PROJECT SUMMARY: Intestinalization of the esophagus, termed Barrett’s esophagus (BE), is thought to develop in response to chronic acid and bile reflux and carries great clinical significance because it is the precursor to esophageal adenocarcinoma (EAC). The incidence of BE is quite high, estimated to be found in at least 1:100 people. While relatively few with BE progress to cancer there is great importance to being able to detect and treat those at risk of progression as EAC is an aggressive cancer with potential for early spread. Efforts to screen for high-risk disease in those with BE have, to date, not been very successful. Therefore, there is profound need to define the process by which BE progresses into EAC, to develop biomarkers to diagnose early progression and assess progression risk in BE tissues as well as to develop novel therapies for treatment. The objective of this R01 proposal is to investigate the ability of biomarkers to identify BE patients at high risk of progression. Using results from two externally funded genomic studies in non-dysplastic BE (NDBE) and BE with low-grade dysplasia (LGD) and previously published results, we will compare biomarkers and determine an optimized combination for risk stratification in two prospective cohorts including patients with NDBE or LGD. We will then validate our risk stratification assay in an independent US cohort. Finally, we will compare our genomic biomarker panel results in paired biopsy and brush samples. A unique collaboration between the PI Dr. Stachler, expert gastroenterologist (Dr. J Bergman), a talented computational biologist (Dr. CZ Zhang), and an expert biostatistician (Dr. K Zwinderman) along with key collaborators allows a truly innovated study to be performed. This will be accomplished using an unprecedented collection of clinically derived samples, a highly optimized targeted sequencing panel, and novel computational approaches that allow a wide array of information to be determined in a cost effective, clinically relevant manor. Aim 1: Identify a set of genomic biomarkers highly predictive of progression in biopsies from a prospective cohort of patients diagnosed with NDBE and LGD and assess whether the addition of methylation-based biomarkers improves stratification. For clinical implementation all biomarkers should be compared head to head in order to determine an optimized combination of biomarkers for risk stratification. Aim 2: Validate the risk stratification assay in a multi-institutional cohort of patients with a baseline diagnosis of NDBE or LGD. For clinical implementation, it is vital to validate any risk stratification assay on completely independent cohorts looking at clinically relevant time points. Aim 3: Determine if brush-based sampling devices improve biomarker detection over standard endoscopic biopsies. Broad sampling of the BE epithelium may allow for increased rates of detection for genomic or methylation biomarkers, therefore we will determine if samples from a brushed based device can better risk stratify patients compared to standard biopsies.

PROJECT NARRATIVE While millions of Americans harbor the pre-cancerous lesion, Barrett’s esophagus, putting them at elevated risk of esophageal cancer, many will not develop cancer and this progression is poorly understood. This proposed research will determine important contributors to progression and identify how they can be used to predict progression risk.