CHROMOSOME ALTERATIONS IN BARRETT'S ESOPHAGUS

巴雷特食管中的染色体改变

• 批准号: 6731175
• 负责人: THOMAS G PAULSON
• 金额: $ 9.88万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6731175
• 关键词: Barretts esophagus; adenocarcinoma; chromosome aberrations; clinical research; enzyme activity; esophagus neoplasm; flow cytometry; human subject; loss of heterozygosity; microarray technology; neoplasm /cancer genetics; neoplastic process; polymerase chain reaction; telomerase; telomere; tumor suppressor genes

DESCRIPTION: (Applicant's Description) The incidence of esophageal adenocarcinoma (EA), a rapidly fatal cancer with 5-year survival of less than 10 percent, has risen more then 350 percent over the past 20 years. Neoplastic progression in Barrett's esophagus (BE), the precursor to EA, is characterized by progressive genetic instability, including mutations (p53, p16), promoter hypermethylation (p16), aneuploidy and chromosomal instability (LOH, deletions and amplifications). Barrett's esophagus is an excellent model of human neoplastic progression because endoscopic surveillance is recommended, permitting serial samples to be evaluated over time in the same patient. Shortened telomeres, p53 and p16 inactivation occur before EA. We hypothesize that telomere shortening causes chromosomal instability in BE as has been proposed in model systems. However, relationships among p16/p53 inactivation, reactivation of telomerase, and chromosomal instability during human neoplastic progression are largely unknown. In this proposal, I will investigate the hypothesis that telomere shortening, abrogation of p16 and p53 function and telomerase reactivation interact to mediate chromosomal instability in BE. We propose to measure telomerase activity in BE samples in 325 patients from the Seattle Barrett's Esophagus Cohort, an extremely well characterized cohort for whom p53 and p16 status and flow cytometric data are already known. We will use clonal ordering to determine relationships among p53 inactivation, p16 inactivation, telomerase reactivation and the development of chromosomal instability, using alterations on chromosome 18 as a model of instability. Chromosome 18 is an appropriate model because it is frequently (75 percent of cases) altered in EA (LOH events, amplifications and deletions) and these alterations are selected before the development of cancer. The methods used in these analyses will include TRAP assays to measure telomerase activity and microsatellite LOH and microarray comparative genomic hybridization (CGH) to assess chromosomal instability. The results from these analyses will be of interest to both clinical and basic researchers in studying EA and other cancers.

描述：（申请人的描述）食管的发生率 腺癌（EA），一种迅速致命的癌症，5年生存率小于 在过去20年中，10％的增长比350％。 Barrett食管（BE）的肿瘤进展，EA的前身是 以进行性遗传不稳定性为特征，包括突变（p53， p16），启动子高甲基化（p16），非整倍性和染色体不稳定性 （LOH，删除和放大）。 巴雷特的食道很棒 人类肿瘤进展的模型，因为内镜监测是 推荐，允许在同一时间随时间评估串行样品 病人。 EA之前发生了缩短的端粒，p53和p16失活。 我们 假设端粒缩短会导致be中的染色体不稳定性 已在模型系统中提出。 但是，p16/p53之间的关系 灭活，端粒酶的重新激活和染色体不稳定性 人类的肿瘤进展在很大程度上是未知的。 在这个建议中，我将 研究端粒缩短，p16和p53的假设 功能和端粒酶激活相互作用以介导染色体 BE的不稳定性。 我们建议测量在BE中的端粒酶活性 来自西雅图巴雷特的食道同类的325名患者，这是一个非常好的井 p53和p16状态和流式细胞术数据的表征是 已经知道。 我们将使用克隆顺序确定 p53失活，p16失活，端粒酶重新激活和 染色体不稳定性的发展，使用对18染色体的改变作为 不稳定的模型。 18染色体是一个合适的模型，因为它是 EA经常发生（75％的病例）（LOH事件，放大和 删除）和这些更改是在开发之前选择的 癌症。 这些分析中使用的方法将包括 测量端粒酶活性和微卫星LOH和微阵列比较 基因组杂交（CGH）评估染色体不稳定性。 结果 从这些分析中，临床和基础研究人员都将很感兴趣 在研究EA和其他癌症时。