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: 8495325
• 负责人: Stephen J Meltzer
• 金额: $ 34.9万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495325
• 关键词: Ablation; Affect; Aneuploidy; Anxiety; Attention; Barrett Esophagus; Biochemical Pathway; Biological Markers; Biology; Candidate Disease Gene; Chronic; Clinical; Colorectal Adenoma; Correlative Study; DNA Methylation; DNA copy number; Data; Databases; Detection; Development; Dysplasia; E-Cadherin; Endoscopes; Endoscopy; Enrollment; Esophageal Adenocarcinoma; Esophagectomy; Event; Evolution; Frequencies; Future; Gastroesophageal reflux disease; Gastrointestinal tract structure; Gene Mutation; General Population; Genes; Genetic; Genomics; Growth; Harvest; Histologic; Human; Hypermethylation; Incidence; Individual; Interobserver Variability; Left; Lesion; Light; Literature; Malignant Neoplasms; Methylation; Microscope; Modeling; Molecular; Molecular Genetics; Ontology; Operative Surgical Procedures; Organ; Patients; Photochemotherapy; Play; Point Mutation; Precancerous Conditions; Predictive Value; Premalignant; Premalignant Change; Prevalence; Procedures; Process; Promoter Regions; Proto-Oncogenes; Reporting; Reproducibility; Rest; Risk; Risk Assessment; Role; Running; Specimen; Staging; Surveillance Program; Syndrome; System; Tissues; Tumor Suppressor Genes; United States; base; cancer risk; clinical risk; clinically relevant; epigenetic marker; epigenome; epigenomics; feeding; high risk; human disease; improved; in vitro Model; in vivo Model; insight; interest; mortality; neoplastic; novel; programs; public health relevance; success; tool; 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.

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，可使个体发生食管腺癌（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，但估计为一般人群的1-10%（2）。EAC是美国增长最快的癌症之一。因此，BE受试者入组监测项目，在其余生中定期接受内镜检查。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。与位于胃肠道另一端的癌前病变结肠直肠腺瘤不同，高危器官被留在原位进行重复的系列观察，通常持续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。在基于人类患病组织的研究中，临床相关性没有问题，人们不需要担心被“沿着（谚语中的）花园小径”引导，有时不相关的发现（陷阱）经常出现在非人类或人类疾病的体外模型中。甲基化已在许多人类恶性肿瘤和癌前综合征中报道，但11年前首次在BE和EAC中报道。在BN的各个阶段受超甲基化影响的肿瘤抑制基因包括p16、p14、E-钙粘蛋白、APC等。然而，这些报告都是候选基因的研究，基于“通常的怀疑”，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BN分子遗传学这一方面的无偏见的表观基因组方法可能会以几种方式改变范式：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，这意味着生长刺激基因的激活或暴露; 2）一些基因在进展的后期改变其甲基化水平，而另一些则在早期改变;这一发现意味着通过使用阵列，我们可以a）为未来找到更好的进展早期预测生物标志物; 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动状态，并且随着Barrett从早期进展前到后期进展前、到LGD、到HGD、最后到EAC的演变而不断变化。发生在此配置文件中的变化反映了生物学的变化，这些变化是由肿瘤前和肿瘤演变过程引起或导致的。通过全面“收获”在进展前和进展期间的不同时间点发生表观遗传学改变的基因，然后将其输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的预进展及其后期肿瘤阶段的进行而被激活（或者在超甲基化的情况下，失活）。

项目成果

MicroRNA involvement in esophageal carcinogenesis.

• DOI: 10.1016/j.coph.2011.09.006
• 发表时间: 2011-12
• 期刊: CURRENT OPINION IN PHARMACOLOGY
• 影响因子: 4
• 作者: David, Stefan;Meltzer, Stephen J.
• 通讯作者: Meltzer, Stephen J.

Inhibition of the miR-192/215-Rab11-FIP2 axis suppresses human gastric cancer progression.

抑制 miR-192/215-Rab11-FIP2 轴可抑制人胃癌进展

• DOI: 10.1038/s41419-018-0785-5
• 发表时间: 2018-07-13
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Zhang X;Peng Y;Huang Y;Deng S;Feng X;Hou G;Lin H;Wang J;Yan R;Zhao Y;Fan X;Meltzer SJ;Li S;Jin Z
• 通讯作者: Jin Z

Endoglin promoter hypermethylation identifies a field defect in human primary esophageal cancer.

内皮糖蛋白启动子高甲基化鉴定了人类原发性食管癌的场缺陷

• DOI: 10.1002/cncr.28276
• 发表时间: 2013-10-15
• 期刊: CANCER
• 影响因子: 6.2
• 作者: Jin, Zhe;Zhao, Zhenfu;Cheng, Yulan;Dong, Ming;Zhang, Xiaojing;Wang, Liang;Fan, Xinmin;Feng, Xianling;Mori, Yuriko;Meltzer, Stephen J.
• 通讯作者: Meltzer, Stephen J.

Long non-coding RNA HNF1A-AS1 regulates proliferation and migration in oesophageal adenocarcinoma cells.

• DOI: 10.1136/gutjnl-2013-305266
• 发表时间: 2014-06
• 期刊: Gut
• 影响因子: 24.5
• 作者: Yang X;Song JH;Cheng Y;Wu W;Bhagat T;Yu Y;Abraham JM;Ibrahim S;Ravich W;Roland BC;Khashab M;Singh VK;Shin EJ;Yang X;Verma AK;Meltzer SJ;Mori Y
• 通讯作者: Mori Y

Integrated miRNA profiling and bioinformatics analyses reveal potential causative miRNAs in gastric adenocarcinoma.

综合 miRNA 分析和生物信息学分析揭示了胃腺癌中潜在的致病 miRNA

• DOI: 10.18632/oncotarget.5419
• 发表时间: 2015-10-20
• 期刊: Oncotarget
• 作者: Zhang X;Peng Y;Jin Z;Huang W;Cheng Y;Liu Y;Feng X;Yang M;Huang Y;Zhao Z;Wang L;Wei Y;Fan X;Zheng D;Meltzer SJ
• 通讯作者: Meltzer SJ