Gastroenterology

Gastroenterology

Volume 155, Issue 1, July 2018, Pages 156-167
Gastroenterology

Original Research
Full Report: Basic and Translational—Alimentary Tract
Detection of Mutations in Barrett’s Esophagus Before Progression to High-Grade Dysplasia or Adenocarcinoma

https://doi.org/10.1053/j.gastro.2018.03.047Get rights and content

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.

Section snippets

Patient and Sample Selection

After IRB approval, patients for our study set were identified from a retrospective cohort with endoscopic biopsies for surveillance of BE performed at 1 of 4 endoscopy centers within the University of Pittsburgh Medical Center system. All patients had histologically confirmed intestinal metaplasia. For detailed patient and sample selection process and comparison to reference populations, please see the Supplementary Methods and Supplementary Table 1 and 2.

A formalin-fixed, paraffin-embedded

Patient Selection

For our study set, we collected archival samples from 24 patients who were under routine BE surveillance and later progressed to HGD (n = 14) or EAC (n = 10) more than 1 year after their index BE diagnosis. The included cases were representative of the population of incident progressors as demonstrated by their similarity to progressors not used in the study with respect to age, sex, BE segment length, and history of IFD and LGD (Supplementary Table 1).

We collected samples from a 73-patient

Discussion

Our finding of highly recurrent, pathogenic TP53 mutations in predominantly non-dysplastic surveillance biopsies taken up to 9 years before a diagnosis of HGD or EAC challenges the prevailing models of BE progression in which these mutations are thought to occur contemporaneously with HGD or cancer. These results likely differ from those in the past, as studies that failed to identify recurrent TP53 mutations in NDBE either did not selectively evaluate patients with subsequent progression or

Acknowledgments

The authors thank the Dana-Farber Center for Cancer Genome Discovery for their assistance. Author contributions: Data analysis: MDS, AN, ART, JMD, AJB. Computational analysis: NDC, MD, SLC. Patient selection and clinical data collection: CD, JMD, MR. Slide cutting and DNA isolation: CD, AK. Histologic review: ATA, RDO, JLH, AN, MR, RHL. Conceived study: MDS, JMD, AJB. Manuscript preparation: MDS, NDC, JMD, AJB. Manuscript review: MDS, ATA, RDO, JLH, AN, ART, SLC, JMD, AJB.

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    Conflicts of interest The authors disclose no conflicts.

    Funding This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases grant K08 DK109209 and Prevent Cancer Foundation grant (MDS), the National Cancer Institute P01 CA098101, pilot project grant, U54 CA163060, pilot project grant, National Institute of Biomedical Imaging and Bioengineering R01 EB022077, and grant from the Broad Next10 Initiative (AJB).

    Author names in bold designate shared co-first authorship.

    Authors share co-first authorsip.

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    Authors share co-senior authorship.

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