PHYLOGENIES of Barrett's Esophagus Lineages

巴雷特食管谱系的系统发育

• 批准号: 8668335
• 负责人: Mary K Kuhner
• 金额: $ 16.71万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-16 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668335
• 关键词: Address; Aneuploidy; Barrett Epithelium; Barrett Esophagus; Benign; Biology; Biopsy; Cell Lineage; Cells; Characteristics; Chromosomal Instability; Chromosome abnormality; Chronic; 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：Barrett‘s食道进展的系统发育分析 人们普遍认为，癌症是通过肿瘤在时间和空间上的演化过程发展起来的。 然而，研究这些进化过程几乎是不可能的，因为组织处于 发展成癌症的风险几乎总是被消除的。我们建议将这些进化描述为 Barrett‘s食道内的突起是食管腺癌的先兆，它在 食道是对慢性反流的一种适应。在以下情况下，这种癌前组织不会从体内移除 检测到；取而代之的是，患者被登记在监测计划中，允许收集活组织检查和 在活体内随时间和空间进化的基因组变化有待研究。我们假设，最初的 在大多数Barrett‘s患者中，Barrett’s上皮的扩张持续终生，并与 罹患癌症的风险很低。在巴雷特的一小部分患者中，二次扩张 基因组变化大大增加的细胞群体在已经建立的 巴雷特的节段，在这个二次扩张中，癌症就会发生。我们建议使用系统发育学 分析，一种从进化生物学改编而来的方法，用来描述决定生物多样性的过程 发生在食管腺癌的进化途径(稳定的良性疾病或进展) 一个个体。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 从248名患者在多个时间点采集的样本的全基因组测序， 其中79人在随访期间进展为癌症。进化史可以区分渐进的和 基因组变化积累过程中的间断动态。系统发育学也允许推断 祖先细胞群体的基因组组成，为早期发现和预防提供新的靶点 战略。这些分析将解决一个几乎不可能研究的关键问题：什么是 控制体内癌症进化的过程。 相关性(请参阅说明)： 我们的研究将使我们能够表征从很早就发生在癌细胞中的基因变化。 癌症的发展过程。几乎不可能研究癌细胞如何变化和 在实际患者中随着时间的推移而演变。我们从这项研究中学到的将有助于确定何时以及哪种类型的 治疗最有可能有助于预防癌症的发展。