Genome Dynamics

基因组动力学

• 批准号: 9059023
• 负责人: BRIAN J REID
• 金额: $ 44.09万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9059023
• 关键词: Barrett Esophagus; Biopsy; Cancer Detection; Case-Control Studies; Chromosomal Instability; Chromosome Arm; Chromosome abnormality; Chromosomes; Cohort Studies; Complex; DNA Sequence Alteration; Data; Detection; Diagnosis; Distal; Epithelial; Esophageal Adenocarcinoma; Esophagus; Evolution; Frequencies; Funding; Genes; Genome; Genomics; Heterogeneity; Individual; Indolent; Malignant Neoplasms; Maps; Mutation; Pathologic; Patients; Pattern; Point Mutation; Population; Population Control; Premalignant; Prevention; Progressive Disease; Research; SNP array; Somatic Mutation; Spatial Distribution; Speed; Testing; Time; Variant; arm; base; clinical practice; cohort; follow-up; genome sequencing; genome-wide; high risk; insertion/deletion mutation; mortality; whole genome

Mutation rate is a fundamental determinant of the speed of genomic evolution that increases the background frequency of non-selected mutations genome-wide as well as infrequent mutations in genes that are selected for progression to cancer. Esophageal adenocarcinoma (EA) is known to have high levels of background mutations, but how this mutation frequency changes over time before EA is unknown. Barrett's esophagus (BE) is the only known precursor to EA, and although BE is commonly called "premalignant", current clinical practices selectively identify slowly or nonprogressive BE that remains stable for a lifetime ("overdiagnosis"), and miss rapidly progressive BE that then presents as an advanced EA with high mortality ("underdiagnosis"). During the current funding period, we made transformative advances in a case-cohort study indicating that chromosome instability underiies rapid progression with a four year window of opportunity for eariy detection. Using one of the best characterized BE cohort:s available, we propose to build on these advances in a case-control study to investigate the full spectrum of somatic genomic alterations (SGA) over time in a population with BE who progressed to EA and in a population with indolent BE that did not progress to EA. We hypothesize the frequency of different classes of mutations changes over time and that these genome dynamics can be used to extend the window of opportunity for eariy detection of EA. We will perform whole genome sequencing of BE biopsies to determine the frequency of somatic micromutations (intergenic, intronic, and exomic point mutations, small indels and complex mutations), structural variations, breakpoints and chromosomal alterations in spatially mapped biopsies collected over time prior to and at the time of EA diagnosis in cases, and during endoscopic follow-up in BE controls who did not progress, matched on level of arraySGA (copy gains, copy losses, copy neutral LOH, and homozygous deletions) and follow-up time in a case-control study. We hypothesize that the variation in frequency over time of different classes of somatic mutations is significantly different in progressors and the frequency of mutations within each mutation class is more spatially heterogeneous as a function of time in progressors, compared to nonprogressors. Our research seeks to shift the existing clinical practice of treating all conditions based on a static pathologic description at a single point in time to the study of genome dynamics of non- or slowly progressive and rapidly progressive disease to increase the window of eariy detection of cancer. Barrett's esophagus is the only known precursor to esophageal adenocarcinoma, a rapidly increasing, highly lethal cancer, but most people with Barrett's esophagus remain free from this cancer for a lifetime. Current clinical practices selectively detect indolent Barrett's esophagus and miss 95% of patients who rapidly progress to cancer. Our study identifies changes in mutation frequency overtime and space that can be used to extend "windows of opportunity" for eariy detection or prevention of esophageal adenocarcinoma.

突变率是基因组进化速度的基本决定因素，它增加了背景 在选择的基因中，非选择性突变的频率以及不频繁的突变的频率 用于癌症的进展。已知食管腺癌（EA）具有高水平的背景 突变，但是在EA未知之前，这种突变频率如何随时间变化。巴雷特的食道 （BE）是唯一已知的EA前体 实践选择性地识别缓慢或非进化的生命（“过度诊断”）， 然后错过迅速进步的是，当时以高死亡率为先进的EA （“诊断不足”）。在当前的资金期间，我们在一个案例 - 霍特（Case-Ohort）中取得了变革性的进步 研究表明，染色体不稳定性在四年的窗口中迅速发展 耳机检测的机会。使用最好的特征之一是同类：S可用，我们建议 在一项病例对照研究中以这些进步为基础，以研究全部体细胞基因组谱 随着时间的流逝，人口的变化（SGA），他们逐渐发展为EA，并且在懒惰的人群中 这没有发展到EA。我们假设不同类别的突变的频率随着 时间，这些基因组动态可用于扩展耳道检测的机会窗口 ea。我们将执行BE活检的整个基因组测序，以确定体细胞的频率 微型（基因间，内含子和外部点突变，小插入和复杂突变）， 收集的空间映射活检中的结构变化，断点和染色体改变 病例诊断前后的时间以及在内窥镜检查期间的对照中的随访期间 没有进步，在Arraysga的级别上匹配（复制收益，复制损失，复制中性LOH和 纯合删除）和一项病例对照研究中的随访时间。我们假设 随着不同类别的体细胞突变的频率，进度者和 在每个突变类中突变的频率在空间上是异质的，随着时间的函数 与非探测器相比，进步者。我们的研究试图改变现有的临床实践 基于单个时间点研究基因组研究的静态病理描述来治疗所有情况 非渐进或缓慢进行性疾病的动力学，以增加耳道的窗口 检测癌症。 巴雷特的食道是食管腺癌的唯一已知前体，迅速增加，高度 致命的癌症，但大多数患有巴雷特食管的人一生都没有这种癌症。当前的 临床实践有选择地检测懒惰的Barrett的食管，而95％的患者却迅速检测 癌症的进展。我们的研究确定了突变频率的加班和空间的变化 用于扩展“机会之窗”，以预防食管腺癌。