PROJECT SUMMARY The goal of this BDL proposal is the discovery and validation of biomarkers for reducing mortality from gastrointestinal cancers. We focus on colorectal cancer (CRC), the second leading cause of cancer deaths in the U.S., and on esophageal adenocarcinoma (EAC), which is increasing rapidly and has an 83% mortality rate. For CRC, we propose to develop biomarkers to accurately identify individuals at high risk for CRC, who benefit from aggressive screening programs. We will conduct EDRN phase 1 and 2 studies to discover and validate a class of methylated DNA based molecular markers found in the normal colon mucosa, which our prior studies have implicated as identifying individuals at increased CRC risk. For EACs, we propose to identify biomarkers that will accurately detect high grade dysplasia (HGD) and early EAC in esophageal cytology samples, which can be obtained with a non-endoscopic device and can be used in a cost-effective BE surveillance program. Thirdly, we will conduct EDRN Phase 1 and 2 studies to discover and validate biomarkers that predict the risk of BE progressing to HGD or early EAC. Our overall vision is to develop accurate biomarker-based tests of esophageal samples that ultimately can be used to predict the risk for HGD and EAC and to detect early HGD and EAC to achieve cost-effective effective BE surveillance using non-endoscopic esophageal cytology samples. We base these Phase 1 and 2 studies on our identification of novel methylated DNA biomarkers that highly discriminate many early EAC and HGD from BE as well on our identification of candidate methylated DNA markers and genetic markers that associate with BE progression to HGD or EAC. We will develop an optimal panel of methylated DNA markers for detecting HGD and early EAC. For the risk marker studies, we will develop a panel of methylated DNA markers and genetic markers for predicting the risk of BE progressing to HGD or EAC. The specific aims of this proposal accordingly are: Aim 1. To assess in EDRN phase 1/2 studies, the sensitivity and specificity of a set of candidate biomarkers whose detection in the normal colon mucosa identifies individuals at increased risk of developing advanced adenoma or CRC. Aim 2. To assess in EDRN phase 1/2 studies the sensitivity and specificity of a set of candidate DNA methylation biomarkers, aneuploidy markers, and copy number alteration (CNA) markers for identifying Barrett’s esophagus that is at risk for progressing to HGD or EAC Aim 3. To develop in EDRN phase 1/2 studies a set of candidate biomarkers for detecting early EAC and HGD as well as “high-risk” low grade dysplasia (LGD) in esophageal cytology samples.