Matthew D Stachler1, Nicholas D Camarda2, Christopher Deitrick3, Anthony Kim4, Agoston T Agoston5, Robert D Odze5, Jason L Hornick5, Anwesha Nag6, Aaron R Thorner6, Matthew Ducar6, Amy Noffsinger7, Richard H Lash8, Mark Redston7, Scott L Carter2, Jon M Davison3, Adam J Bass9. 1. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, Massachusetts. 2. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts; Eli and Edythe L. Broad Institute, Cambridge, Massachusetts; Department of Molecular Oncology, Dana Farber Cancer Institute, Boston, Massachusetts; Joint Center for Cancer Precision Medicine, Dana Farber Cancer Institute, Boston, Massachusetts. 3. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 4. Department of Molecular Oncology, Dana Farber Cancer Institute, Boston, Massachusetts. 5. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. 6. Center for Cancer Genome Discovery, Dana Farber Cancer Institute, Boston, Massachusetts. 7. Inform Diagnostics Research Institute, Needham, Massachusetts. 8. Inform Diagnostics Research Institute, Irving, Texas. 9. Eli and Edythe L. Broad Institute, Cambridge, Massachusetts; Department of Molecular Oncology, Dana Farber Cancer Institute, Boston, Massachusetts. Electronic address: Adam_Bass@dfci.harvard.edu.
Abstract
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.
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.
Authors: Lucas C Duits; Myrtle J van der Wel; Cary C Cotton; K Nadine Phoa; Fiebo J W Ten Kate; Cees A Seldenrijk; G Johan A Offerhaus; Mike Visser; Sybren L Meijer; Rosalie C Mallant-Hent; Kausilia K Krishnadath; Roos E Pouw; Jan G P Tijssen; Nicholas J Shaheen; Jacques J G H M Bergman Journal: Gastroenterology Date: 2016-12-22 Impact factor: 22.682
Authors: Armando Del Portillo; Stephen M Lagana; Yuan Yao; Takeshi Uehara; Nirag Jhala; Tapan Ganguly; Peter Nagy; Jorge Gutierrez; Aesis Luna; Julian Abrams; Yang Liu; Randall Brand; Jorge L Sepulveda; Gary W Falk; Antonia R Sepulveda Journal: J Mol Diagn Date: 2015-06-08 Impact factor: 5.568
Authors: Amitabh Srivastava; Henry Appelman; Jeffrey D Goldsmith; Jon M Davison; John Hart; Alyssa M Krasinskas Journal: Am J Surg Pathol Date: 2017-05 Impact factor: 6.394
Authors: A S Jonason; S Kunala; G J Price; R J Restifo; H M Spinelli; J A Persing; D J Leffell; R E Tarone; D E Brash Journal: Proc Natl Acad Sci U S A Date: 1996-11-26 Impact factor: 11.205
Authors: Thomas G Paulson; Patricia C Galipeau; Lianjun Xu; Heather D Kissel; Xiaohong Li; Patricia L Blount; Carissa A Sanchez; Robert D Odze; Brian J Reid Journal: PLoS One Date: 2008-11-27 Impact factor: 3.240
Authors: Matthew D Stachler; Amaro Taylor-Weiner; Shouyong Peng; Aaron McKenna; Agoston T Agoston; Robert D Odze; Jon M Davison; Katie S Nason; Massimo Loda; Ignaty Leshchiner; Chip Stewart; Petar Stojanov; Sara Seepo; Michael S Lawrence; Daysha Ferrer-Torres; Jules Lin; Andrew C Chang; Stacey B Gabriel; Eric S Lander; David G Beer; Gad Getz; Scott L Carter; Adam J Bass Journal: Nat Genet Date: 2015-07-20 Impact factor: 38.330
Authors: Swathi Eluri; William R Brugge; Ebubekir S Daglilar; Sara A Jackson; Mindi A Styn; Keith M Callenberg; Derek C Welch; Todd M Barr; Lucas C Duits; Jacques J Bergman; Nicholas J Shaheen Journal: Am J Gastroenterol Date: 2015-05-26 Impact factor: 10.864
Authors: Xiaofang Huo; Kerry B Dunbar; Xi Zhang; Qiuyang Zhang; Stuart Jon Spechler; Rhonda F Souza Journal: Am J Physiol Gastrointest Liver Physiol Date: 2020-01-27 Impact factor: 4.052
Authors: Jorge L Sepulveda; Elena V Komissarova; Sarawut Kongkarnka; Richard A Friedman; Jon M Davison; Brynn Levy; Diana Bryk; Vaidehi Jobanputra; Armando Del Portillo; Gary W Falk; Joshua R Sonett; Charles J Lightdale; Julian A Abrams; Timothy C Wang; Antonia R Sepulveda Journal: Int J Cancer Date: 2019-05-02 Impact factor: 7.396
Authors: James J Saller; Linda B Mora; Aejaz Nasir; Zachary Mayer; Mohammad Shahid; Domenico Coppola Journal: Cancer Genomics Proteomics Date: 2022 Mar-Apr Impact factor: 4.069
Authors: Christopher Douville; Helen R Moinova; Prashanthi N Thota; Nicholas J Shaheen; Prasad G Iyer; Marcia Irene Canto; Jean S Wang; John A Dumot; Ashley Faulx; Kenneth W Kinzler; Nickolas Papadopoulos; Bert Vogelstein; Sanford D Markowitz; Chetan Bettegowda; Joseph E Willis; Amitabh Chak Journal: Gastroenterology Date: 2021-01-22 Impact factor: 22.682
Authors: Melissa Schmidt; Richard J Hackett; Ann-Marie Baker; Stuart A C McDonald; Michael Quante; Trevor A Graham Journal: Nat Rev Gastroenterol Hepatol Date: 2021-11-02 Impact factor: 46.802
Authors: Jesús García-Foncillas; Jesús Argente; Luis Bujanda; Victoria Cardona; Bonaventura Casanova; Ana Fernández-Montes; José A Horcajadas; Andrés Iñiguez; Alberto Ortiz; José L Pablos; María Vanessa Pérez Gómez Journal: Mol Diagn Ther Date: 2021-07-30 Impact factor: 4.074