Genomics and Mechanisms of Esophageal Carcinogenesis

1巴雷特食道(BE)影响美国约330万成年人1。一小部分患有 从肠化生(BIM-P)到低度异型增生(LGD)、高度异型增生(LGD)、 3异型增生(HGD)和食管腺癌(EAC)。EAC的发病率增加了超过5- 在过去的40年里，4倍于美国2。无不典型增生的BIM患者的 5高级别异型增生的EAC危险性高于重度异型增生。为了有效的医疗保健，分子标记的鉴定 6预测BIM向HGD/EAC的进展是非常可取的，因为BIM-P可能被监测并积极 7接受治疗以抑制进展为EAC。我们的实验室和其他实验室已经发现了可能 8驱动HGD/EAC的发生，包括点突变6和拷贝数变化。我们发现频繁(50%) 9在BIM-P中含有CDKN2A/p16的染色体9p区丢失，而在非进展者中未发现。停用 10CDKN2A/p16甲基化是BE向HGD/EAC7-9转化过程中频繁发生的事件。分子 监测活检的11个基因组/表观基因组检测可确定CLOSE的候选高危BIM患者 12 HGD/EAC监测和化学预防。我们提出了一种脱甲基剂的组合来 13逆转p16和其他可能导致肿瘤进展的基因的CpG甲基化 14炎症性药物，已被证明可以减少HGD/EAC的发展13 14.我们的假设是 15 cdkn2a基因产物p16是决定其中大量患者疾病进展的关键。 16是发生异型增生/EAC和检测CDKN2A/p16改变和/或 CDKN2A/p16失活导致的17个分子基因组、表观遗传学和表达变化 18可用于指导早期治疗干预，以防止EAC的发展。我们将解决这一问题 三个具体目标中的19个假设。目标1：描述导致全球转录水平改变的特征 20来自CDKN2A/p16基因组和表观遗传学失活，导致逃避衰老和增加 21在进展为HGD/EAC的BE患者中，增殖。这些改动将允许识别 22个高危BIM患者的分子途径、潜在的新治疗靶点和生物标志物，他们是 23个候选介入治疗(如去甲基化和抗炎药物)以预防HGD/EAC。 24目的2：探讨CDKN2A/p16在食管异型增生和腺癌发生发展中的作用 25小鼠食道Barrett样化生模型进展为HGD/EAC。目标3：实现 26调查去甲基化和抗炎药物在活性和非活性背景下的作用 27 CDKN2A/p16在已建立的小鼠食道异型增生和腺癌发生发展中的作用 28个型号。鉴定CDKN2A/p16导致的全面转录改变 29在有BE样病变的小鼠中，在治疗和不治疗的影响下进展为HGD/EAC。 30只转录小鼠的数据将与在目标1中测试的人类组织的数据进行比较。

1 Barrett's esophagus (BE) affects about 3.3 million adults in the United States1. A small subset of patients with 2 BE may sequentially progress from intestinal metaplasia (BIM-P) to low-grade dysplasia (LGD), high-grade 3 dysplasia (HGD) and esophageal adenocarcinoma (EAC). The incidence of EAC has increased greater than 5- 4 fold over the past 4 decades in the United States2. Patients with BIM without dysplasia have a much lower 5 EAC risk than those with high-grade dysplasia. For effective health care, identification of molecular markers 6 that predict progression of BIM to HGD/EAC is highly desirable, as BIM-P may be monitored and aggressively 7 treated to inhibit progression to EAC. Our laboratory and others have identified genomic alterations that may 8 drive HGD/EAC development, including point mutations 6 and copy number changes. We found frequent (50%) 9 losses in chromosome 9p areas containing CDKN2A/p16 in BIM-P but not in non-progressors. Inactivation of 10 CDKN2A/p16 by methylation is a frequent event in BE progression to HGD/EAC7-9. Molecular 11 genomic/epigenomic testing of surveillance biopsies may identify candidate high-risk BIM patients for closer 12 surveillance and chemoprevention of HGD/EAC. We propose a combination of demethylating agents to 13 reverse CpG methylation in p16 and other genes that may contribute to neoplastic progression with anti- 14 inflammatory drugs, which have been shown to reduce HGD/EAC development 13 14. Our hypothesis is that 15 the CDKN2A gene product p16 is key in determining disease progression in a large number of those 16 BE patients who develop dysplasia/EAC and that detection of CDKN2A/p16 alterations and/or 17 molecular genomic, epigenetic and expression alterations that result from CDKN2A/p16 inactivation 18 may be used to direct early therapeutic intervention to prevent EAC development. We will address this 19 hypothesis in three specific aims. Aim 1: To characterize the global transcriptomic alterations that result 20 from CDKN2A/p16 genomic and epigenetic inactivation, leading to evasion from senescence and increased 21 proliferation, in patients with BE who progress to HGD/EAC. These alterations will permit the identification of 22 molecular pathways, potential novel treatment targets and biomarkers of high-risk BIM patients, who are 23 candidates for intervention therapy (such as demethylating and anti-inflammatory drugs) to prevent HGD/EAC. 24 Aim 2: To investigate the role of CDKN2A/p16 in esophageal dysplasia and adenocarcinoma development and 25 progression in mouse models of esophageal Barrett's-like metaplasia progressing to HGD/EAC. Aim 3: To 26 investigate the effect of demethylating and anti-inflammatory drugs in the context of active and inactive 27 CDKN2A/p16, in the development of esophageal dysplasia and adenocarcinoma in the established mouse 28 models. To characterize the comprehensive transcriptomic alterations that result from CDKN2A/p16 29 inactivation, in mice with BE-like lesions that progress to HGD/EAC under effect of treatment vs. no treatment. 30 Transcriptomic mouse data will be compared with data from human tissues tested in aim 1.