Project Summary Gastrointestinal (GI) cancers are a major cause of mortality and morbidity in the U.S. and their treatment uses a substantial proportion of healthcare resources. Of the GI cancers, colorectal cancer (CRC) and esophageal cancer (EAC) account for a majority of the cancer related deaths, and both are preventable by screening and surveillance. The current screening tests are suboptimal and have variable success. A major goal of CRC screening tests is to identify advanced tubular and serrated adenomas, which are high-risk for becoming CRC, as well as early stage CRC. The risk for CRC is variable with some people being at high risk because of family histories of CRC, hereditary cancer syndromes, or a personal history of adenomas. High risk people are placed on aggressive colonoscopy based surveillance programs and low-risk people are placed on minimal surveillance programs. Unfortunately, our current system for identifying high and low CRC risk is suboptimal resulting in under and over surveillance and preventable interval CRCs. Better risk markers for CRC to are needed to prevent interval CRCs and improve the overall effectiveness of CRC screening. Analogous to CRC, EAC arises from a precancerous condition of the esophagus called Barretts esophagus (BE), which is a specialized intestinal metaplasia of the esophagus and the highest risk factor for EAC. It is present in 5% of the US population. BE progresses to EAC through successive histologic steps of low grade dysplasia (LGD), high grade dysplasia (HGD) and then EAC. Screening and surveillance for BE is recommended using serial upper endoscopy, which is controversial in its effectiveness for preventing deaths from EAC. This is in part because, as with CRC, BE patients have variable risk of EAC and are placed on high- risk and low-risk screening programs. However, the current system for assigning risk is not accurate and the current screening test is expensive. More cost effective and accurate EAC and HGD screening/surveillance assays and accurate BE risk biomarkers are needed. We propose to develop an EDRN BCC that is integrated into the EDRN consortium and, through collaborations within and outside the EDRN, will develop effective GI cancer screening biomarkers. We propose to identify, validate, and develop accurate CLIA compliant risk biomarkers for CRC and for EAC in order to prevent EAC and CRC missed under current screening protocols. Moreover, the accurate risk stratification of patients for CRC and EAC will reduce the financial impact of current CRC and EAC prevention programs. We also propose to identify and validate accurate CLIA compliant early detection markers for HGD and early stage EAC that can be used in an inexpensive, non-endoscopic surveillance test.

PROJECT NARRATIVE Colorectal cancer (CRC) and (EAC) account for the majority of gastrointestinal cancer deaths but can be prevented with screening. For the screening tests to be most effective they need to be optimized for individuals at low-risk and high-risk for CRC and EAC; however, the current methods for CRC and EAC risk prediction have low accuracy. We propose to create an integrated and highly collaborative Biomarker Characterization Center to discover, validate and develop into clinic-ready assays, tests for accurate CRC and EAC risk prediction. We further propose to discover and validate tests based on simple brushing samples of the esophagus that can detect a nascent cancer condition called high grade dysplasia (HGD) and early EAC in people with Barretts esophagus (BE), a high risk precancerous condition for EAC, which will decrease deaths from EAC and the burden of BE surveillance.