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Project 2

Barrett's Esophagus Translational Research Network (BETRNet)

Project 2: The Biology and Translation of Epigenetic Alterations in Barrett’s Esophagus

Principal Investigator: William M. Grady, MD
Co-Investigator: Andrew M. Kaz, MD
Biostatisticians: Jill S. Barnholtz-Sloan, PhD and Chao-Jen Wong, PhD

The development and progression of esophageal adenocarcinoma (EAC) is a multi-step process that involves the progression of Barrett's 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.

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 high throughput, 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. In Phase 2, 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. Finally, 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).

Specific Aims

Aim 1: To characterize the genome wide methylation status of BE, BE+LGD, BE+HGD, and EAC and to correlate the methylation status with clinicopathological features of the patients.

Aim 1A: To determine the genome wide methylation status of BE, BE+LGD, BE+HGD, and EAC.

Aim 1B: To identify methylated genes that are more commonly methylated in BE+HGD and EAC compared to BE and that have potential to be predictive markers for BE progression to EAC.

Aim 1C: To determine whether a high and low level molecular subclass of BE and/or EAC exists and, if so, to correlate the methylator status with clinicopathological features of the cases.

Aim 2: To determine the methylome of familial vs. sporadic BE and EAC cases and determine if familial cases differ from sporadic cases based on the methylation status of the BE and EAC.

Aim 3: To determine whether methylated genes can be used as detection molecular markers for the identification of people with BE using Cytosponge esophageal brushings.

Aim 4: To determine if methylated genes can be used for the prediction of recurrent BE in Barrett's esophagus patients after RFA.