PHYLOGENIES of Barrett's Esophagus Lineages

巴雷特食管谱系的系统发育

• 批准号: 8933435
• 负责人: Mary K Kuhner
• 金额: $ 35.65万
• 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/8933435
• 关键词: Address; Aneuploidy; Barrett Epithelium; Barrett Esophagus; Benign; Biology; Biopsy; Cell Lineage; Cells; Characteristics; Chromosomal Instability; Chromosome abnormality; Chronic; DNA Sequence Alteration; Data; Development; Disease; Early Diagnosis; Enrollment; Esophageal Adenocarcinoma; Esophageal Neoplasms; Esophagus; Event; Evolution; Generations; Genetic; Genome; Genomics; Goals; Individual; Instruction; Learning; Lesion; Loss of Heterozygosity; Maintenance; Malignant Neoplasms; Metaplasia; Methods; Mutation; Neoplastic Processes; Pathway interactions; Patients; Pattern; Phylogenetic Analysis; Phylogeny; Play; Point Mutation; Population; Premalignant; Prevention strategy; Process; Reflux; Risk; Sampling; Staging; Surveillance Program; Testing; Tetraploidy; Time; Tissue Therapy; Tissues; base; cancer cell; cancer site; cohort; density; genome sequencing; high risk; improved; in vivo; novel; prevent; response; success

Project 3: Phylogenetic Analysis of Progression in Barrett's Esophagus It is generally accepted that cancer develops through a process of neoplastic evolution over time and space in the body, yet studying these evolutionary processes has proven nearly impossible, since tissue that is at risk for developing into cancer is almost always removed. We propose to characterize these evolutionary processes in Barrett's esophagus, a precursor to esophageal adenocarcinoma, which develops in the esophagus as an adaptation to chronic reflux. This premalignant tissue is not removed from the body when detected; instead, patients are enrolled in surveillance programs, allowing biopsies to be collected and genomic changes that evolve over time and space in vivo to be studied. We hypothesize that the initial expansion of Barrett's epithelium persists for a lifetime in most individuals with Barrett's and is associated with a low risk of progression to cancer. In a small percentage of Barrett's patients, a secondary expansion of cell populations with greatly increased genomic alterations spreads across in the already established Barrett's segment, and in this secondary expansion cancer develops. We propose to use phylogenetic analysis, a method adapted from evolutionary biology, to characterize the processes that determine the evolutionary pathway (stable, benign disease or progression to esophageal adenocarcinoma) that occurs in an individual. This will be accomplished using somatic genomic alteration data from high density SNP arrays and from whole genome sequencing of samples taken at multiple time points from a cohort of 248 patients, 79 of whom progressed to cancer during followup. Phylogenies can distinguish between gradual versus punctuated dynamics in the accumulation of genomic alterations. Phylogenies also allow inference ofthe genomic makeup of ancestral cell populations, providing novel targets for early detection and prevention strategies. These analyses will address a critical question that has been almost impossible to study: what are the processes that govern the evolution of cancer in vivo. RELEVANCE (See instructions): Our study will allow us to characterize the genetic changes that occur in cancer cells from very eariy on in the process of cancer development. It has been neariy impossible to study how cancer cells change and evolve over time in actual patients. What we learn from this study will help identify when and what kind of treatments are most likely to help prevent the development of cancer.

项目3：巴雷特食管进展的系统发育分析 人们普遍认为，癌症是通过随时间和空间的肿瘤进化过程而发展的 在体内，研究这些进化过程几乎是不可能的，因为 几乎总是消除患癌症的风险。我们建议表征这些进化 Barrett食管的过程，这是食管腺癌的前体，它在 食道适应慢性反流。当这种预示威的组织不会从体内移除 检测到；取而代之的是，患者参加了监视计划，可以收集活检，并 基因组变化会随着时间和空间的体内发展而发展。我们假设最初 在大多数患有巴雷特的人中，Barrett上皮的扩展持续了一生，并且相关 癌症进展的风险很低。在一小部分巴雷特患者中，次要扩张 基因组改变大大增加的细胞群体在已经建立的 Barrett的细分市场以及在这种二次扩张中发展。我们建议使用系统发育 分析是一种从进化生物学改编的方法，以表征确定的过程 进化途径（稳定，良性疾病或向食管腺癌的进展）发生在 一个人。这将使用来自高密度SNP阵列的体细胞基因组改变数据来完成 以及从248名患者队列中多个时间点采集的样品的整个基因组测序中， 其中79人在随访期间发展为癌症。系统发育可以区分逐渐的 基因组改变积累的标点动力学。系统发育也可以推断 祖先细胞种群的基因组构成，为早期检测和预防提供了新的靶标 策略。这些分析将解决一个几乎无法研究的关键问题：什么是 控制体内癌症演变的过程。 相关性（请参阅说明）： 我们的研究将使我们能够表征癌细胞中从Eariy On开始的遗传变化 癌症发展的过程。研究癌细胞的变化和 随着时间的流逝，实际患者会进化。我们从这项研究中学到的东西将有助于确定何时以及哪种 治疗最有可能有助于预防癌症的发展。