Background and aims

Barrett's esophagus (BE) is the precursor to esophageal adenocarcinoma. A major challenge is identifying the small group with BE who will progress to advanced disease from the many who will not. Assessment of p53 status has promise as a predictive biomarker, but analytic limitations and lack of validation have precluded its use. The aim of this study was to develop a robust criteria for grading abnormal immunohistochemical (IHC) expression of p53 and to test its utility as a biomarker for progression in BE.

Methods

Criteria for abnormal IHC of p53 were developed in BE biopsies and validated with sequencing to assess TP53 mutations. The utility of p53 IHC as a biomarker for progression of BE was tested retrospectively in 561 patients with BE with or without known progression. The findings were prospectively validated in a clinical practice setting in 1487 patients with BE.

Results

Abnormal p53 IHC highly correlated with TP53 mutation status (90.6% agreement) and was strongly associated with neoplastic progression in the retrospective cohorts, regardless of histologic diagnosis (P < .001). In the retrospective cohort, abnormal p53 was associated with a hazard ratio of 5.03 (95% confidence interval, 3.88-6.5) and a hazard ratio of 5.27 (95% confidence interval, 3.93-7.07) for patients with exclusively nondysplastic disease before progression. In the prospective validation cohort, p53 IHC predicted progression among nondysplastic BE, indefinite for dysplasia, and low-grade dysplasia (P < .001).

Conclusions

p53 IHC identifies patients with BE at higher risk of progression, including in patients without evidence of dysplasia. p53 IHC is inexpensive, easily integrated into routine practice, and should be considered in biopsies from all BE patients without high-grade dysplasia or cancer.

Background & aims

Barrett's esophagus (BE) is the greatest risk factor for esophageal adenocarcinoma (EAC), but only a small proportion of patients with BE develop cancer. Biomarkers might be able to identify patients at highest risk of progression. We investigated genomic differences in surveillance biopsies collected from patients whose BE subsequently progressed compared to patients whose disease did not progress.

Methods

We performed a retrospective case-control study of 24 patients with BE that progressed to high-grade dysplasia (HGD, n = 14) or EAC (n = 10). The control group (n = 73, called non-progressors) comprised patients with BE and at least 5 years of total endoscopic biopsy surveillance without progression to HGD or EAC. From each patient, we selected a single tissue sample obtained more than 1 year before progression (cases) or more than 2 years before the end of follow-up (controls). Pathogenic mutations, gene copy numbers, and ploidy were compared between samples from progressors and non-progressors.

Results

TP53 mutations were detected in 46% of samples from progressors and 5% of non-progressors. In this case-control sample set, TP53 mutations in BE tissues increased the adjusted risk of progression 13.8-fold (95% confidence interval, 3.2-61.0) (P < .001). We did not observe significant differences in ploidy or copy-number profile between groups. We identified 147 pathogenic mutations in 57 distinct genes-the average number of pathogenic mutations was higher in samples from progressors (n = 2.5) than non-progressors (n = 1.2) (P < .001). TP53 and other somatic mutations were recurrently detected in samples with limited copy-number changes (aneuploidy).

Conclusions

In genomic analyses of BE tissues from patients with or without later progression to HGD or EAC, we found significantly higher numbers of TP53 mutations in BE from patients with subsequent progression. These mutations were frequently detected before the onset of dysplasia or substantial changes in copy number.