 为了实现精准医学的前景，需要更好的生物标志物来指导临床决策。 需要新的标记物来预测有患疾病风险的个人，从而可能受益于 特别干预。专注于突变的标记是一个很有前途的策略，因为突变是 所有遗传变异的最终来源，以及突变的基因驱动了许多重要的致病过程， 比如癌症。然而，缺乏评估突变与疾病风险相关的关键因素。 缺少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存储的样本；以及可靠监控的能力 人类的体细胞突变。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、生物统计学和人口科学家利用异常敏感的NEXT 我们最近开发的基于世代测序(NGS)的突变分析及其在 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)研究。我们的首要目标是为实现精准预防的承诺做出贡献。 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靶点；2)检查体细胞突变诱导的效用 诱变暴露的生物标记物及其对患肺癌的吸烟者和 3)测试监测体细胞突变率作为易感/风险生物标志物的有效性 找出可能罹患癌症的个体。总体而言，我们的建议在技术方面是创新的 以及它在高度精制的人体样本中的应用。这个项目将突出潜在的效用 监测体内突变诱导以分层癌症风险，为指导医疗干预提供依据， 生活方式的改变(即限制诱变剂暴露)、早期诊断和/或化学预防的应用 有可能最终拯救生命的措施。

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.