Validation of a biomarker panel in Barrett's esophagus to predict progression to esophageal adenocarcinoma

Abstract

In a prior study, baseline mutational load (ML) predicted progression to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) in Barrett's esophagus (BE) with an area under the curve (AUC) of 0.95.We aimed to validate the test characteristics of this predictive biomarker panel using crude DNA lysates in a larger wellcharacterized cohort.We performed a nested case-control study of BE patients fromthree tertiary referral centers in the Netherlands. Cases had baseline nondysplastic BE (NDBE) and developed HGD/EAC ≥ 2 years later. Controls were matched 2:1, had baseline NDBE, and no progression. Polymerase chain reaction (PCR)-based mutational analysis was performed on crude lysates fromformalin-fixed, paraffin-embedded tissue.MLwas calculated fromloss of heterozygosity (LOH) and microsatellite instability (MSI) at 10 genomic loci. Receiver operator characteristic (ROC) curves were created to assess the diagnostic utility of various cutoffs ofML for progression. Of 159 subjects, 58 were progressors and 101 were nonprogressors, there was no difference in mean ML in preprogression tissue in progressors and nonprogressors (ML = 0.73 ± 0.69 vs. ML = 0.74 ± 0.61, P = 0.93). ROC curves showed poor discrimination ofML in predicting progression with AUC of 0.50 atML ≥ 1. AUC did not vary with differentML cut-points. The utility of the ML to stratify BE patients for risk of progression was not confirmed in this study. The etiology for discrepancies between this and prior studies showing high predictiveness is likely due to the use of crude lysates in this study, but requires further investigation.