CLONAL EVOLUTION

克隆进化

• 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
• 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

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观遗传和遗传在期间发展 巴雷特食管中的肿瘤进化，遗传和表观遗传改变之间的关系仍然是 理解不佳，部分原因是许多研究仅研究一个或另一个研究，部分原因是很少 已经进行了纵向研究。项目1将使用新颖和创新的方法评估 具有遗传和表观遗传学改变的克隆的演变，以确定他们预测的程度 在614例巴雷特食管（BE）患者的纵向队列研究中，肿瘤进展 预计有52,167个人月的随访。我们假设i）表观遗传异常出现为 在广泛的基因组不稳定性之前，有限数量的CPG岛中的早期事件； ii）早期 BE进展中的染色体不稳定性的特征是LOH的局部区域和拷贝数 变化涉及相对少量的基因（p16，p18inkc，pi3kr3），这些基因与早期结合 选定基因中CpG岛的差异甲基化倾向于损失TP53和广泛 染色体不稳定性在进展和iii中发展为较晚事件，而NSAID的使用提前调节 BE中遗传和表观遗传替代的演变。项目1将比较 对先前报道的遗传学的表观遗传学和遗传改变的组合（p16 LOH，TP53 LOH， 四倍体，非倍型）和表观遗传学（p16，runx3，hpp1）面板。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）和表观遗传学（差甲基化 CPG岛）生物标志物以及克隆进化动力学的评估以确定遗传 与宿主和环境风险最密切相关的进展的表观遗传阶段 保护因素。项目1还提供了项目3的这些措施，以调查 具有克隆进化的遗传不稳定生物制造商（端粒，脆弱位点）。最后，项目1将发展 临床上兼容的DNA生物标志物平台，用于我们经过验证的标记，以便在其他 中心和多中心研究。