The Presence of Genetic Mutations at Key Loci Predicts Progression to Esophageal Adenocarcinoma in Barrett's Esophagus

Abstract

Objectives: Risk stratification in Barrett's esophagus (BE) is challenging. We evaluated the ability of a panel of genetic markers to predict progression to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC).

Methods: In this case-control study, we assessed a measure of genetic instability, the mutational load (ML), in predicting progression to HGD or EAC. Cases had nondysplastic BE or low-grade dysplasia (LGD) at baseline and developed HGD/EAC ≥1 year later. Controls were matched 2:1, had nondysplastic BE or LGD, and no progression at follow-up. Formalin-fixed, paraffin-embedded tissue was microdissected for the epithelium. Loss of heterozygosity (LOH) and microsatellite instability (MSI) were assessed. ML was calculated from derangements in 10 genomic loci. High-clonality LOH mutations were assigned a value of 1, low-clonality mutations were assigned a value of 0.5, and MSI 0.75 at the first loci, and 0.5 for additional loci. These values were summed to the ML. Receiver operator characteristic (ROC) curves were created.

Results: There were 69 patients (46 controls and 23 cases). Groups were similar in age, follow-up time, baseline histology, and the number of microdissected targets. Mean ML in pre-progression biopsies was higher in cases (2.21) than in controls (0.42; P<0.0001). Sensitivity was 100% at ML ≥0.5 and specificity was 96% at ML ≥1.5. Accuracy was highest at 89.9% for ML ≥1. ROC curves for ML ≥1 demonstrated an area under the curve (AUC) of 0.95.

Conclusions: ML in pre-progression BE tissue predicts progression to HGD or EAC. Although further validation is necessary, ML may have utility as a biomarker in endoscopic surveillance of BE.

Figure 1

Mutational load (ML) of each nonprogressor and progressor patient at baseline index time point. ML per patient was the maximum ML in all microdissected histological targets at baseline time point for the patient. The most severe histology found in each patient's clinical pathology report at that same index time point is indicated as intestinal metaplasia (IM) or low-grade dysplasia (LGD) (IM=orange circle; LGD=green circle).

Figure 2

Receiver operator characteristic (ROC) for the performance of mutational load (ML) in predicting progression at baseline index time points for each patient. Area under the curve (AUC)=0.95 (95% confidence interval (CI) 0.89–0.99).

Figure 3

Receiver operator characteristic (ROC) for performance of mutational load (ML) in predicting progression at baseline time points for each patient based on subsets of genomic loci included in ML calculations.