CLONAL EVOLUTION

克隆进化

基本信息

批准号：
7305719
负责人：
BRIAN J REID
金额：
$ 61.37万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7305719
关键词：
Aneuploidy Barrett Esophagus Behavior Biological Biological Markers CDKN2A gene Chromosomal Instability Chromosome Fragile Sites Chromosome abnormality Clinical Research Clonal Evolution Cohort Studies Communities Compatible Condition CpG Islands Cross-Sectional Studies DNA Disease Doctor of Philosophy Early Diagnosis Environmental Risk Factor Epigenetic Process Esophageal Adenocarcinoma Evaluation Event Evolution Funding Genes Genetic Genome Genomic Instability Genomics Laboratories Learning Localized Longitudinal Studies Malignant Neoplasms Measures Methods Methylation Mitotic Recombination Molecular Abnormality Multicenter Studies Mutation Natural Selections Non-Steroidal Anti-Inflammatory Agents Numbers Outcome Patients Persons Ploidies Prevention Research Randomized Relative Risks Reporting Research Research Personnel Risk Role Sensitivity and Specificity Sorting - Cell Movement Staging Susceptibility Gene TP53 gene Testing Tetraploidy Training Translational Research Variant cancer prevention comparative genomic hybridization epigenomics follow-up genetic association genetic evolution improved innovation neoplastic novel programs prospective telomere time interval tumor progression user-friendly

项目摘要

In spite of abundant evidence from multiple laboratories that epigenetic and genetic develop during neoplastic evolution in Barrett's esophagus, relationships among genetic and epigenetic alterations are still poorly understood, in part because many studies investigate only one or the other and in part because few longitudinal studies have been performed. Project 1 will use novel and innovative methods to assess the evolution of clones with genetic and epigenetic alterations to determine the extent to which they predict neoplastic progression in a longitudinal cohort study of 614 patients with Barrett's esophagus (BE) with an anticipated 52,167 person-months of follow-up. We hypothesize that i) epigenetic abnormalities arise as early events in a limited number of CpG islands before widespread genomic instability; ii) early chromosomal instability in BE progression is characterized by localized regions of LOH and copy number change involving a relatively small number of genes (p16, p18INKc, PI3KR3) that in combination with early differential methylation of CpG islands in selected genes predispose to loss of TP53 and widespread chromosomal instability that develops as a late event in progression and iii) NSAID use modulates early evolution of genetic and epigenetic alternations in BE. Project 1will compare the sensitivity and specificity of a combined panel of epigenetic and genetic alterations to previously reported genetic (p16 LOH, TP53 LOH, tetraploidy, aneuploidy) and epigenetic (p16, RUNX3, HPP1) panels. Project 1 provides Project 2 with clonal genetic (LOH, copy number change and DNA content abnormalities) and epigenetic (differential methylation of CpG islands) biomarkers, as well as assessmentof clonal evolutionary dynamics to determine the genetic and epigenetic stages of progression that are most closely associated with host and environmental risk and protective factors. Project 1 also provides these measures to Project 3 to investigate the association of genetic instability biomakers (telomeres, fragile sites) with clonal evolution. Finally, Project 1 will develop clinically compatible DNA biomarker platforms for our validated markers so that they can be used in other centers and multicenter studies.

尽管来自多个实验室的大量证据表明表观遗传和遗传在巴雷特食管的肿瘤进化、遗传和表观遗传改变之间的关系仍然存在理解甚少，部分原因是许多研究只调查其中之一，部分原因是很少有研究已经进行了纵向研究。项目1将使用新颖和创新的方法来评估具有遗传和表观遗传改变的克隆的进化，以确定它们预测的程度一项针对 614 名 Barrett 食管 (BE) 患者的纵向队列研究中的肿瘤进展预计 52,167 人月的随访。我们假设 i) 表观遗传异常是由于在广泛的基因组不稳定之前，有限数量的 CpG 岛发生了早期事件； ii) 早期 BE 进展中的染色体不稳定性以 LOH 和拷贝数的局部区域为特征涉及相对较少数量的基因（p16、p18INKc、PI3KR3）的变化，与早期相结合选定基因中 CpG 岛的差异甲基化容易导致 TP53 丢失并广泛传播染色体不稳定，作为进展中的晚期事件而发展，并且 iii) NSAID 的使用在早期进行调节 BE遗传和表观遗传改变的进化。项目1将比较敏感性和特异性对先前报道的遗传（p16 LOH、TP53 LOH、四倍体、非整倍体）和表观遗传（p16、RUNX3、HPP1）组。项目 1 为项目 2 提供克隆遗传（LOH、拷贝数变化和 DNA 含量异常）和表观遗传（差异甲基化 CpG 岛）生物标志物，以及评估克隆进化动力学以确定遗传和与宿主和环境风险最密切相关的表观遗传进展阶段保护因素。项目 1 还向项目 3 提供这些措施来调查具有克隆进化的遗传不稳定性生物标记（端粒、脆弱位点）。最后，项目1将开发临床兼容的 DNA 生物标记物平台，用于我们经过验证的标记物，以便它们可用于其他中心和多中心研究。