Predictive biomarkers for Barrett's esophagus: so near and yet so far

Abstract

SUMMARY Barrett’s esophagus (BE) is the strongest risk factor for the development of esophageal adenocarcinoma. However, the risk of cancer progression is difficult to ascertain in individuals, as a significant number of patients with BE do not necessarily progress to esophageal adenocarcinoma. There are several issues with the current strategy of using dysplasia as a marker of disease progression. It is subject to sampling error during biopsy acquisition and interobserver variability among gastrointestinal pathologists. Ideal biomarkers with high sensitivity and specificity are needed to accurately detect high-risk BE patients for early intervention and appropriate cost-effective surveillance. To date, there are no available molecular tests in routine clinical practice despite known genetic and epigenetic aberrations in the Barrett’s epithelium. In this review, we present potential biomarkers for the prediction of malignant progression in BE. These include markers of genomic instability, tumor suppressor loci abnormalities, epigenetic changes, proliferation markers, cell cycle predictors, and immunohistochemical markers. Further work in translating biomarkers for routine clinical use may eventually lead to accurate risk stratification.

Diagnostic and Management Implications of Basic Science Advances in Barrett’s Esophagus

“…Phases 3 and 4 entails validation in retrospective and prospective studies, respectively. This is followed by Phase 5 studies that evaluate the impact of a biomarker on the population disease burden and primary outcomes such as costs and mortality rates [24]. Although many biomarkers have been identified and evaluated in Phase 3 and few in Phase 4 studies, none have progressed through and validated in a Phase 5 trial.…”

Molecular biomarkers added to image-enhanced endoscopic imaging: Will they further improve diagnostic accuracy?

“…38 An important epigenetic change is the methylation of CpG nucleotides found in promoter genes which can regulate gene expression and silencing. 38,39 Both hypermethylation and hypomethylation can contribute to cancer development based on involvement of suppression gene or oncogene. Studies have identified differences in methylation patterns of normal esophageal mucosa and BE / EAC.…”

“…6,46 While P53 can be used in combination with dysplasia to predict increased risk of cancer, it has limited role in risk stratification of non-dysplastic BE. 38 IHC of p53 along with histopathology exam is likely more practical than genotyping for LOH of p53 which can potentially identify all mutations in the p53 gene. Recent British society of gastroenterology (BSG) BE guidelines recommends consideration of p53 immunostaining as an adjunct to routine histopathologic diagnosis of dysplasia in the risk stratification of BE subjects.…”

“…Cyclin D1 and Cyclin A) are associated with increased risk of cancer in BE. 38 Similarly, overexpression of proliferation marker, minichromosome maintenance deficient 2 (Mcm2) has been reported to increase the risk of EAC. 52 Other potential biomarkers that have been studied in BE include alterations in mitochondrial DNA, telomere shortening and tumor cell markers such as HER2/neu, APC and EGFR.…”

“…52 Other potential biomarkers that have been studied in BE include alterations in mitochondrial DNA, telomere shortening and tumor cell markers such as HER2/neu, APC and EGFR. 38 …”