The temporal epigenomic program of Barrett's neoplastic progression

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，是一种恶性前病变，使个体发展为食管腺癌（EAC）的机会增加30-125倍。GERD患者中BE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，BE患者被纳入监测项目，在他们的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。不像结直肠腺瘤（胃肠道另一端的癌前病变），有危险的器官被留在原位进行重复的连续观察，通常为30或40年。这种BE模型很容易适用于“组织是问题”的分子遗传学研究。在基于人类病变组织的研究中，不存在临床相关性的问题，人们不必担心在非人类或体外人类疾病模型中经常出现的有时不相关的发现（陷阱）会“引导到（众所周知的）花园小径上”。甲基化在许多人类恶性肿瘤和癌前综合征中都有报道，但首次报道是在11年前的BE和EAC中。在BN的各个阶段受高甲基化影响的肿瘤抑制基因包括p16、p14、E-cadherin、APC等。然而，这些报告都是候选基因研究，基于“通常的怀疑”，通常关注“当月的肿瘤抑制基因”。我们的初步数据表明，对BN分子遗传学这方面的无偏见的、全表观基因组的方法可能会在几个方面改变范式：1)在进展过程中主要的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了生长刺激基因；2)一些基因的甲基化水平改变较晚，而另一些基因的甲基化水平改变较早；这一发现意味着，通过使用阵列，我们可以a)为未来找到更好的早期预测进展的生物标志物；b)对于当前项目，剖析Barrett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恒定的流变状态，并随着Barrett从早期进展前期、晚期进展前期、LGD、HGD、最后到EAC的演变而不断变化。发生在这一侧面的变化反映了生物学上的变化，这些变化是由肿瘤前和肿瘤进化过程引起或导致的。通过全面“收集”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，我们将获得关于细胞和生化途径的新见解，这些途径在Barrett的前期进展和后期肿瘤阶段进行时被激活（或者，在超甲基化的情况下，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.