Abstract 2292: Epigenetic alterations in Barrett's esophagus and esophageal adenocarcinoma: identification and evaluation of potential biomarkers

Abstract

Abstract Patients diagnosed with esophageal adenocarcinoma (EAC) have poor long-term survival rates. Currently, patients identified with Barrett's esophagus (BE), the strongest risk factor for EAC, are placed in costly and invasive surveillance programs. The impact of these surveillance programs on decreasing EAC related mortality is debatable, presumably because many patients with BE are not diagnosed until they develop cancer and because of suboptimal BE risk markers for EAC. Thus, there is a need for more accurate biomarkers. Epigenetic alterations in BE have the potential to be detection and risk markers for BE and EAC. In order to identify individual gene methylation patterns of normal squamous (SQ) epithelium, BE, low-grade dysplasia, high-grade dysplasia and EAC tissues, we have conducted genome-wide methylation assessments of these tissue types using HumanMethylation450 arrays (Illumina). Unique methylation signatures for each histological subtype have been identified by unsupervised clustering. Additionally, we determined the mean methylation state (‘beta value’) for more than 480,000 CpGs for each sample group. After normalization and filtering, differentially methylated loci (FDR p < 0.05) with mean beta values with differences greater than 0.20 between the different tissue types were used to identify potential biomarkers. These biomarkers were then subjected to technical and clinical validation studies. We have currently identified and validated four potential biomarkers that may be useful in detection assays for BE and EAC. We have found two CpGs that distinguish EAC from BE, and two other CpGs that distinguish BE from SQ epithelium. The best performing biomarker has 100% sensitivity and 87.5% specificity in its ability to distinguish BE from EAC in the validation set of tissue samples. We presently have a number of additional candidates in various stages of validation. In summary, we have shown that differential methylation patterns exist between the various stages of progression from normal SQ epithelium to BE and ultimately EAC. Furthermore, some of these methylated CpGs have potential to be used as detection markers for BE or EAC. Citation Format: Rachele M. Stockdale, Andrew M. Kaz, Shelli M. Morris, Amitabh Chak, Joseph Willis, Dean Brenner, Sharmila Anandabapasathy, Maria Westerhoff, Chao-Jen Wong, Jill Barnholtz-Sloan, Yanwen Chen, William M. Grady. Epigenetic alterations in Barrett's esophagus and esophageal adenocarcinoma: identification and evaluation of potential biomarkers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2292. doi:10.1158/1538-7445.AM2014-2292