The temporal epigenomic program of Barrett's neoplastic progression

描述(申请人提供)：巴雷特食道(BE)是慢性胃食道反流病(GERD)的后遗症，是一种癌前疾病，可使个人患食管腺癌(EAC)的几率增加30-125倍。BE在GERD患者中的确切患病率尚不清楚，但估计占总人口的1-10%(2)。EAC是美国增长最快的癌症之一。因此，患有BE的受试者被登记参加监测计划，在该计划中，他们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癌前事件的事实上的人类模型。与结直肠腺瘤不同，结直肠腺瘤是胃肠道另一端的癌前病变，高危器官被留在原地重复连续观察，通常是30或40年。这种BE模型非常适合分子遗传学研究，在分子遗传学研究中，“组织是问题”。在基于人类疾病的组织研究中，临床相关性是没有问题的，人们也不需要担心被有时在非人类或人类疾病体外模型中突然出现的无关发现(陷阱)引导到(众所周知的)花园小路上。甲基化在许多人类恶性肿瘤和癌前综合征中已有报道，但11年前在BE和EAC首次报道。在BN的不同阶段受高甲基化影响的抑癌基因包括p16、p14、E-钙粘素、APC等。然而，这些报告都是候选基因研究，基于“常见的怀疑”，通常集中在“本月的肿瘤抑制基因”上。我们的初步数据表明，对于BN分子遗传学的这一方面，一种无偏见的、表观基因组范围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，意味着生长刺激基因的激活或揭开；2)一些基因在进展的准备阶段后期改变其甲基化水平，而其他基因变化更早；这一发现意味着，通过使用阵列，我们可以a)在未来找到更好的早期预测进展的生物标志物；b)对于当前的项目，剖析Barrett肿瘤发展的临时表观基因组计划。假设：Barrett‘s食道的甲基化状态是恒定的，并且随着Barrett’s的早期进展前期、后期进展前期、LGD阶段、HGD阶段、最后EAC阶段的演变，甲基化水平持续变化。在这个轮廓中发生的变化反映了生物学上的变化，这些变化引起或导致了癌前病变和肿瘤的进化过程。通过全面“采集”在进展前和进展过程中的不同时间点发生表观遗传改变的基因，然后将它们送入基因本体论程序和数据库，我们将获得对细胞和生化途径的新见解，这些途径随着巴雷特进展前期及其后期肿瘤的进行而变得激活(或在超甲基化的情况下，变得失活)。

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.