Biomarkers of Barrett's Esophagus: From the Laboratory to Clinical Practice

Abstract

The currently recommended approach to managing cancer risk for patients with Barrett's esophagus is endoscopic surveillance including a biopsy protocol to sample the esophageal tissue randomly to detect dysplasia. However, there are numerous limitations in this practice that rely on the histopathological grading of dysplasia alone to make clinical decisions. The availability of in silico models demonstrating the potential cost-effectiveness of biomarker-based stratification has increased interest in finding a clinically relevant "Barrett's biomarker." The success of endoscopic eradication therapy in preventing neoplastic progression of dysplastic Barrett's esophagus has promoted the desire to stratify non-dysplastic Barrett's esophagus to those with "high risk" that may benefit from endotherapy. Furthermore, on the other end of the spectrum, there is interest in searching for a "low risk" marker that may identify those that would not likely benefit from endoscopy screening or surveillance. This review highlights recent data from the genomics (r)evolution revealing new genetic biomarkers of susceptibility to the development of Barrett's esophagus and novel pathways for its neoplastic progression, addresses the development of new modes of tissue sampling and imaging to detect early neoplasia in Barrett's esophagus, and discusses current progress in moving biomarkers from the laboratory into clinical practice in the era of precision medicine.

Keywords: Adenocarcinoma; Endoscopic imaging; Endotherapy; Genomics; Risk Stratification.

Figure 1

Cancer Hallmarks. The essential properties of cancer cells are shown in the green boxes. In general, activation of oncogenes such as ERBB2 is the way in which Barrett’s cells can proliferate without exogenous stimulation and inactivation of tumor suppressor genes such as p53 and p16 is a common way in which Barrett’s cells resist growth-inhibitory signals. The two additional cancer hallmarks proposed in 2011 are shown in the orange circles. The rounded boxes in blue are the accelerating features such as whole genome doubling and a microenvironment rich in oxidative stress as a result of chronic GERD that allow Barrett’s cells faster acquisition of the cancer hallmarks.

Figure 2

The “omics” (R)Evolution on Pathways of Neoplastic Progression in Barrett’s Esophagus. Metaplastic Barrett’s cells first acquire a mutation leading to inactivation of p53. The traditional pathway involves the step-wise accumulation of alterations in tumor suppressor genes such as p16, followed by oncogene activation, and genomic instability, finally resulting in cancer formation. In the genome-doubled pathway, the p53-mutant Barrett’s cells undergo whole genome doubling, followed by genomic instability and oncogene amplification, resulting in cancer formation. It has been proposed that the genome-doubled pathway may be a more rapid pathway to cancer development, and may possibly explain the failure of endoscopic surveillance to detect early cancer progression in Barrett’s esophagus.

Figure 3

The Future of Biomarkers in the “omics” (R)Evolution. In the era of precision medicine, it is conceivable that patients with Barrett’s esophagus would have testing for germline susceptibility (SNPs) performed on whole-blood DNA, somatic sequencing for mutations or whole genomic doubling performed on Barrett’s tissues specimens acquired by endoscopic biopsy, a family history, and an assessment for environmental risk factors that will all be synthesized into a single, risk prediction model for neoplastic progression.

Figure 4

Sources of Biomarkers. The sources for interrogation of biomarkers in Barrett’s esophagus has extended from beyond the acquisition of tissue with endoscopic biopsy to include cell sampling without the need for endoscopy and imaging molecular markers without the need for tissue. Furthermore, molecular markers available in the whole body may be utilized and sources include blood samples which can provide information encoded in DNA and volatile organic compounds (VOCs) which can be interrogated via the novel electronic nose.