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. Public Health Relevance: 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 current proposal hypothesizes that 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, and 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.

Public Health Relevance

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 current proposal hypothesizes that 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, and 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK087454-05
Application #
8495325
Study Section
Special Emphasis Panel (ZRG1-GGG-M (53))
Program Officer
Hamilton, Frank A
Project Start
2009-09-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$348,999
Indirect Cost
$136,195
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Yang, Xue; Song, Jee Hoon; Cheng, Yulan et al. (2014) Long non-coding RNA HNF1A-AS1 regulates proliferation and migration in oesophageal adenocarcinoma cells. Gut 63:881-90
Joseph, Christine G; Hwang, Heejung; Jiao, Yuchen et al. (2014) Exomic analysis of myxoid liposarcomas, synovial sarcomas, and osteosarcomas. Genes Chromosomes Cancer 53:15-24
Jin, Zhe; Wang, Liang; Zhang, Yuan et al. (2013) MAL hypermethylation is a tissue-specific event that correlates with MAL mRNA expression in esophageal carcinoma. Sci Rep 3:2838
Jin, Zhe; Zhao, Zhenfu; Cheng, Yulan et al. (2013) Endoglin promoter hypermethylation identifies a field defect in human primary esophageal cancer. Cancer 119:3604-9
Wang, Li-Dong; Bi, Xiuli; Song, Xin et al. (2013) A sequence variant in the phospholipase C epsilon C2 domain is associated with esophageal carcinoma and esophagitis. Mol Carcinog 52 Suppl 1:E80-6
Jin, Zhe; Feng, Xianling; Jian, Qianhe et al. (2013) Aberrant methylation of the Ras-related associated with diabetes gene in human primary esophageal cancer. Anticancer Res 33:5199-203
Merchant, Nipun B; Dutta, Sudhir K; Girotra, Mohit et al. (2013) Evidence for enhanced telomerase activity in Barrett's esophagus with dysplasia and adenocarcinoma. Asian Pac J Cancer Prev 14:679-83
Wu, Wenjing; Bhagat, Tushar D; Yang, Xue et al. (2013) Hypomethylation of noncoding DNA regions and overexpression of the long noncoding RNA, AFAP1-AS1, in Barrett's esophagus and esophageal adenocarcinoma. Gastroenterology 144:956-966.e4
Vega, Kenneth J; May, Randal; Sureban, Sripathi M et al. (2012) Identification of the putative intestinal stem cell marker doublecortin and CaM kinase-like-1 in Barrett's esophagus and esophageal adenocarcinoma. J Gastroenterol Hepatol 27:773-80
You, Yan-Jie; Chen, Yu-Ping; Zheng, Xiao-Xuan et al. (2012) Aberrant methylation of the PTPRO gene in peripheral blood as a potential biomarker in esophageal squamous cell carcinoma patients. Cancer Lett 315:138-44

Showing the most recent 10 out of 14 publications