The development and progression of esophageal adenocarcinoma (EAC) is a multi-step process that involves the progression of Barretts esophagus (BE) to low-grade dysplasia (LGD), highgrade- dysplasia (HGD) and then EAC. This sequence results from the accumulation of genetic and epigenetic alterations in esophageal epithelial cells. The aberrant methylation of 5'gene promoter associated CpG islands, which can silence the expression of tumor suppressor genes, is the major epigenetic alteration in EAC that has been recognized to date, and begins at the pre-cancer phase of EAC formation. Notably, the DNA methylation events are also intimately associated with environmental exposures such as folate, tobacco, etc. (1, 2) The identification of genetic and epigenetic alterations has led to the largely still unrealized hope that these molecular events can be used for the prevention or early detection of BE and/or EAC. We propose that this unrealized potential is primarily a consequence of the lack of sufficiently complex analysis of the molecular alterations in most studies of BE and EAC, which has resulted in the lack of discovery of markers that could be effective biomarkers. In addition, a large well-annotated cohort of BE and EAC patients that has sufficient power to identify prognostic and predictive molecular markers has been difficult to assemble, but is critical to the success of these studies. Recently, reliable highthroughput, genome wide methylation assays have become available, making the genome-wide assessment of methylated genes in BE and EAC feasible. By virtue of the nature of genes affected by epigenetic alterations, it is likely that the comprehensive methylation profiles generated by such new technology will be useful for determining prognosis, for predicting the response to treatment, and for assessing the effect of environmental factors on the molecular pathogenesis of BE and EAC. The project will be conducted in a two-phase process with Phase 1 involving the use of HumanMethylation450 arrays, a comprehensive review of the published literature, and results from methylation array studies previously carried out in our lab. We will examine both novel and known methylated genes to ultimately determine a panel of promising methylated genes that will function as BE or EAC biomarkers and assess if these methylated genes are involved in the molecular pathogenesis of familial vs. sporadic BE as well as in the recurrence of BE after ablation therapy (Aims 1, 2 and 4). In Phase 2 (Aim 3), these results will be used to develop a focused and rational panel of methylated genes that serve as accurate biomarkers for BE. These results will subsequently be translated into esophageal brushing-based diagnostic and/or predictive BE biomarkers (Aim 3). Finally, in Aim 4, we will also determine whether methylated genes can be used to identify individuals at risk for recurrence of BE from neosquamous epithelium after radiofrequency ablation (RFA).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA163060-03
Application #
8567050
Study Section
Special Emphasis Panel (ZCA1-SRLB-1)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$252,605
Indirect Cost
$68,776
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Fecteau, Ryan E; Kong, Jianping; Kresak, Adam et al. (2016) Association Between Germline Mutation in VSIG10L and Familial Barrett Neoplasia. JAMA Oncol 2:1333-1339
Sun, Xiangqing; Elston, Robert C; Barnholtz-Sloan, Jill S et al. (2016) Predicting Barrett's Esophagus in Families: An Esophagus Translational Research Network (BETRNet) Model Fitting Clinical Data to a Familial Paradigm. Cancer Epidemiol Biomarkers Prev 25:727-35
Sun, Xiangqing; Elston, Robert; Falk, Gary W et al. (2016) Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas. Mol Genet Genomic Med 4:407-19
Curtius, Kit; Wong, Chao-Jen; Hazelton, William D et al. (2016) A Molecular Clock Infers Heterogeneous Tissue Age Among Patients with Barrett's Esophagus. PLoS Comput Biol 12:e1004919
Kaz, Andrew M; Wong, Chao-Jen; Varadan, Vinay et al. (2016) Global DNA methylation patterns in Barrett's esophagus, dysplastic Barrett's, and esophageal adenocarcinoma are associated with BMI, gender, and tobacco use. Clin Epigenetics 8:111
Blum, Andrew E; Venkitachalam, Srividya; Guo, Yan et al. (2016) RNA Sequencing Identifies Transcriptionally Viable Gene Fusions in Esophageal Adenocarcinomas. Cancer Res 76:5628-5633
Krishnamoorthi, Rajesh; Borah, Bijan; Heien, Herbert et al. (2016) Rates and predictors of progression to esophageal carcinoma in a large population-based Barrett's esophagus cohort. Gastrointest Endosc 84:40-46.e7
Fiuza-Luces, C; Simpson, R J; Ramírez, M et al. (2016) Physical function and quality of life in patients with chronic GvHD: a summary of preclinical and clinical studies and a call for exercise intervention trials in patients. Bone Marrow Transplant 51:13-26
Cummings, Linda C; Kou, Tzuyung Doug; Schluchter, Mark D et al. (2016) Outcomes after endoscopic versus surgical therapy for early esophageal cancers in an older population. Gastrointest Endosc 84:232-240.e1
Kong, Jianping; Whelan, Kelly A; Laczkó, Dorottya et al. (2016) Autophagy levels are elevated in barrett's esophagus and promote cell survival from acid and oxidative stress. Mol Carcinog 55:1526-1541

Showing the most recent 10 out of 52 publications