Genomics and Mechanisms of Esophageal Carcinogenesis

1巴雷特食管（BE）影响美国约330万成年人1。一小部分患者 2 BE可从肠上皮化生（BIM-P）依次进展为低度异型增生（LGD）、高度异型增生（LGD）和高度异型增生（LGD）。 3例异型增生（HGD）和食管腺癌（EAC）。EAC的发病率增加超过5- 在过去的40年里，美国的4倍2。无发育不良的BIM患者的 5 EAC风险高于高度异型增生者。为了有效的医疗保健，分子标记的识别 6预测BIM向HGD/EAC的进展是非常可取的，因为BIM-P可以被监控和积极地 7例接受治疗以抑制进展为EAC。我们的实验室和其他人已经确定了基因组的改变， 8驱动HGD/EAC发展，包括点突变6和拷贝数变化。我们发现频繁（50%） 9例BIM-P中含有CDKN 2A/p16的染色体9 p区域丢失，但在非进展者中未丢失。失活 CDKN 2A/p16甲基化是BE进展为HGD/EAC 7 -9的常见事件。分子 监测活检的基因组/表观基因组检测可以识别候选的高风险BIM患者， HGD/EAC的监测和化学预防。我们提出了一种脱甲基剂的组合， 13逆转p16和其他可能导致肿瘤进展的基因中的CpG甲基化， 14炎性药物，已显示减少HGD/EAC发展13 14。我们的假设是 CDKN 2A基因产物p16是决定大量这些患者疾病进展的关键。 16例BE患者发生异型增生/EAC，检测到CDKN 2A/p16改变和/或 CDKN 2A/p16失活导致的17种分子基因组、表观遗传和表达改变 18可用于指导早期治疗干预以预防EAC发展。我们会解决这个问题 19假设在三个具体目标。目的1：表征导致的全局转录组学改变 20来自CDKN 2A/p16基因组和表观遗传失活，导致衰老逃避并增加 21例增殖，在进展为HGD/EAC的BE患者中。这些改动将允许识别 22个分子通路，潜在的新治疗靶点和高危BIM患者的生物标志物， 23个候选干预治疗（如去甲基和抗炎药物），以防止HGD/EAC。 目的2：研究CDKN 2A/p16在食管异型增生和腺癌发展中的作用， 25食管Barrett样化生进展为HGD/EAC的小鼠模型中的进展。目标3： 26研究去甲基化和抗炎药物在活性和非活性背景下的作用 27 CDKN 2A/p16，在建立的小鼠食管异型增生和腺癌的发展中 28个模特描述CDKN 2A/p16导致的全面转录组学改变 29灭活，在具有BE样病变的小鼠中，在治疗的作用下与没有治疗相比进展为HGD/EAC。 将转录组小鼠数据与目标1中测试的人组织数据进行比较。

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.