Original ResearchFull Report: Basic and Translational—Alimentary TractDetection of Mutations in Barrett’s Esophagus Before Progression to High-Grade Dysplasia or Adenocarcinoma
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.
References (48)
- et al.
Epidemiology and pathogenesis of esophageal cancer
Semin Radiat Oncol
(2007) - et al.
The Location and frequency of intestinal metaplasia at the esophagogastric junction in 223 consecutive autopsies: implications for patient treatment and preventive strategies in Barrett's esophagus
Mod Pathol
(2000) - et al.
Prevalence of Barrett’s esophagus in the general population: an endoscopic study
Gastroenterology
(2005) - et al.
Observer variation in the diagnosis of dysplasia in Barrett’s esophagus
Hum Pathol
(1988) - et al.
Evaluation of p53 mutations in premalignant esophageal lesions and esophageal adenocarcinoma using laser capture microdissection
Mod Pathol
(2004) - et al.
Patients with Barrett’s esophagus and confirmed persistent low-grade dysplasia are at increased risk for progression to neoplasia
Gastroenterology
(2017) - et al.
The evolving genomic landscape of Barrett’s esophagus and esophageal adenocarcinoma
Gastroenterology
(2017) - et al.
Incidence of adenocarcinoma of the esophagus among white Americans by sex, stage, and age
J Natl Cancer Inst
(2008) - et al.
The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett’s oesophagus: a meta-analysis
Gut
(2012) - et al.
ACG Clinical Guideline: diagnosis and management of barrett’s esophagus
Am J Gastroenterol
(2016)
Low-grade dysplasia in Barrett’s esophagus: overdiagnosed and underestimated
Am J Gastroenterol
The presence of genetic mutations at key loci predicts progression to esophageal adenocarcinoma in Barrett’s esophagus
Am J Gastroenterol
Assessment of esophageal adenocarcinoma risk using somatic chromosome alterations in longitudinal samples in Barrett’s esophagus
Cancer Prev Res
A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett’s esophagus
Cancer Res
p16 mutation spectrum in the premalignant condition Barrett’s esophagus
PLoS One
p16 INK4a lesions are common, early abnormalities that undergo clonal expansion in Barrett's metaplastic epithelium p16 ink4a lesions are common, early abnormalities that undergo clonal expansion
Cancer Res
Temporal and spatial evolution of somatic chromosomal alterations: a case-cohort study of Barrett’s esophagus
Cancer Prev Res
Genome-wide catalogue of chromosomal aberrations in barrett’s esophagus and esophageal adenocarcinoma: a high-density single nucleotide polymorphism array analysis
Cancer Prev Res
Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis
Nat Genet
TP53 gene mutations are rare in nondysplastic Barrett’s esophagus
Dig Dis Sci
p53 protein accumulation predicts malignant progression in Barrett’s metaplasia: a prospective study of 275 patients
Histopathology
Dysplasia in Barrett’s oesophagus: p53 immunostaining is more reproducible than haematoxylin and eosin diagnosis and improves overall reliability, while grading is poorly reproducible
Histopathology
Aberrant TP53 detected by combining immunohistochemistry and DNA-FISH improves Barrett’s esophagus progression prediction: a prospective follow-up study
Genes Chromosomes Cancer
Aberrant p53 protein expression is associated with an increased risk of neoplastic progression in patients with Barrett’s oesophagus
Gut
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2024, Clinical Gastroenterology and HepatologyCharacterizing isoform switching events in esophageal adenocarcinoma
2022, Molecular Therapy Nucleic AcidsCitation Excerpt :Although enriched processes had a significant p-value (≤0.05), none of the enriched processes unique to BE.LGD TP53 WT versus BE.HGD TP53 MUT reached a significant false discovery rate (FDR) ≤0.05, but instead ranged from 0.08 to 0.16, suggesting greater heterogeneity of isoform-enriched genes in that grouping. TP53 is the strongest known genetic driver of EAC with a mutation frequency of over 70% in EAC patients.8,13 In turn, isoform-switched genes with direct interaction with TP53 were identified using the STRING database (Figure S3).
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.
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Authors share co-first authorsip.
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Authors share co-senior authorship.