Detection of Mutations in Barrett's Esophagus Before Progression to High-Grade Dysplasia or Adenocarcinoma.

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.

[1]  Icgc,et al.  Pan-cancer analysis of whole genomes , 2017, bioRxiv.

[2]  Benjamin J. Raphael,et al.  The evolutionary history of 2,658 cancers , 2017, Nature.

[3]  R. Fitzgerald,et al.  The Evolving Genomic Landscape of Barrett's Esophagus and Esophageal Adenocarcinoma. , 2017, Gastroenterology.

[4]  A. Krasinskas,et al.  The Use of Ancillary Stains in the Diagnosis of Barrett Esophagus and Barrett Esophagus-associated Dysplasia: Recommendations From the Rodger C. Haggitt Gastrointestinal Pathology Society. , 2017, The American journal of surgical pathology.

[5]  G. Ergun,et al.  p53 protein accumulation predicts malignant progression in Barrett's metaplasia: a prospective study of 275 patients , 2017, Histopathology.

[6]  J. Xiong,et al.  Meta‐analysis of biomarkers predicting risk of malignant progression in Barrett's oesophagus , 2017, The British journal of surgery.

[7]  J. Tijssen,et al.  Patients With Barrett's Esophagus and Confirmed Persistent Low-Grade Dysplasia Are at Increased Risk for Progression to Neoplasia. , 2017, Gastroenterology.

[8]  L. Macconaill,et al.  Validation of OncoPanel: A Targeted Next-Generation Sequencing Assay for the Detection of Somatic Variants in Cancer. , 2017, Archives of pathology & laboratory medicine.

[9]  Marian Harris,et al.  Institutional implementation of clinical tumor profiling on an unselected cancer population. , 2016, JCI insight.

[10]  M. Ilyas,et al.  Dysplasia in Barrett's oesophagus: p53 immunostaining is more reproducible than haematoxylin and eosin diagnosis and improves overall reliability, while grading is poorly reproducible , 2016, Histopathology.

[11]  F. Wians,et al.  Healthcare Cost of Over-Diagnosis of Low-Grade Dysplasia in Barrett’s Esophagus , 2016, Advances in Therapy.

[12]  Nicholas J Shaheen,et al.  ACG Clinical Guideline: Diagnosis and Management of Barrett’s Esophagus , 2016, The American Journal of Gastroenterology.

[13]  P. Martinez,et al.  Evolution of oesophageal adenocarcinoma from metaplastic columnar epithelium without goblet cells in Barrett's oesophagus , 2015, Gut.

[14]  S. Tavaré,et al.  Whole-genome sequencing provides new insights into the clonal architecture of Barrett’s esophagus and esophageal adenocarcinoma , 2015, Nature Genetics.

[15]  A. Sepulveda,et al.  Evaluation of Mutational Testing of Preneoplastic Barrett's Mucosa by Next-Generation Sequencing of Formalin-Fixed, Paraffin-Embedded Endoscopic Samples for Detection of Concurrent Dysplasia and Adenocarcinoma in Barrett's Esophagus. , 2015, The Journal of molecular diagnostics : JMD.

[16]  Patricia L. Blount,et al.  Assessment of Esophageal Adenocarcinoma Risk Using Somatic Chromosome Alterations in Longitudinal Samples in Barrett's Esophagus , 2015, Cancer Prevention Research.

[17]  P. Martinez,et al.  Derivation of genetic biomarkers for cancer risk stratification in Barrett’s oesophagus: a prospective cohort study , 2015, Gut.

[18]  A. McKenna,et al.  Paired Exome Analysis of Barrett’s Esophagus and Adenocarcinoma , 2015, Nature Genetics.

[19]  M. Styn,et al.  The Presence of Genetic Mutations at Key Loci Predicts Progression to Esophageal Adenocarcinoma in Barrett's Esophagus , 2015, The American Journal of Gastroenterology.

[20]  M. Stratton,et al.  High burden and pervasive positive selection of somatic mutations in normal human skin , 2015, Science.

[21]  P. Fockens,et al.  Aberrant TP53 detected by combining immunohistochemistry and DNA‐FISH improves Barrett's esophagus progression prediction: A prospective follow‐up study , 2015, Genes, chromosomes & cancer.

[22]  Jan G P Tijssen,et al.  Barrett's oesophagus patients with low-grade dysplasia can be accurately risk-stratified after histological review by an expert pathology panel , 2014, Gut.

[23]  Rebecca C Fitzgerald,et al.  Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis , 2014, Nature Genetics.

[24]  Zoltan Szallasi,et al.  Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution. , 2014, Cancer discovery.

[25]  Carissa A. Sanchez,et al.  Temporal and Spatial Evolution of Somatic Chromosomal Alterations: A Case-Cohort Study of Barrett's Esophagus , 2013, Cancer Prevention Research.

[26]  E. Kuipers,et al.  Aberrant p53 protein expression is associated with an increased risk of neoplastic progression in patients with Barrett's oesophagus , 2012, Gut.

[27]  L. Wernisch,et al.  DNA Methylation as an Adjunct to Histopathology to Detect Prevalent, Inconspicuous Dysplasia and Early-Stage Neoplasia in Barrett's Esophagus , 2012, Clinical Cancer Research.

[28]  A. McKenna,et al.  Absolute quantification of somatic DNA alterations in human cancer , 2012, Nature Biotechnology.

[29]  Jashanpreet Singh,et al.  The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett's oesophagus: a meta-analysis , 2011, Gut.

[30]  Kenneth K Wang,et al.  Genome-Wide Catalogue of Chromosomal Aberrations in Barrett's Esophagus and Esophageal Adenocarcinoma: A High-Density Single Nucleotide Polymorphism Array Analysis , 2010, Cancer Prevention Research.

[31]  G. Meijer,et al.  Low-Grade Dysplasia in Barrett's Esophagus: Overdiagnosed and Underestimated , 2010, The American Journal of Gastroenterology.

[32]  A. Axon,et al.  A study of indefinite for dysplasia in Barrett’s oesophagus: reproducibility of diagnosis, clinical outcomes and predicting progression with AMACR (α‐methylacyl‐CoA‐racemase) , 2010, Histopathology.

[33]  A. Bhattacharyya,et al.  A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett's esophagus. , 2009, Cancer research.

[34]  Carissa A. Sanchez,et al.  p16 Mutation Spectrum in the Premalignant Condition Barrett's Esophagus , 2008, PloS one.

[35]  W. Chow,et al.  Incidence of adenocarcinoma of the esophagus among white Americans by sex, stage, and age. , 2008, Journal of the National Cancer Institute.

[36]  R. Holmes,et al.  Epidemiology and pathogenesis of esophageal cancer. , 2007, Seminars in radiation oncology.

[37]  M. Trková,et al.  TP53 Gene Mutations Are Rare in Nondysplastic Barrett's Esophagus , 2006, Digestive Diseases and Sciences.

[38]  Michael Vieth,et al.  Prevalence of Barrett's esophagus in the general population: an endoscopic study. , 2005, Gastroenterology.

[39]  David Pellman,et al.  Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells , 2005, Nature.

[40]  O. Kocher,et al.  Evaluation of p53 mutations in premalignant esophageal lesions and esophageal adenocarcinoma using laser capture microdissection , 2004, Modern Pathology.

[41]  Patricia L. Blount,et al.  The Combination of Genetic Instability and Clonal Expansion Predicts Progression to Esophageal Adenocarcinoma , 2004, Cancer Research.

[42]  R. Sutton,et al.  TP53 mutations in malignant and premalignant Barrett's esophagus. , 2003, Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus.

[43]  G. Jenkins,et al.  Early p53 mutations in nondysplastic Barrett's tissue detected by the restriction site mutation (RSM) methodology , 2003, British Journal of Cancer.

[44]  Patricia L. Blount,et al.  p16(INK4a) lesions are common, early abnormalities that undergo clonal expansion in Barrett's metaplastic epithelium. , 2001, Cancer research.

[45]  J. Goldblum,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 , 2000, Modern Pathology.

[46]  R. Tarone,et al.  Frequent clones of p53-mutated keratinocytes in normal human skin. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[47]  J. Roth,et al.  Mutations of p53 in Barrett's esophagus and Barrett's cancer: a prospective study of ninety-eight cases. , 1996, The Journal of thoracic and cardiovascular surgery.

[48]  G Van Belle,et al.  Observer variation in the diagnosis of dysplasia in Barrett's esophagus. , 1988, Human pathology.