The temporal epigenomic program of Barrett's neoplastic progression

巴雷特肿瘤进展的时间表观基因组程序

• 批准号: 7726344
• 负责人: Stephen J Meltzer
• 金额: $ 38.18万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7726344
• 关键词: Affect; Barrett Esophagus; Biochemical Pathway; Biological Markers; Biology; Candidate Disease Gene; Chronic; Colorectal Adenoma; Data; Databases; Development; E-Cadherin; Endoscopy; Enrollment; Esophageal Adenocarcinoma; Event; Evolution; Future; Gastroesophageal reflux disease; Gastrointestinal tract structure; General Population; Genes; Growth; Harvest; Human; Hypermethylation; Individual; Left; Lesion; Life; Malignant Neoplasms; Methylation; Modeling; Molecular Genetics; Ontology; Organ; Patients; Precancerous Conditions; Premalignant; Prevalence; Process; Reporting; Rest; Risk; Running; Staging; Surveillance Program; Syndrome; Tissues; Tumor Suppressor Genes; United States; base; clinically relevant; epigenomics; feeding; human disease; in vitro Model; insight; neoplastic; novel; programs; public health relevance; tumor progression

DESCRIPTION (provided by applicant): Barrett's esophagus (BE), a sequela of chronic gastroesophageal reflux disease (GERD), is a premalignant condition that increases an individual's chance of developing esophageal adenocarcinoma (EAC) by 30-125- fold. The precise prevalence of BE among patients with GERD is unknown but has been estimated at 1-10% of the general population (2). EAC is one of the most rapidly increasing cancers in the United States. Therefore, subjects with BE are enrolled in surveillance programs in which they undergo endoscopy at regular intervals for the rest of their lives. Due to frequent endoscopic surveillance, BE has become, by default, a de facto human model of early human preneoplastic events. Unlike colorectal adenomas, the premalignant lesions at the other end of the GI tract, the at-risk organ is left in place for repeat serial observations, often for 30 or 40 years. This BE model lends itself quite readily to molecular genetic studies in which "tissue is the issue." In human diseased tissue-based studies, there is no problem with clinical relevance, and one doesn't need to worry about being "led down the (proverbial) garden path" by the sometimes irrelevant findings (traps) that often crop up in nonhuman or in vitro models of human disease. Methylation has been reported in many human malignancies and premalignant syndromes, but was first reported in BE and EAC 11 years ago. Tumor suppressor genes affected by hypermethylation at various stages of BN include p16, p14, E-cadherin, APC, and others. However, these reports have all been candidate gene studies, based on "the usual suspects," typically focusing on "the tumor suppressor gene of the month." Our Preliminary Data suggest that an unbiased, epigenome-wide approach to this aspect of BN molecular genetics is likely to shift the paradigm in several ways: 1) the predominant epigenomic change in progression appears to be hypomethylation, rather than hypermethylation, implying the activation or unmasking of growth-stimulatory genes; 2) some genes change their methylation levels late during the run-up to progression, while others change earlier; this finding implies that by using arrays, we can a) for the future, find better early predictive biomarkers of progression; b) for the current project, dissect out the temporal epigenomic program of Barrett's neoplastic development. Hypothesis: The global methylation profile of Barrett's esophagus is in a constant state of flux and changes continuously as Barrett's evolves from early pre-progression, to later pre-progression, to LGD, to HGD, and finally to EAC. Changes that occur in this profile reflect changes in biology that cause or result from this process of preneoplastic and neoplastic evolution. By comprehensively "harvesting" genes that are epigenetically altered at different timepoints prior to and during progression, then feeding them into gene ontology programs and databases, we will gain novel insights into the cellular and biochemical pathways that become activated (or, in the case of hypermethylation, inactivated) as Barrett's pre-progression and its later neoplastic stages proceed. Public Health Relevance: Barrett's esophagus (BE), a sequela of chronic gastroesophageal reflux disease (GERD), is a premalignant condition that increases an individual's chance of developing esophageal adenocarcinoma (EAC) by 30-125- fold. The current proposal hypothesizes that the global methylation profile of Barrett's esophagus is in a constant state of flux and changes continuously as Barrett's evolves from early pre-progression, to later pre- progression, to LGD, to HGD, and finally to EAC, and changes that occur in this profile reflect changes in biology that cause or result from this process of preneoplastic and neoplastic evolution. By comprehensively "harvesting" genes that are epigenetically altered at different timepoints prior to and during progression, then feeding them into gene ontology programs and databases, we will gain novel insights into the cellular and biochemical pathways that become activated (or, in the case of hypermethylation, inactivated) as Barrett's pre- progression and its later neoplastic stages proceed.

描述（由申请人提供）：巴雷特食管 (BE) 是慢性胃食管反流病 (GERD) 的后遗症，是一种癌前病变，可使个体患食管腺癌 (EAC) 的机会增加 30-125 倍。 GERD 患者中 BE 的准确患病率尚不清楚，但估计占一般人群的 1-10% (2)。 EAC 是美国增长最快的癌症之一。因此，BE 受试者被纳入监测计划，在余生中定期接受内窥镜检查。由于频繁的内窥镜监测，BE 已默认成为早期人类肿瘤前事件的事实上的人类模型。与结肠直肠腺瘤（胃肠道另一端的癌前病变）不同，高危器官会被留在原处进行重复连续观察，通常持续 30 或 40 年。这种 BE 模型非常适合以“组织为问题”的分子遗传学研究。在基于人类患病组织的研究中，临床相关性不存在问题，并且无需担心被非人类中经常出现的有时不相关的发现（陷阱）“引向（众所周知的）花园小路”。或人类疾病的体外模型。甲基化已在许多人类恶性肿瘤和癌前综合征中被报道，但 11 年前首次在 BE 和 EAC 中报道。 BN 各个阶段受高甲基化影响的抑癌基因包括 p16、p14、E-cadherin、APC 等。然而，这些报告都是基于“常见嫌疑人”的候选基因研究，通常侧重于“本月的抑癌基因”。我们的初步数据表明，对 BN 分子遗传学这一方面采取公正的、全表观基因组的方法可能会在几个方面改变范式：1）进展中的主要表观基因组变化似乎是低甲基化，而不是高甲基化，这意味着激活或揭示生长刺激基因； 2）一些基因在进展后期改变其甲基化水平，而另一些基因则更早改变；这一发现意味着，通过使用芯片，我们可以a）在未来找到更好的进展早期预测生物标志物； b) 对于当前项目，剖析巴雷特肿瘤发展的时间表观基因组程序。假设：Barrett 食管的整体甲基化谱处于不断变化的状态，并且随着 Barrett 食管从早期进展前，到后期进展前，LGD，HGD，最后到 EAC 的演变，不断变化。该谱中发生的变化反映了由肿瘤前和肿瘤进化过程引起或导致的生物学变化。通过全面“收获”在进展之前和过程中不同时间点发生表观遗传改变的基因，然后将它们输入基因本体程序和数据库，我们将获得对被激活的细胞和生化途径的新见解（或者，在随着巴雷特的进展前期和后期肿瘤阶段的进行，高甲基化（失活）。公共卫生相关性：巴雷特食管 (BE) 是慢性胃食管反流病 (GERD) 的后遗症，是一种癌前病变，可使个体患食管腺癌 (EAC) 的几率增加 30-125 倍。目前的提议假设，Barrett 食管的整体甲基化谱处于不断变化的状态，并且随着 Barrett 食管从早期进展前、后期进展前、LGD、HGD、最后到 EAC 的演变而不断变化，并发生变化。该谱中发生的变化反映了肿瘤前和肿瘤进化过程引起或导致的生物学变化。通过全面“收获”在进展之前和过程中不同时间点发生表观遗传改变的基因，然后将它们输入基因本体程序和数据库，我们将获得对被激活的细胞和生化途径的新见解（或者，在随着 Barrett 的前期进展及其后期肿瘤阶段的进行，高甲基化（失活）。