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：Barrett食管进展的系统发育分析 人们普遍认为，癌症的发展是一个随着时间和空间的肿瘤演变过程 然而，研究这些进化过程已被证明几乎是不可能的，因为组织是在 发展成癌症的风险几乎总是被消除。我们建议将这些进化的 Barrett食管中的突起，食管腺癌的前体，其在食管中发展。 食管作为适应慢性反流。这种癌前组织不会从体内移除， 检测;相反，患者被纳入监测计划，允许收集活检， 基因组的变化，随着时间和空间的演变，在体内进行研究。我们假设最初的 在大多数巴雷特上皮病患者中，巴雷特上皮的扩张持续一生， 发展成癌症的风险很低在一小部分巴雷特的患者中， 基因组改变大大增加的细胞群在已经建立的细胞群中传播， 巴雷特的部分，并在此二次扩张癌症的发展。我们建议使用系统发育 分析，一种从进化生物学中改编而来的方法，用来描述决定生物学特性的过程。 发生在以下疾病中的进化途径（稳定、良性疾病或进展为食管腺癌） 单个.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 以及来自在多个时间点从248名患者的队列中获取的样品的全基因组测序， 其中79人在随访期间进展为癌症。系统发育可以区分渐进与渐进 基因组变异累积的间断动态。系统发育也允许推断 祖先细胞群体的基因组组成，为早期检测和预防提供新的靶点 战略布局这些分析将解决一个几乎不可能研究的关键问题： 控制癌症在体内演变的过程。 相关性（参见说明）： 我们的研究将使我们能够描述癌细胞中发生的基因变化， 癌症发展的过程。几乎不可能研究癌细胞如何变化， 随着时间的推移，在实际的病人身上。我们从这项研究中了解到的信息将有助于确定何时以及何种类型的 治疗最有可能帮助预防癌症的发展。