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Vithayathil M, Modolell I, Ortiz-Fernandez-Sordo J, Oukrif D, Pappas A, Januszewicz W, O'Donovan M, Hadjinicolaou A, Bianchi M, Blasko A, White J, Kaye P, Novelli M, Wernisch L, Ragunath K, di Pietro M. Image-Enhanced Endoscopy and Molecular Biomarkers Vs Seattle Protocol to Diagnose Dysplasia in Barrett's Esophagus. Clin Gastroenterol Hepatol 2022; 20:2514-2523.e3. [PMID: 35183768 DOI: 10.1016/j.cgh.2022.01.060] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/21/2022] [Accepted: 01/28/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Dysplasia in Barrett's esophagus often is invisible on high-resolution white-light endoscopy (HRWLE). We compared the diagnostic accuracy for inconspicuous dysplasia of the combination of autofluorescence imaging (AFI)-guided probe-based confocal laser endomicroscopy (pCLE) and molecular biomarkers vs HRWLE with Seattle protocol biopsies. METHODS Barrett's esophagus patients with no dysplastic lesions were block-randomized to standard endoscopy (HRWLE with the Seattle protocol) or AFI-guided pCLE with targeted biopsies for molecular biomarkers (p53 and cyclin A by immunohistochemistry; aneuploidy by image cytometry), with crossover to the other arm after 6 to 12 weeks. The primary end point was the histologic diagnosis from all study biopsies (trial histology). A sensitivity analysis was performed for overall histology, which included diagnoses within 12 months from the first study endoscopy. Endoscopists were blinded to the referral endoscopy and histology results. The primary outcome was diagnostic accuracy for dysplasia by real-time pCLE vs HRWLE biopsies. RESULTS Of 154 patients recruited, 134 completed both arms. In the primary outcome analysis (trial histology analysis), AFI-guided pCLE had similar sensitivity for dysplasia compared with standard endoscopy (74.3%; 95% CI, 56.7-87.5 vs 80.0%; 95% CI, 63.1-91.6; P = .48). Multivariate logistic regression showed pCLE optical dysplasia, aberrant p53, and aneuploidy had the strongest correlation with dysplasia (secondary outcome). This 3-biomarker panel had higher sensitivity for any grade of dysplasia than the Seattle protocol (81.5% vs 51.9%; P < .001) in the overall histology analysis, but not in the trial histology analysis (91.4% vs 80.0%; P = .16), with an area under the receiver operating curve of 0.83. CONCLUSIONS Seattle protocol biopsies miss dysplasia in approximately half of patients with inconspicuous neoplasia. AFI-guided pCLE has similar accuracy to the current gold standard. The addition of molecular biomarkers could improve diagnostic accuracy.
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Affiliation(s)
- Mathew Vithayathil
- Medical Research Council Cancer Unit, University of Cambridge, United Kingdom
| | - Ines Modolell
- Department of Gastroenterology, University Hospital National Health Service Foundation Trust, United Kingdom
| | - Jacobo Ortiz-Fernandez-Sordo
- Nottingham Digestive Diseases Centre, National Institute of Health Research Nottingham Biomedical Research Centre, United Kingdom
| | - Dahmane Oukrif
- Department of Histopathology, University College London Hospital, Longdon, United Kingdom
| | - Apostolos Pappas
- Medical Research Council Cancer Unit, University of Cambridge, United Kingdom
| | - Wladyslaw Januszewicz
- Medical Research Council Cancer Unit, University of Cambridge, United Kingdom; Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Centre for Postgraduate Education, Warsaw, Poland
| | - Maria O'Donovan
- Department of Histopathology, Cambridge University Hospital National Health Service Foundation Trust, United Kingdom
| | - Andreas Hadjinicolaou
- Medical Research Council Cancer Unit, University of Cambridge, United Kingdom; Department of Gastroenterology, University Hospital National Health Service Foundation Trust, United Kingdom
| | - Michele Bianchi
- Medical Research Council Cancer Unit, University of Cambridge, United Kingdom
| | - Adrienn Blasko
- Medical Research Council Cancer Unit, University of Cambridge, United Kingdom
| | - Jonathan White
- Nottingham Digestive Diseases Centre, National Institute of Health Research Nottingham Biomedical Research Centre, United Kingdom
| | - Philip Kaye
- Department of Histopathology, Nottingham University Hospitals National Health Service Trust, University of Nottingham, United Kingdom
| | - Marco Novelli
- Department of Histopathology, University College London Hospital, Longdon, United Kingdom
| | - Lorenz Wernisch
- BIOS Health, Ltd, Cambridge, United Kingdom; Medical Research Council Biostatistics Unit, University of Cambridge, United Kingdom
| | - Krish Ragunath
- Nottingham Digestive Diseases Centre, National Institute of Health Research Nottingham Biomedical Research Centre, United Kingdom
| | - Massimiliano di Pietro
- Medical Research Council Cancer Unit, University of Cambridge, United Kingdom; Department of Gastroenterology, University Hospital National Health Service Foundation Trust, United Kingdom.
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Uno K, Koike T, Hatta W, Saito M, Tanabe M, Masamune A. Development of Advanced Imaging and Molecular Imaging for Barrett's Neoplasia. Diagnostics (Basel) 2022; 12:2437. [PMID: 36292126 PMCID: PMC9600913 DOI: 10.3390/diagnostics12102437] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 10/04/2022] [Indexed: 11/17/2022] Open
Abstract
Barrett esophagus (BE) is a precursor to a life-threatening esophageal adenocarcinoma (EAC). Surveillance endoscopy with random biopsies is recommended for early intervention against EAC, but its adherence in the clinical setting is poor. Dysplastic lesions with flat architecture and patchy distribution in BE are hardly detected by high-resolution endoscopy, and the surveillance protocol entails issues of time and labor and suboptimal interobserver agreement for diagnosing dysplasia. Therefore, the development of advanced imaging technologies is necessary for Barrett's surveillance. Recently, non-endoscopic or endoscopic technologies, such as cytosponge, endocytoscopy, confocal laser endomicroscopy, autofluorescence imaging, and optical coherence tomography/volumetric laser endomicroscopy, were developed, but most of them are not clinically available due to the limited view field, expense of the equipment, and significant time for the learning curve. Another strategy is focused on the development of molecular biomarkers, which are also not ready to use. However, a combination of advanced imaging techniques together with specific biomarkers is expected to identify morphological abnormalities and biological disorders at an early stage in the surveillance. Here, we review recent developments in advanced imaging and molecular imaging for Barrett's neoplasia. Further developments in multiple biomarker panels specific for Barrett's HGD/EAC include wide-field imaging systems for targeting 'red flags', a high-resolution imaging system for optical biopsy, and a computer-aided diagnosis system with artificial intelligence, all of which enable a real-time and accurate diagnosis of dysplastic BE in Barrett's surveillance and provide information for precision medicine.
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Affiliation(s)
- Kaname Uno
- Division of Gastroenterology, Tohoku University Hospital, Sendai 981-8574, Japan
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3
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Chen L, Fang B, Qiao L, Zheng Y. Discovery of Anticancer Activity of Amentoflavone on Esophageal Squamous Cell Carcinoma: Bioinformatics, Structure-Based Virtual Screening, and Biological Evaluation. J Microbiol Biotechnol 2022; 32:718-729. [PMID: 35484963 PMCID: PMC9628896 DOI: 10.4014/jmb.2203.03050] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/21/2022] [Accepted: 04/28/2022] [Indexed: 12/15/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is the most common primary esophageal malignancy with poor prognosis. Here, due to the necessity for exploring potential therapies against ESCC, we obtained the gene expression data on ESCC from the TCGA and GEO databases. Venn diagram analysis was applied to identify common targets. The protein-protein interaction network was constructed by Cytoscape software, and the hub targets were extracted from the network via cytoHubba. The potential hub nodes as drug targets were found by pharmacophore-based virtual screening and molecular modeling, and the antitumor activity was evaluated through in vitro studies. A total of 364 differentially expressed genes (DEGs) in ESCC were identified. Pathway enrichment analyses suggested that most DEGs were mainly involved in the cell cycle. Three hub targets were retrieved, including CENPF, CCNA2 (cyclin A), and CCNB1 (cyclin B1), which were highly expressed in esophageal cancer and associated with prognosis. Moreover, amentoflavone, a promising drug candidate found by pharmacophore-based virtual screening, showed antiproliferative and proapoptotic effects and induced G1 in esophageal squamous carcinoma cells. Taken together, our findings suggested that amentoflavone could be a potential cell cycle inhibitor targeting cyclin B1, and is therefore expected to serve as a great therapeutic agent for treating esophageal squamous cell carcinoma.
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Affiliation(s)
- Lei Chen
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Bo Fang
- College of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Liman Qiao
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Yihui Zheng
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China,Corresponding author Phone/Fax : 86-0577-6288-2358 E-mail:
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4
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Hoefnagel SJM, Mostafavi N, Timmer MR, Lau CT, Meijer SL, Wang KK, Krishnadath KK. A genomic biomarker-based model for cancer risk stratification of non-dysplastic Barrett's esophagus patients after extended follow up; results from Dutch surveillance cohorts. PLoS One 2020; 15:e0231419. [PMID: 32282835 PMCID: PMC7153893 DOI: 10.1371/journal.pone.0231419] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 03/23/2020] [Indexed: 12/19/2022] Open
Abstract
Barrett’s esophagus is the only known mucosal precursor for the highly malignant esophageal adenocarcinoma. Malignant degeneration of non-dysplastic Barrett’s esophagus occurs in < 0.6% per year in Dutch surveillance cohorts. Therefore, it has been proposed to increase the surveillance intervals from 3 to 5 years, potentially increasing development of advanced stage interval cancers. To prevent such cases robust biomarkers for more optimal stratification over longer follow up periods for non-dysplastic Barrett’s patients are required. In this multi-center study, aberrations for chromosomes 7, 17, and structural abnormalities for c-MYC, CDKN2A, TP53, Her-2/neu and 20q assessed by DNA fluorescence in situ hybridization on brush cytology specimens, were used to determine marker scores and to perform clonal diversity measurements, as described previously. In this study, these genetic biomarkers were combined with clinical variables and analyzed to obtain the most efficient cancer prediction model after an extended period of follow-up (median time of 7 years) by applying Cox regression modeling, bootstrapping and leave-one-out analyses. A total of 334 patients with Barrett’s esophagus without dysplasia from 6 community hospitals (n = 220) and one academic center (n = 114) were included. The annual progression rate to high grade dysplasia and/or esophageal adenocarcinoma was 1.3%, and to adenocarcinoma alone 0.85%. A prediction model including age, Barrett circumferential length, and a clonicity score over the genomic set including chromosomes 7, 17, 20q and c-MYC, resulted in an area under the curve of 0.88. The sensitivity and specificity of this model were 0.91 and 0.38. The positive and negative predictive values were 0.13 (95% CI 0.09 to 0.19) and 0.97 (95% CI 0.93 to 0.99). We propose the implementation of the model to identify non-dysplastic Barrett’s patients, who are required to remain in surveillance programs with 3-yearly surveillance intervals from those that can benefit from less frequent or no surveillance.
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Affiliation(s)
- S. J. M. Hoefnagel
- Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands
| | - N. Mostafavi
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands
| | - M. R. Timmer
- Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands
| | - C. T. Lau
- Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - S. L. Meijer
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - K. K. Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - K. K. Krishnadath
- Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands
- * E-mail:
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5
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Duits LC, Klaver E, Bureo Gonzalez A, Boerwinkel DF, Ten Kate FJW, Offerhaus GJA, Meijer SL, Visser M, Seldenrijk CA, Krishnadath KK, Schoon EJ, Weusten BLAM, Mallant-Hent RC, Pouw RE, Bergman JJGHM. The Amsterdam ReBus progressor cohort: identification of 165 Barrett's surveillance patients who progressed to early neoplasia and 723 nonprogressor patients. Dis Esophagus 2019; 32:5032889. [PMID: 29873685 DOI: 10.1093/dote/doy037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 03/20/2018] [Accepted: 03/27/2018] [Indexed: 12/11/2022]
Abstract
Patient selection is suboptimal in most studies focused on identifying biological markers for neoplastic progression in Barrett's esophagus (BE). This study aims to describe a stringently selected community-based case-control cohort of non-dysplastic BE (NDBE) patients who progressed to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) and BE patients who never progressed to be used for future biomarker studies. We identified all patients referred for endoscopic work-up of BE neoplasia at three tertiary referral centers for treatment of BE neoplasia between 2000 and 2013. We performed a detailed registration of any endoscopic surveillance history before neoplastic progression. Controls were selected from a retrospective BE surveillance registration in 10 community hospitals. A total of 887 patients were referred for endoscopic work-up of BE neoplasia. Based on predefined selection criteria, we identified 165 progressor patients (82% men; mean age 55 years ± 10.4) with a baseline endoscopy demonstrating NDBE > 2 years before neoplastic progression. Using the same predefined selection criteria, 723 nonprogressor patients (67% men; mean age 57 years ± 11.3) with >2 years of endoscopic surveillance were identified. Median length of the BE segment was 5 cm (IQR 4-7) in progressors and 4 cm (IQR 2-6) in controls. Median duration of surveillance was 89 months (IQR 54-139) in progressors and 76 months (IQR 47-116) in nonprogressors. Paraffin embedded biopsies are available for biomarker research in all patients. Ethical approval was obtained and material transfer agreements were signed with all 58 contributing pathology labs. This is the largest community-based case-control cohort of BE patients with and without progression to early neoplasia. The stringent selection criteria and the availability of paraffin embedded biopsy specimens make this a unique cohort for biomarker studies.
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Affiliation(s)
- L C Duits
- Departments of Gastroenterology and Hepatology
| | - E Klaver
- Departments of Gastroenterology and Hepatology
| | | | | | - F J W Ten Kate
- Pathology, Academic Medical Center, Amsterdam.,Department of Pathology, University Medical Center, Utrecht
| | - G J A Offerhaus
- Pathology, Academic Medical Center, Amsterdam.,Department of Pathology, University Medical Center, Utrecht
| | - S L Meijer
- Pathology, Academic Medical Center, Amsterdam
| | - M Visser
- Pathology, Academic Medical Center, Amsterdam
| | | | | | - E J Schoon
- Gastroenterology, St Antonius Ziekenhuis, Nieuwegein
| | | | | | - Roos E Pouw
- Departments of Gastroenterology and Hepatology
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6
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Duits LC, Lao-Sirieix P, Wolf WA, O’Donovan M, Galeano-Dalmau N, Meijer SL, Offerhaus GJA, Redman J, Crawte J, Zeki S, Pouw RE, Chak A, Shaheen NJ, Bergman JJGHM, Fitzgerald RC. A biomarker panel predicts progression of Barrett's esophagus to esophageal adenocarcinoma. Dis Esophagus 2019; 32:5212855. [PMID: 30496496 PMCID: PMC6303732 DOI: 10.1093/dote/doy102] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is uncommon but the consequences are serious. Predictors of progression are essential to optimize resource utilization. This study assessed the utility of a promising panel of biomarkers applicable to routine paraffin embedded biopsies (FFPE) to predict progression of BE to EAC in a large population-based, nested case-control study.We utilized the Amsterdam-based ReBus nested case-control cohort. BE patients who progressed to high-grade dysplasia (HGD)/EAC (n = 130) and BE patients who never progressed (n = 130) were matched on age, sex, length of the BE segment, and duration of endoscopic surveillance. All progressors had minimum 2 years of endoscopic surveillance without HGD/EAC to exclude prevalent neoplasia. We assessed abnormal DNA content, p53, Cyclin A, and Aspergillus oryzae lectin (AOL) in FFPE sections. We performed conditional logistic regression analysis to estimate odds ratio (OR) of progression based on biomarker status.Expert LGD (OR, 8.3; 95% CI, 1.7-41.0), AOL (3 vs. 0 epithelial compartments abnormal; OR, 3.6; 95% CI, 1.2-10.6) and p53 (OR, 2.3; 95% CI, 1.2-4.6) were independently associated with neoplastic progression. Cyclin A did not predict progression and DNA ploidy analysis by image cytometry was unsuccessful in the majority of cases, both were excluded from the multivariate analysis. The multivariable biomarker model had an area under the receiver operating characteristic curve of 0.73.Expert LGD, AOL, and p53 independently predict neoplastic progression in BE patients and are applicable to routine practice. These biomarkers can aid in selecting patients for endoscopic ablation or more intensive surveillance.
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Affiliation(s)
- L C Duits
- Amsterdam UMC, University of Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam, the Netherlands
| | - P Lao-Sirieix
- Medical Research Council Cancer Unit, Hutchison-MRC Research Center, University of Cambridge,Cambridge,United Kingdom
| | - W A Wolf
- Center for Esophageal Diseases and Swallowing, Department of Medicine, Division of Gastroenterology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - M O’Donovan
- Department of Pathology, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom
| | - N Galeano-Dalmau
- Medical Research Council Cancer Unit, Hutchison-MRC Research Center, University of Cambridge,Cambridge,United Kingdom
| | - S L Meijer
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - G J A Offerhaus
- Department of Pathology, University Medical Center, Utrecht, the Netherlands
| | - J Redman
- Medical Research Council Cancer Unit, Hutchison-MRC Research Center, University of Cambridge,Cambridge,United Kingdom
| | - J Crawte
- Medical Research Council Cancer Unit, Hutchison-MRC Research Center, University of Cambridge,Cambridge,United Kingdom
| | - S Zeki
- Medical Research Council Cancer Unit, Hutchison-MRC Research Center, University of Cambridge,Cambridge,United Kingdom
| | - R E Pouw
- Amsterdam UMC, University of Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam, the Netherlands
| | - A Chak
- Division of Gastroenterology and Liver Disease, Case Western Reserve University, Cleveland, Ohio, USA
| | - N J Shaheen
- Center for Esophageal Diseases and Swallowing, Department of Medicine, Division of Gastroenterology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - J J G H M Bergman
- Amsterdam UMC, University of Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam, the Netherlands
| | - R C Fitzgerald
- Medical Research Council Cancer Unit, Hutchison-MRC Research Center, University of Cambridge,Cambridge,United Kingdom
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Janmaat VT, van Olphen SH, Biermann KE, Looijenga LHJ, Bruno MB, Spaander MCW. Use of immunohistochemical biomarkers as independent predictor of neoplastic progression in Barrett's oesophagus surveillance: A systematic review and meta-analysis. PLoS One 2017; 12:e0186305. [PMID: 29059206 PMCID: PMC5653304 DOI: 10.1371/journal.pone.0186305] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 09/28/2017] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION The low incidence of oesophageal adenocarcinoma (EAC) in Barrett's oesophagus (BE) patients reinforces the need for risk stratification tools to make BE surveillance more effective. Therefore, we have undertaken a systematic review and meta-analysis of published studies on immunohistochemical (IHC) biomarkers in BE to determine the value of IHC biomarkers as neoplastic predictors in BE surveillance. MATERIALS AND METHODS We searched MEDLINE, EMBASE, Web of Science, CENTRAL, Pubmed publisher, and Google scholar. All studies on IHC biomarkers in BE surveillance were included. ORs were extracted and meta-analyses performed with a random effects model. RESULTS 16 different IHC biomarkers were studied in 36 studies. These studies included 425 cases and 1835 controls. A meta- analysis was performed for p53, aspergillus oryzae lectin (AOL), Cyclin A, Cyclin D and alpha-methylacyl-CoA racemase. Aberrant p53 expression was significantly associated with an increased risk of neoplastic progression with an OR of 3.18 (95% CI 1.68 to 6.03). This association was confirmed for both non-dysplastic BE and BE with low-grade dysplasia (LGD). Another promising biomarker to predict neoplastic progression was AOL, with an OR of 3.04 (95% CI 2.05 to 4.49). DISCUSSION Use of p53 IHC staining may improve risk stratification in BE surveillance. Aberrant p53 expression in BE patients appeared to be associated with a significantly increased risk of neoplastic progression for both non-dysplastic and LGD BE patients.
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Affiliation(s)
- Vincent T. Janmaat
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Sophie H. van Olphen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Katharina E. Biermann
- Department of Pathology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Leendert H. J. Looijenga
- Department of Pathology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Marco B. Bruno
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Manon C. W. Spaander
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
- * E-mail:
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8
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Nwachokor J, Tawfik O, Danley M, Mathur S, House J, Sharma P, Christenson LK, Bansal A. Quantitation of spatial and temporal variability of biomarkers for Barrett's Esophagus. Dis Esophagus 2017; 30:1-8. [PMID: 28859356 PMCID: PMC6036660 DOI: 10.1093/dote/dox023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Accepted: 03/03/2017] [Indexed: 12/11/2022]
Abstract
Chemoprevention and risk-stratification studies in Barrett's esophagus (BE) rely on biomarkers but the variability in their temporal and spatial expression is unknown. If such variability exists, it will impact sampling techniques and sample size calculations. Specimens from three levels of biopsies over two serial endoscopies in nondysplastic BE patients were analyzed for aneuploidy, proliferation markers (Ki67, Mcm2), and cell cycle markers (cyclin A and cyclin D1). A modification of the image cytometry technique, where cytokeratin staining automatically distinguished epithelial and stromal cells, measured aneuploidy on whole tissue sections. Other biomarkers were studied by immunohistochemistry. Coefficient of variability (SD/mean) was calculated; a value <10% indicated low variability. A total of 120 specimens (20 subjects each with three biopsy levels at two time points) from nondysplastic BE patients (71 ± 8.8 years, all Caucasian, 90% males, C5.1M7.5 ± 3.4 cm) were analyzed. The mean interval between endoscopies was 32.8 ± 8.4 months. Aneuploidy had a spatial variability of 6.8% at visit 1 (mean diploid index: 1.1 ± 0.09) and 7.9% at visit 2 (mean diploid index: 1.1 ± 0.06) and a temporal variability of 7.0-8.1% for the three levels. For other biomarkers, the spatial variability ranged from ∼5 to 30% at visit 1 and 11-92% at visit 2 and the temporal variability ranged from 0 to 77%. To conclude, of all the biomarkers, only aneuploidy had both spatial and temporal variability of <10%. Spatial and temporal variability were biomarker dependent and could be as high as 90% even without progression. These data will be useful to design chemoprevention and risk-stratification studies in BE.
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Affiliation(s)
| | - O. Tawfik
- Pathology and Laboratory Medicine, the University of Kansas School of Medicine,The Kansas Cancer Institute, Kansas City, KS
| | - M. Danley
- Pathology and Laboratory Medicine, the University of Kansas School of Medicine
| | - S. Mathur
- Pathology and Laboratory Medicine, the University of Kansas School of Medicine,Department of Pathology and Laboratory Medicine, the Veterans Affairs Medical Center
| | - J. House
- Department of Biostatistics, Saint Lukes Mid-America Heart Institute
| | - P. Sharma
- The Kansas Cancer Institute, Kansas City, KS,Department of Gastroenterology and Hepatology, the Veterans Affairs Medical Center, Kansas City, MO,Departments of Gastroenterology and Hepatology
| | - L. K. Christenson
- Molecular and Integrative Physiology, the University of Kansas Medical Center, Kansas City, KS
| | - A. Bansal
- The Kansas Cancer Institute, Kansas City, KS,Department of Gastroenterology and Hepatology, the Veterans Affairs Medical Center, Kansas City, MO,Departments of Gastroenterology and Hepatology
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9
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van Olphen SH, ten Kate FJ, Doukas M, Kastelein F, Steyerberg EW, Stoop HA, Spaander MC, Looijenga LH, Bruno MJ, Biermann K. Value of cyclin A immunohistochemistry for cancer risk stratification in Barrett esophagus surveillance: A multicenter case-control study. Medicine (Baltimore) 2016; 95:e5402. [PMID: 27893678 PMCID: PMC5134871 DOI: 10.1097/md.0000000000005402] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The value of endoscopic Barrett esophagus (BE) surveillance based on histological diagnosis of low-grade dysplasia (LGD) remains debated given the lack of adequate risk stratification. The aim of this study was to evaluate the predictive value of cyclin A expression and to combine these results with our previously reported immunohistochemical p53, AMACR, and SOX2 data, to identify a panel of biomarkers predicting neoplastic progression in BE.We conducted a case-control study within a prospective cohort of 720 BE patients. BE patients who progressed to high-grade dysplasia (HGD, n = 37) or esophageal adenocarcinoma (EAC, n = 13), defined as neoplastic progression, were classified as cases and patients without neoplastic progression were classified as controls (n = 575). Cyclin A expression was determined by immunohistochemistry in all 625 patients; these results were combined with the histological diagnosis and our previous p53, AMACR, and SOX2 data in loglinear regression models. Differences in discriminatory ability were quantified as changes in area under the ROC curve (AUC) for predicting neoplastic progression.Cyclin A surface positivity significantly increased throughout the metaplasia-dysplasia-carcinoma sequences and was seen in 10% (107/1050) of biopsy series without dysplasia, 33% (109/335) in LGD, and 69% (34/50) in HGD/EAC. Positive cyclin A expression was associated with an increased risk of neoplastic progression (adjusted relative risk (RR) 2.4; 95% CI: 1.7-3.4). Increases in AUC were substantial for P53 (+0.05), smaller for SOX2 (+0.014), minor for cyclin A (+0.003), and none for AMARC (0.00).Cyclin A immunopositivity was associated with an increased progression risk in BE patients. However, compared to p53 and SOX2, the incremental value of cyclin A was limited. The use of biomarkers has the potential to significantly improve risk stratification in BE.
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Affiliation(s)
| | | | | | | | - Ewout W. Steyerberg
- Department of Public Health, Erasmus University Medical Center, Rotterdam, The Netherlands
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Kresty LA, Weh KM, Zeyzus-Johns B, Perez LN, Howell AB. Cranberry proanthocyanidins inhibit esophageal adenocarcinoma in vitro and in vivo through pleiotropic cell death induction and PI3K/AKT/mTOR inactivation. Oncotarget 2016; 6:33438-55. [PMID: 26378019 PMCID: PMC4741777 DOI: 10.18632/oncotarget.5586] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 08/19/2015] [Indexed: 12/22/2022] Open
Abstract
Cranberries are rich in bioactive constituents known to improve urinary tract health and more recent evidence supports cranberries possess cancer inhibitory properties. However, mechanisms of cancer inhibition by cranberries remain to be elucidated, particularly in vivo. Properties of a purified cranberry-derived proanthocyanidin extract (C-PAC) were investigated utilizing acid-sensitive and acid-resistant human esophageal adenocarcinoma (EAC) cell lines and esophageal tumor xenografts in athymic NU/NU mice. C-PAC induced caspase-independent cell death mainly via autophagy and low levels of apoptosis in acid-sensitive JHAD1 and OE33 cells, but resulted in cellular necrosis in acid-resistant OE19 cells. Similarly, C-PAC induced necrosis in JHAD1 cells pushed to acid-resistance via repeated exposures to an acidified bile cocktail. C-PAC associated cell death involved PI3K/AKT/mTOR inactivation, pro-apoptotic protein induction (BAX, BAK1, deamidated BCL-xL, Cytochrome C, PARP), modulation of MAPKs (P-P38/P-JNK) and G2-M cell cycle arrest in vitro. Importantly, oral delivery of C-PAC significantly inhibited OE19 tumor xenograft growth via modulation of AKT/mTOR/MAPK signaling and induction of the autophagic form of LC3B supporting in vivo efficacy against EAC for the first time. C-PAC is a potent inducer of EAC cell death and is efficacious in vivo at non-toxic behaviorally achievable concentrations, holding promise for preventive or therapeutic interventions in cohorts at increased risk for EAC, a rapidly rising and extremely deadly malignancy.
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Affiliation(s)
- Laura A Kresty
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Katherine M Weh
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Bree Zeyzus-Johns
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Laura N Perez
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Amy B Howell
- Marucci Center for Blueberry and Cranberry Research, Rutgers University, Chatsworth, New Jersey, USA
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11
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di Pietro M, Bird-Lieberman EL, Liu X, Nuckcheddy-Grant T, Bertani H, O'Donovan M, Fitzgerald RC. Autofluorescence-Directed Confocal Endomicroscopy in Combination With a Three-Biomarker Panel Can Inform Management Decisions in Barrett's Esophagus. Am J Gastroenterol 2015; 110:1549-58. [PMID: 26416188 DOI: 10.1038/ajg.2015.295] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 07/16/2015] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Barrett's esophagus (BE) surveillance with white-light endoscopy and quadrantic biopsies (Seattle protocol) is resource intensive and limited by sampling error. Previous work suggests that autofluorescence imaging (AFI) in combination with a molecular panel might reduce the number of biopsies, but this was not sufficiently sensitive for low-grade dysplasia, now a point for endoscopic intervention. Here we used AFI to direct narrow-field imaging tools for real-time optical assessment of dysplasia and biopsies for a biomarker panel. We compared the new diagnostic algorithm with the current standard. METHODS A total of 55 patients with BE were recruited at a single tertiary referral center. Patients underwent high-resolution endoscopy followed by AFI. AFI-targeted areas (n=194) were examined in turn by narrow-band imaging with magnification (NBIz) and probe-based confocal laser endomicroscopy (pCLE). Biopsies were taken from AFI-targeted areas and tested using an established molecular panel comprising aneuploidy plus cyclin A and p53 immunohistochemistry. RESULTS In the per-patient analysis the overall sensitivity and specificity of AFI-targeted pCLE were 100% and 53.6% for high-grade dysplasia/intramucosal cancer and 96.4% and 74.1% for any grade of dysplasia, respectively. NBIz had equal specificity for dysplasia detection (74.1%), but significantly lower sensitivity (57.1%) than pCLE. The time required to perform AFI-targeted pCLE was shorter that that taken by the Seattle protocol (P=0.0004). We found enrichment of molecular abnormalities in areas with optical dysplasia by pCLE (P<0.001), regardless of histologic dysplasia. The addition of the 3-biomarker panel reduced the false positive rate of pCLE by 50%, leading to sensitivity and specificity for any grade of dysplasia of 89.2% and 88.9%, respectively. CONCLUSIONS The combination of pCLE on AFI-targeted areas and a 3-biomarker panel identifies patients with dysplasia.
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Affiliation(s)
| | - Elizabeth L Bird-Lieberman
- MRC Cancer Unit, University of Cambridge, Cambridge, UK.,Translational Gastroenterology Unit, Experimental Medicine Division, John Radcliffe Hospital, Oxford, UK
| | - Xinxue Liu
- MRC Cancer Unit, University of Cambridge, Cambridge, UK
| | | | - Helga Bertani
- Department of Digestive Endoscopy, Nuovo Ospedale Civile S. Agostino, Modena, Italy
| | - Maria O'Donovan
- Department of Histopathology, Cambridge University Hospitals, Cambridge, UK
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12
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Abstract
BACKGROUND There is need for the application of biomarkers in a clinical setting in order to improve patient care. Current surveillance methods are costly for health care systems and invasive for patients, and subjective methodology leads to frequent misdiagnosis. This review summarises the most advanced recent and relevant literature in the field of biomarker development in the context of Barrett's esophagus and comments on their potential application. Studies included roughly correlate with Early Detection Research Network phases three and four. RECENT FINDINGS A number of individual candidate and panels of biomarkers have been investigated recently. These include: gene-specific mutations such as loss of heterozygosity, copy number alterations (in particular aneuploidy) methylation panels, altered gene expression, and glycosylation assayed by lectin binding, as well as genetic and clonal diversity measures. Immunostaining for p53 is the only candidate biomarker deemed "ready for prime time." This has been recommended for use clinically as an adjunct to histological diagnosis of dysplastic Barrett's esophagus in the 2014 British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's esophagus. CONCLUSIONS Progress is being made but in many cases further prospective validation studies are required before clinical application can take place. Limitations to furthering these studies include the large patient cohorts required for prospective validation studies, costs associated with studies, and reproducibility of methods across laboratories. Continued research in this area is strongly recommended as, in the long run, biomarker application has the potential to significantly improve patient care.
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Affiliation(s)
- Eleanor M Gregson
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Biomedical Campus, Box 197, Cambridge, CB2 0XZ, UK,
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13
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Brown CS, Ujiki MB. Risk factors affecting the Barrett's metaplasia-dysplasia-neoplasia sequence. World J Gastrointest Endosc 2015; 7:438-445. [PMID: 25992184 PMCID: PMC4436913 DOI: 10.4253/wjge.v7.i5.438] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 10/27/2014] [Accepted: 01/20/2015] [Indexed: 02/05/2023] Open
Abstract
Esophageal adenocarcinoma has the fastest growing incidence rate of any cancer in the United States, and currently carries a very poor prognosis with 5 years relative survival rates of less than 15%. Current curative treatment options are limited to esophagectomy, a procedure that suffers from high complication rates and high mortality rates. Metaplasia of the esophageal epithelium, a condition known as Barrett’s esophagus (BE), is widely accepted as the precursor lesion for adenocarcinoma of the esophagus. Recently, radio-frequency ablation has been shown to be an effective method to treat BE, although there is disagreement as to whether radio-frequency ablation should be used to treat all patients with BE or whether treatment should be reserved for those at high risk for progressing to esophageal adenocarcinoma while continuing to endoscopically survey those with low risk. Recent research has been targeted towards identifying those at greater risk for progression to esophageal adenocarcinoma so that radio-frequency ablation therapy can be used in a more targeted manner, decreasing the total health care cost as well as improving patient outcomes. This review discusses the current state of the literature regarding risk factors for progression from BE through dysplasia to esophageal adenocarcinoma, as well as the current need for an integrated scoring tool or risk stratification system capable of differentiating those patients at highest risk of progression in order to target these endoluminal therapies.
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14
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di Pietro M, Chan D, Fitzgerald RC, Wang KK. Screening for Barrett's Esophagus. Gastroenterology 2015; 148:912-23. [PMID: 25701083 PMCID: PMC4703087 DOI: 10.1053/j.gastro.2015.02.012] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 02/04/2015] [Accepted: 02/04/2015] [Indexed: 12/20/2022]
Abstract
The large increase in the incidence of esophageal adenocarcinoma in the West during the past 30 years has stimulated interest in screening for Barrett's esophagus (BE), a precursor to esophageal cancer. Effective endoscopic treatments for dysplasia and intramucosal cancer, coupled with screening programs to detect BE, could help reverse the increase in the incidence of esophageal cancer. However, there are no accurate, cost-effective, minimally invasive techniques available to screen for BE, reducing the enthusiasm of gastroenterologists. Over the past 5 years, there has been significant progress in the development of screening technologies. We review existing and developing technologies, new minimally invasive imaging techniques, nonendoscopic devices for cell collection, and biomarkers that can be measured in blood or stool samples. We discuss the status of these approaches, data from clinical studies of their effects, and their anticipated strengths and weaknesses in screening. The area is rapidly evolving, and new tools will soon be ready for prime time.
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Affiliation(s)
| | - Daniel Chan
- Barrett's Esophagus Unit, Mayo Clinic, Rochester, Minnesota
| | | | - Kenneth K Wang
- Barrett's Esophagus Unit, Mayo Clinic, Rochester, Minnesota.
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15
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di Pietro M, Boerwinkel DF, Shariff MK, Liu X, Telakis E, Lao-Sirieix P, Walker E, Couch G, Mills L, Nuckcheddy-Grant T, Slininger S, O'Donovan M, Visser M, Meijer SL, Kaye PV, Wernisch L, Ragunath K, Bergman JJGHM, Fitzgerald RC. The combination of autofluorescence endoscopy and molecular biomarkers is a novel diagnostic tool for dysplasia in Barrett's oesophagus. Gut 2015; 64:49-56. [PMID: 24721904 PMCID: PMC4283667 DOI: 10.1136/gutjnl-2013-305975] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 01/24/2014] [Accepted: 03/03/2014] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Endoscopic surveillance for Barrett's oesophagus (BO) is limited by sampling error and the subjectivity of diagnosing dysplasia. We aimed to compare a biomarker panel on minimal biopsies directed by autofluorescence imaging (AFI) with the standard surveillance protocol to derive an objective tool for dysplasia assessment. DESIGN We performed a cross-sectional prospective study in three tertiary referral centres. Patients with BO underwent high-resolution endoscopy followed by AFI-targeted biopsies. 157 patients completed the biopsy protocol. Aneuploidy/tetraploidy; 9p and 17p loss of heterozygosity; RUNX3, HPP1 and p16 methylation; p53 and cyclin A immunohistochemistry were assessed. Bootstrap resampling was used to select the best diagnostic biomarker panel for high-grade dysplasia (HGD) and early cancer (EC). This panel was validated in an independent cohort of 46 patients. RESULTS Aneuploidy, p53 immunohistochemistry and cyclin A had the strongest association with dysplasia in the per-biopsy analysis and, as a panel, had an area under the receiver operating characteristic curve of 0.97 (95% CI 0.95 to 0.99) for diagnosing HGD/EC. The diagnostic accuracy for HGD/EC of the three-biomarker panel from AFI+ areas was superior to AFI- areas (p<0.001). Compared with the standard protocol, this panel had equal sensitivity for HGD/EC, with a 4.5-fold reduction in the number of biopsies. In an independent cohort of patients, the panel had a sensitivity and specificity for HGD/EC of 100% and 85%, respectively. CONCLUSIONS A three-biomarker panel on a small number of AFI-targeted biopsies provides an accurate and objective diagnosis of dysplasia in BO. The clinical implications have to be studied further.
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Affiliation(s)
| | - David F Boerwinkel
- Department of Gastroenterology, Academic Medical Centre, Amsterdam, The Netherlands
| | | | - Xinxue Liu
- Medical Research Council, Cancer Unit, University of Cambridge, Cambridge, UK
| | | | - Pierre Lao-Sirieix
- Medical Research Council, Cancer Unit, University of Cambridge, Cambridge, UK
| | - Elaine Walker
- Medical Research Council, Cancer Unit, University of Cambridge, Cambridge, UK
| | - George Couch
- Medical Research Council, Cancer Unit, University of Cambridge, Cambridge, UK
| | - Leanne Mills
- Medical Research Council, Cancer Unit, University of Cambridge, Cambridge, UK
| | | | - Susan Slininger
- Digestive Disease Centre, NIHR Biomedical Research Unit, Nottingham University Hospitals NHS trust, Nottingham, UK
| | - Maria O'Donovan
- Medical Research Council, Cancer Unit, University of Cambridge, Cambridge, UK
| | - Mike Visser
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
| | - Sybren L Meijer
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
| | - Philip V Kaye
- Department of Pathology, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | | | - Krish Ragunath
- Digestive Disease Centre, NIHR Biomedical Research Unit, Nottingham University Hospitals NHS trust, Nottingham, UK
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16
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Fouad YM, Mostafa I, Yehia R, El-Khayat H. Biomarkers of Barrett's esophagus. World J Gastrointest Pathophysiol 2014; 5:450-456. [PMID: 25400988 PMCID: PMC4231509 DOI: 10.4291/wjgp.v5.i4.450] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 07/02/2014] [Accepted: 07/17/2014] [Indexed: 02/06/2023] Open
Abstract
Barrett's esophagus is the strongest risk for esophageal adenocarcinoma (EAC). Metaplasia in patients with BE may progress to dysplasia and then invasive carcinoma. Well-defined diagnostic, progressive, predictive, and prognostic biomarkers are needed to identify the presence of the disease, estimate the risk of malignant transformation, and predict the therapeutic outcome and survival of EAC patients. There are many predictive and prognostic markers that lack substantial validation, and do not allow stratification of patients with gastroesophageal reflux disease in clinical practice for outcome and effectiveness of therapy. In this short review we summarize the current knowledge regarding possible biomarkers, focusing on the pathophysiologic mechanisms to improve prognostic and therapeutic approaches.
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17
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di Pietro M, Alzoubaidi D, Fitzgerald RC. Barrett's esophagus and cancer risk: how research advances can impact clinical practice. Gut Liver 2014; 8:356-70. [PMID: 25071900 PMCID: PMC4113043 DOI: 10.5009/gnl.2014.8.4.356] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 04/15/2014] [Indexed: 12/18/2022] Open
Abstract
Barrett’s esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), whose incidence has increased sharply in the last 4 decades. The annual conversion rate of BE to cancer is significant, but small. The identification of patients at a higher risk of cancer therefore poses a clinical conundrum. Currently, endoscopic surveillance is recommended in BE patients, with the aim of diagnosing either dysplasia or cancer at early stages, both of which are curable with minimally invasive endoscopic techniques. There is a large variation in clinical practice for endoscopic surveillance, and dysplasia as a marker of increased risk is affected by sampling error and high interobserver variability. Screening programs have not yet been formally accepted, mainly due to the economic burden that would be generated by upper gastrointestinal endoscopy. Screening programs have not yet been formally accepted, mainly due to the economic burden that would be generated by widespread indication to upper gastrointestinal endoscopy. In fact, it is currently difficult to formulate an accurate algorithm to confidently target the population at risk, based on the known clinical risk factors for BE and EAC. This review will focus on the clinical and molecular factors that are involved in the development of BE and its conversion to cancer and on how increased knowledge in these areas can improve the clinical management of the disease.
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Affiliation(s)
| | - Durayd Alzoubaidi
- Department of Gastroenterology, Basildon and Thurrock University Hospital, Basildon, UK
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18
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Ramzan Z, Nassri AB, Huerta S. The use of imaging and biomarkers in diagnosing Barrett's esophagus and predicting the risk of neoplastic progression. Expert Rev Mol Diagn 2014; 14:575-91. [PMID: 24831686 DOI: 10.1586/14737159.2014.919856] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Long-standing gastroesophageal reflux disease can result in transformation of the normal squamous lining of the esophagus into columnar epithelium (with goblet cells). This condition, Barrett's esophagus (BE), is considered a risk factor for esophageal cancer (EAC) and may be the cause of the increased incidence of EAC over the last few decades. Currently, endoscopy with biopsies revealing dysplasia is the best predictor for neoplastic progression in patients with BE. However, the use of more sophisticated imaging techniques and biomarkers with or without histological assessment may be helpful in more accurate prediction of malignant transformation in these patients. New approaches to the evaluation of BE such as epigenetics, miRNA analysis, detection of DNA content abnormalities and loss of heterozygosity have great potential to shed light on the complex gastroesophageal reflux disease -BE-EAC sequence.
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Affiliation(s)
- Zeeshan Ramzan
- VA North Texas Healthcare System - Dallas VA Medical Center, University of Texas Southwestern Medical Center, 4500 S. Lancaster Road, Dallas, TX 75216, USA
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19
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Cowie A, Noble F, Underwood T. Strategies to improve outcomes in esophageal adenocarcinoma. Expert Rev Anticancer Ther 2014; 14:677-87. [PMID: 24621143 DOI: 10.1586/14737140.2014.895668] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Esophageal adenocarcinoma is one of the fastest rising cancers in Western society. Incidence has increased by 600% within the last 30 years. Rates of diagnosis and death run parallel due to the poor prognosis and a lack of effective treatments. Potentially curative treatments are followed by high rates of disease recurrence. For the majority of patients, who present with advanced disease, we have no effective treatment. We discuss the key areas of progress in this demanding field and offer our views on the direction of future research and treatment.
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Affiliation(s)
- Andrew Cowie
- Cancer Sciences Unit, Somers Cancer Research Building, Faculty of Medicine, University of Southampton, SO16 6YD, UK
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20
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Timmer MR, Sun G, Gorospe EC, Leggett CL, Lutzke L, Krishnadath KK, Wang KK. Predictive biomarkers for Barrett's esophagus: so near and yet so far. Dis Esophagus 2013; 26:574-81. [PMID: 23316980 PMCID: PMC4466900 DOI: 10.1111/dote.12015] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Barrett's esophagus (BE) is the strongest risk factor for the development of esophageal adenocarcinoma. However, the risk of cancer progression is difficult to ascertain in individuals, as a significant number of patients with BE do not necessarily progress to esophageal adenocarcinoma. There are several issues with the current strategy of using dysplasia as a marker of disease progression. It is subject to sampling error during biopsy acquisition and interobserver variability among gastrointestinal pathologists. Ideal biomarkers with high sensitivity and specificity are needed to accurately detect high-risk BE patients for early intervention and appropriate cost-effective surveillance. To date, there are no available molecular tests in routine clinical practice despite known genetic and epigenetic aberrations in the Barrett's epithelium. In this review, we present potential biomarkers for the prediction of malignant progression in BE. These include markers of genomic instability, tumor suppressor loci abnormalities, epigenetic changes, proliferation markers, cell cycle predictors, and immunohistochemical markers. Further work in translating biomarkers for routine clinical use may eventually lead to accurate risk stratification.
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Affiliation(s)
- M. R. Timmer
- Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA,Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - G. Sun
- Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA,Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China
| | - E. C. Gorospe
- Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - C. L. Leggett
- Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - L. Lutzke
- Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - K. K. Krishnadath
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - K. K. Wang
- Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Abstract
Oesophageal adenocarcinoma will soon cease to be a rare form of cancer for people born after 1940. In many Western countries, its incidence has increased more rapidly than other digestive cancers. Incidence started increasing in the Seventies in England and USA, 15 years later in Western Europe and Australia. The cumulative risk between the ages of 15 and 74 is particularly striking in the UK, with a tenfold increase in men and fivefold increase in women in little more than a single generation. Prognosis is poor with a 5-year relative survival rate of less than 10%. The main known risk factors are gastro-oesophageal reflux, obesity (predominantly mediated by intra-abdominal adipose tissues) and smoking. Barrett's oesophagus is a precancerous lesion, however, the risk of degeneration has been overestimated. In population-based studies the annual risk of adenocarcinoma varied between 0.12% and 0.14% and its incidence between 1.2 and 1.4 per 1000 person-years. Only 5% of subjects with Barrett's oesophagus die of oesophageal adenocarcinoma. On the basis of recent epidemiological data, new surveillance strategies should be developed. The purpose of this review is to focus on the epidemiology and risk factors of oesophageal adenocarcinoma.
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22
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Tänzer M, Liebl M, Quante M. Molecular biomarkers in esophageal, gastric, and colorectal adenocarcinoma. Pharmacol Ther 2013; 140:133-47. [PMID: 23791941 DOI: 10.1016/j.pharmthera.2013.06.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Accepted: 06/06/2013] [Indexed: 02/06/2023]
Abstract
Cancers of the esophagus, stomach and colon contribute to a major health burden worldwide and over 20% of all cancer deaths. Biomarkers that should indicate pathogenic process and are measureable in an objective manner for these tumors are rare and not established in the clinical setting. In general biomarkers can be very useful for cancer management as they can improve clinical decision-making regarding diagnosis, surveillance, and therapy. Biomarkers can be different types of molecular entities (such as DNA, RNA or proteins), which can be detected, in different tissues or body fluids. However, more important is the type of biomarker itself, which allows diagnostic, prognostic or predictive analyses for different clinical problems. This review aims to systematically summarize the recent findings of genetic and epigenetic markers for gastrointestinal tumors within the last decade. While many biomarkers seem to be very promising, especially if used as panels, further development is urgently needed to address practical considerations of biomarkers in cancer treatment.
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Affiliation(s)
- Marc Tänzer
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany
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23
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The molecular changes driving the carcinogenesis in Barrett's esophagus: Which came first, the chicken or the egg? Crit Rev Oncol Hematol 2013; 86:278-89. [DOI: 10.1016/j.critrevonc.2012.12.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Revised: 09/21/2012] [Accepted: 12/10/2012] [Indexed: 02/06/2023] Open
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GERD-Barrett-Adenocarcinoma: Do We Have Suitable Prognostic and Predictive Molecular Markers? Gastroenterol Res Pract 2013; 2013:643084. [PMID: 23573078 PMCID: PMC3615572 DOI: 10.1155/2013/643084] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 02/18/2013] [Indexed: 02/07/2023] Open
Abstract
Due to unfavorable lifestyle habits (unhealthy diet and tobacco abuse) the incidence of gastroesophageal reflux disease (GERD) in western countries is increasing. The GERD-Barrett-Adenocarcinoma sequence currently lacks well-defined diagnostic, progressive, predictive, and prognostic biomarkers (i) providing an appropriate screening method identifying the presence of the disease, (ii) estimating the risk of evolving cancer, that is, the progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC), (iii) predicting the response to therapy, and (iv) indicating an overall survival—prognosis for EAC patients. Based on histomorphological findings, detailed screening and therapeutic guidelines have been elaborated, although epidemiological studies could not support the postulated increasing progression rates of GERD to BE and EAC. Additionally, proposed predictive and prognostic markers are rather heterogeneous by nature, lack substantial proofs, and currently do not allow stratification of GERD patients for progression, outcome, and therapeutic effectiveness in clinical practice. The aim of this paper is to discuss the current knowledge regarding the GERD-BE-EAC sequence mainly focusing on the disputable and ambiguous status of proposed biomarkers to identify promising and reliable markers in order to provide more detailed insights into pathophysiological mechanisms and thus to improve prognostic and predictive therapeutic approaches.
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25
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di Pietro M, Fitzgerald RC. Screening and risk stratification for Barrett's esophagus: how to limit the clinical impact of the increasing incidence of esophageal adenocarcinoma. Gastroenterol Clin North Am 2013; 42:155-73. [PMID: 23452636 DOI: 10.1016/j.gtc.2012.11.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Barrett's esophagus (BE) and gastroesophageal reflux disease are the strongest risk factors for esophageal adenocarcinoma. To reduce the clinical impact of this disease, endoscopic screening to detect BE has been proposed and nonendoscopic diagnostic techniques are under investigation. Because screening would result in new diagnoses of BE and additional costs related to endoscopic surveillance, novel tools for risk stratification are also warranted. Dysplasia is the gold standard for risk stratification. Molecular biomarkers may provide a more objective and reproducible estimation of the individual risk, and further prospective studies are required as a prelude to introducing biomarkers into routine clinical practice.
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26
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Miyazaki T, Inose T, Tanaka N, Yokobori T, Suzuki S, Ozawa D, Sohda M, Nakajima M, Fukuchi M, Kato H, Kuwano H. Management of Barrett's esophageal carcinoma. Surg Today 2013; 43:353-60. [PMID: 23283352 DOI: 10.1007/s00595-012-0468-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Accepted: 05/13/2012] [Indexed: 02/07/2023]
Abstract
Barrett's esophagus (BE) is the premalignant lesion from which esophageal adenocarcinoma near the esophagogastric junction arises. The management of BE and the treatment of Barrett's esophageal adenocarcinoma (BEA) are important clinical issues in Europe and the United States. As the Helicobacter pylori infection rate in Japan is decreasing in the younger population, the incidence of BE and adenocarcinoma arising from BE may start increasing. Thus, we review the current status of BEA and its management. Magnifying endoscopy with narrow-band imaging is important for diagnosing dysplasia arising from BE. In Japan, adenocarcinoma arising from BE is managed the same way as squamous cell carcinoma in the same location. Strategies to prevent BEA may include medication such as non-steroidal anti-inflammatory drugs and proton pump inhibitors, and anti-reflux surgery. Understanding the pathophysiology of BE will help to reduce the incidence of BEA.
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Affiliation(s)
- Tatsuya Miyazaki
- Department of General Surgical Science, Gunma University Graduate School, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
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Bird-Lieberman EL, Dunn JM, Coleman HG, Lao-Sirieix P, Oukrif D, Moore CE, Varghese S, Johnston BT, Arthur K, McManus DT, Novelli MR, O'Donovan M, Cardwell CR, Lovat LB, Murray LJ, Fitzgerald RC. Population-based study reveals new risk-stratification biomarker panel for Barrett's esophagus. Gastroenterology 2012; 143:927-35.e3. [PMID: 22771507 DOI: 10.1053/j.gastro.2012.06.041] [Citation(s) in RCA: 134] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Revised: 06/20/2012] [Accepted: 06/22/2012] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS The risk of progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is low and difficult to calculate. Accurate tools to determine risk are needed to optimize surveillance and intervention. We assessed the ability of candidate biomarkers to predict which cases of BE will progress to EAC or high-grade dysplasia and identified those that can be measured in formalin-fixed tissues. METHODS We analyzed data from a nested case-control study performed using the population-based Northern Ireland BE Register (1993-2005). Cases who progressed to EAC (n = 89) or high-grade dysplasia ≥ 6 months after diagnosis with BE were matched to controls (nonprogressors, n = 291), for age, sex, and year of BE diagnosis. Established biomarkers (abnormal DNA content, p53, and cyclin A expression) and new biomarkers (levels of sialyl Lewis(a), Lewis(x), and Aspergillus oryzae lectin [AOL] and binding of wheat germ agglutinin) were assessed in paraffin-embedded tissue samples from patients with a first diagnosis of BE. Conditional logistic regression analysis was applied to assess odds of progression for patients with dysplastic and nondysplastic BE, based on biomarker status. RESULTS Low-grade dysplasia and all biomarkers tested, other than Lewis(x), were associated with risk of EAC or high-grade dysplasia. In backward selection, a panel comprising low-grade dysplasia, abnormal DNA ploidy, and AOL most accurately identified progressors and nonprogressors. The adjusted odds ratio for progression of patients with BE with low-grade dysplasia was 3.74 (95% confidence interval, 2.43-5.79) for each additional biomarker and the risk increased by 2.99 for each additional factor (95% confidence interval, 1.72-5.20) in patients without dysplasia. CONCLUSIONS Low-grade dysplasia, abnormal DNA ploidy, and AOL can be used to identify patients with BE most likely to develop EAC or high-grade dysplasia.
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Varghese S, Lao-Sirieix P, Fitzgerald RC. Identification and clinical implementation of biomarkers for Barrett's esophagus. Gastroenterology 2012; 142:435-441.e2. [PMID: 22266150 DOI: 10.1053/j.gastro.2012.01.013] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Sibu Varghese
- MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, UK
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Yang M, Wu S, Jia J, May WS. JAZ mediates G1 cell cycle arrest by interacting with and inhibiting E2F1. Cell Cycle 2011; 10:2390-9. [PMID: 21715977 PMCID: PMC3322471 DOI: 10.4161/cc.10.14.16587] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2011] [Accepted: 05/23/2011] [Indexed: 12/26/2022] Open
Abstract
We discovered and reported JAZ as a unique dsRNA binding zinc finger protein that functions as a direct, positive regulator of p53 transcriptional activity to mediate G1 cell cycle arrest in a mechanism involving upregulation of the p53 target gene, p21. We now find that JAZ can also negatively regulate the cell cycle in a novel, p53-independent mechanism resulting from the direct interaction with E2F1, a key intermediate in regulating cell proliferation and tumor suppression. JAZ associates with E2F1's central DNA binding/dimerization region and its C-terminal transactivation domain. Functionally, JAZ represses E2F1 transcriptional activity in association with repression of cyclin A expression and inhibition of G1/S transition. This mechanism involves JAZ-mediated inhibition of E2F1's specific DNA binding activity. JAZ directly binds E2F1 in vitro in a dsRNA-independent manner, and JAZ's dsRNA binding ZF domains, which are necessary for localizing JAZ to the nucleus, are required for repression of transcriptional activity in vivo. Importantly for specificity, siRNA-mediated "knockdown" of endogenous JAZ increases E2F transcriptional activity and releases cells from G1 arrest, indicating a necessary role for JAZ in this transition. Although JAZ can directly inhibit E2F1 activity independently of p53, if functional p53 is expressed, JAZ may exert a more potent inhibition of cell cycle following growth factor withdrawal. Therefore, JAZ plays a dual role in cell cycle regulation by both repressing E2F1 transcriptional activity and activating p53 to facilitate efficient growth arrest in response to cellular stress, which may potentially be exploited therapeutically for tumor growth inhibition.
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Affiliation(s)
- Mingli Yang
- Department of Medicine, Division of Hematology/Oncology, Shands Cancer Center, University of Florida, Gainesville, FL, USA
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Evidence for DNA damage checkpoint activation in barrett esophagus. Transl Oncol 2011; 3:33-42. [PMID: 20165693 DOI: 10.1593/tlo.09187] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2009] [Revised: 09/25/2009] [Accepted: 10/02/2009] [Indexed: 11/18/2022] Open
Abstract
Barrett esophagus is an epithelial metaplasia that predisposes to adenocarcinoma. Better markers of cancer risk are urgently needed to identify those patients who are likely to benefit most from emerging methods of endoscopic ablation. Disease progression is associated with genomic DNA changes (segmental gains, losses, or loss of heterozygosity). Although these changes are not easily assayed directly, we hypothesized that the underlying DNA damage should activate a DNA damage response (DDR), detectable by immunohistochemical (IHC) assays of checkpoint proteins and the resulting replicative phase cell cycle delays. Surgical specimens and endoscopic biopsies (N = 28) were subjected to IHC for the cell cycle markers cyclin A and phosphorylated histone H3 (P-H3), the DDR markers gammaH2AX and phosphorylated ATM/ATR substrates (P-ATM/ATRsub), and the DNA damage-responsive tumor suppressors p16 and p53. Correlations were made with histologic diagnoses. The fractions of cells that stained for cyclin A, P-H3, and gammaH2AX increased in parallel in dysplastic tissue, consistent with checkpoint-mediated cell cycle delays. Foci of nuclear gammaH2AX and P-ATM/ATRsub were demonstrated by standard and confocal immunofluorescence. Staining for p16 was more prevalent in early-stage disease with lower staining for gammaH2AX and P-H3. Staining for p53 was moderately increased in some early-stage disease and strongly increased in some advanced disease, consistent with checkpoint-mediated induction and mutational inactivation of p53, respectively. We suggest that IHC for DDR-associated markers may help stratify risk of disease progression in Barrett.
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Kadri S, Lao-Sirieix P, Fitzgerald RC. Developing a nonendoscopic screening test for Barrett's esophagus. Biomark Med 2011; 5:397-404. [PMID: 21657849 DOI: 10.2217/bmm.11.40] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Barrett's esophagus (BE) arises as a complication of chronic gastro-esophageal reflux disease and is the precursor lesion for esophageal adenocarcinoma. The prevalence of esophageal adenocarcinoma has been increasing in Western countries and the overall prognosis from this cancer remains dismal. Surveillance for BE is highly controversial since although early cancer detection through surveillance programs benefits individuals, surveillance has not been proven to reduce population mortality from the disease. One factor contributing to this apparent paradox is that an estimated >80% cases of BE are undiagnosed and, therefore, do not have the benefit of surveillance. Some form of screening modality is required to achieve more comprehensive detection of BE, which in turn, may lead to early detection of cancerous lesions and early intervention in order to reduce progression to invasive and symptomatic cancer. The advent of endoscopic therapy makes this paradigm attractive. A number of methods could be considered for screening. These include a nonendoscopic sampling method using a Cytosponge that needs to be coupled with a biomarker to obtain required levels of sensitivity and specificity. For screening to be recommended consideration needs to be given to the point of delivery, cost and acceptability to patients.
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Affiliation(s)
- Sudarshan Kadri
- MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, UK
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32
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Kim DH, Park SE, Kim M, Ji YI, Kang MY, Jung EH, Ko E, Kim Y, Kim S, Shim YM, Park J. A functional single nucleotide polymorphism at the promoter region of cyclin A2 is associated with increased risk of colon, liver, and lung cancers. Cancer 2011; 117:4080-91. [DOI: 10.1002/cncr.25930] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Revised: 11/13/2010] [Accepted: 12/08/2010] [Indexed: 01/10/2023]
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Ong CAJ, Lao-Sirieix P, Fitzgerald RC. Biomarkers in Barrett's esophagus and esophageal adenocarcinoma: predictors of progression and prognosis. World J Gastroenterol 2010; 16:5669-81. [PMID: 21128316 PMCID: PMC2997982 DOI: 10.3748/wjg.v16.i45.5669] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2010] [Revised: 07/28/2010] [Accepted: 08/04/2010] [Indexed: 02/07/2023] Open
Abstract
Barrett's esophagus is a well-known premalignant lesion of the lower esophagus that is characterized by intestinal metaplasia of the squamous epithelium. It is clinically important due to the increased risk (0.5% per annum) of progression to esophageal adenocarcinoma (EA), which has a poor outcome unless diagnosed early. The current clinical management of Barrett's esophagus is hampered by the lack of accurate predictors of progression. In addition, when patients develop EA, the current staging modalities are limited in stratifying patients into different prognostic groups in order to guide the optimal therapy for an individual patient. Biomarkers have the potential to improve radically the clinical management of patients with Barrett's esophagus and EA but have not yet entered mainstream clinical practice. This is in contrast to other cancers like breast and prostate for which biomarkers are utilized routinely to inform clinical decisions. This review aims to highlight the most promising predictive and prognostic biomarkers in Barrett's esophagus and EA and to discuss what is required to move the field forward towards clinical application.
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Abstract
Biomarkers are needed to screen multiple stages in the clinical pathway of Barrett's oesophagus patients; from disease diagnosis to risk stratification and predicting response to therapy. Routes to the identification of biomarkers have been recognized by known molecular features of the disease and more recently through transcriptomic, methylation and proteomic screening approaches. The majority of Barrett's oesophagus patients remain undiagnosed in the general population. In order to develop a tool to screen for Barrett's oesophagus in the primary care setting, minimally invasive sampling methods coupled with immunocytology-based biomarkers are currently being assessed. Biomarkers may also have utility in surveillance programmes by allowing endoscopic interval to be adjusted according to individual neoplastic risk. Many individual biomarkers have been proposed in this regard, but have frequently been assessed in studies of limited power, or have lacked sufficient sensitivity or specificity when assessed in wider population-based studies. Biomarker panels may provide a route forward. In this regard, a panel of methylation markers has shown promise in a multicentre, double-blind, validation study. Biomarkers are also being developed to improve detection of high-grade dysplasia and oesophageal adenocarcinoma, utilizing brush cytology combined with FISH (fluorescence in situ hybridization), and to assess therapeutic success and risk of complication during photodynamic therapy. Finally, we outline progress in identifying alternative sources of biomarkers for this condition.
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35
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Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers. Proc Natl Acad Sci U S A 2010; 107:2177-82. [PMID: 20080664 DOI: 10.1073/pnas.0909797107] [Citation(s) in RCA: 159] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The stromal compartment is increasingly recognized to play a role in cancer. However, its role in the transition from preinvasive to invasive disease is unknown. Most gastrointestinal tumors have clearly defined premalignant stages, and Barrett's esophagus (BE) is an ideal research model. Supervised clustering of gene expression profiles from microdissected stroma identified a gene signature that could distinguish between BE metaplasia, dysplasia, and esophageal adenocarcinoma (EAC). EAC patients overexpressing any of the five genes (TMEPAI, JMY, TSP1, FAPalpha, and BCL6) identified from this stromal signature had a significantly poorer outcome. Gene ontology analysis identified a strong inflammatory component in BE disease progression, and key pathways included cytokine-cytokine receptor interactions and TGF-beta. Increased protein levels of inflammatory-related genes significantly up-regulated in EAC compared with preinvasive stages were confirmed in the stroma of independent samples, and in vitro assays confirmed functional relevance of these genes. Gene set enrichment analysis of external datasets demonstrated that the stromal signature was also relevant in the preinvasive to invasive transition of the stomach, colon, and pancreas. These data implicate inflammatory pathways in the genesis of gastrointestinal tract cancers, which can affect prognosis.
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Abstract
Barrett's esophagus is a condition in which the stratified squamous epithelium of the distal esophagus is replaced by specialized intestinal metaplasia. Clinical management of Barrett's esophagus, like many other "premalignant" conditions, is characterized by overdiagnosis of benign early changes that will not cause death or suffering during the lifetime of an individual and underdiagnosis of life-threatening early disease. Recent studies of a number of different types of cancer have revealed much greater genomic complexity than was previously suspected. This genomic complexity could create challenges for early detection and prevention if it develops in premalignant epithelia prior to cancer. Neoplastic progression unfolds in space and time, and Barrett's esophagus provides one of the best models for rapid advances, including "gold standard" cohort studies, to distinguish individuals who do and do not progress to cancer. Specialized intestinal metaplasia has many properties that appear to be protective adaptations to the abnormal environment of gastroesophageal reflux. A large body of evidence accumulated over several decades implicates chromosome instability in neoplastic progression from Barrett's esophagus to esophageal adenocarcinoma. Small, spatial scale studies have been used to infer the temporal order in which genomic abnormalities develop during neoplastic progression in Barrett's esophagus. These spatial studies have provided the basis for prospective cohort studies of biomarkers, including DNA content abnormalities (tetraploidy, aneuploidy) and a biomarker panel of 9p LOH, 17p LOH and DNA content abnormalities. Recent advances in SNP array technology provide a uniform platform to assess chromosome instability.
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Affiliation(s)
- Brian J Reid
- Fred Hutchinson Cancer Research Center, Divisions of Human Biology and Public Health Sciences, Department of Genome Sciences, University of Washington, Seattle, WA, USA.
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37
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Barbiere JM, Lyratzopoulos G. Cost-effectiveness of endoscopic screening followed by surveillance for Barrett's esophagus: a review. Gastroenterology 2009; 137:1869-76. [PMID: 19840798 DOI: 10.1053/j.gastro.2009.10.011] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Screening interventions for Barrett's esophagus (BE) are appealing, but there is little supporting evidence. We reviewed health economics studies about BE endoscopic screening followed by, as required, endoscopic surveillance ("screening and surveillance" hereafter) to help inform the design and conduct of future research. Health economics studies about BE screening and surveillance were identified using electronic database searches and personal contact with authors of identified studies. No studies examined general population screening. Five US studies published between 2003 and 2007 examined the cost effectiveness of screening and surveillance (against no intervention) in patients with chronic gastroesophageal reflux disease (GERD). There was no randomized trial evidence to inform model construction. Assumptions about prevalence and transition probabilities between BE histologic subtypes and about surveillance and treatment protocols varied substantially between studies. Parameters such as potential BE diagnosis-related reduction in quality of life or increase in health care use, diagnostic accuracy, and infrastructural costs (for quality assurance) were considered either "optimistically" or not at all. Only 2 studies considered endoscopic treatments. No study considered the recently introduced radiofrequency ablation technique, or the potential for biomarker-based risk stratification of surveillance interval or duration. Current health economics evidence is likely to have provided optimistic cost-effectiveness estimates and is not sufficient to support introduction of endoscopic BE screening programs among GERD patients. The evidence does not adequately incorporate novel (endoscopic) treatments and the potential for (clinical, endoscopic, or biomarker-based) risk stratification of surveillance. Future research should aim to encompass both these factors.
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Affiliation(s)
- Josephine M Barbiere
- Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
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38
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Abstract
There are 5 to 6 levels of biomarker validation. Those for Barrett's esophagus are currently at level 3, despite small prospective studies. What is ideally required is a very large prospective assessment of biopsies in large cohorts, such as the ASPirin Esomeprazole Chemoprevention Trial (AspECT) and Barrett's Oesophagus Surveillance Study (BOSS) trials, so that unbiased and random selection of cases can be subjected to rigorous pathology and biomarker assessment (level 4). Only then can the predictive power of the data be exploited in a randomized intervention trial (level 5) whereby a series of biomarkers would trigger therapy. The real trouble is that this spot is currently occupied, satisfactorily according to some researchers, by conventional histological identification of high-grade dysplasia (HGD) as used in a recent randomized study of ablation in Barrett's esophagus (BE).
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di Pietro M, Fitzgerald RC. Barrett's oesophagus: an ideal model to study cancer genetics. Hum Genet 2009; 126:233-46. [PMID: 19365640 DOI: 10.1007/s00439-009-0665-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2009] [Accepted: 04/01/2009] [Indexed: 12/16/2022]
Abstract
Chronic gastro-oesophageal reflux disease can induce a metaplastic change of the distal oesophagus called Barrett's oesophagus whereby the normal squamous epithelium is substituted by a columnar epithelium. Patients with Barrett's oesophagus are at increased risk of oesophageal adenocarcinoma which occurs through dysplastic stages with increasing degree of cellular and architectural disorganization. Barrett's oesophagus represents an ideal model to study the genetic events supporting the onset of an invasive tumour since patients with this condition are surveilled with endoscopic tissue sampling until high grade dysplasia or intramucosal carcinoma develop. However, due to the relatively low incidence of this disease compared to other cancers, i.e. colon and breast, it is only recently that researchers have concentrated on understanding the genetic events supporting the onset of Barrett's and its transformation to cancer. Here, we review the knowledge acquired so far on the genetic and molecular alterations along the oesophageal metaplasia-dysplasia-carcinoma sequence.
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40
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Bird-Lieberman EL, Fitzgerald RC. Early diagnosis of oesophageal cancer. Br J Cancer 2009; 101:1-6. [PMID: 19513070 PMCID: PMC2713695 DOI: 10.1038/sj.bjc.6605126] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2009] [Revised: 04/27/2009] [Accepted: 05/18/2009] [Indexed: 12/26/2022] Open
Abstract
Squamous cell carcinoma and adenocarcinoma of the oesophagus are cancers that develop from distinct epithelial sub-types; however, they are both related to chronic inflammation of differing aetiologies. Inflammation leads to somatically inherited genetic mutations altering control of the cell cycle, DNA replication and apoptosis, which together result in autonomous and uncontrolled proliferation. These cancers have often metastasised to lymph nodes and distant organs before symptomatic presentation and therefore carry a poor prognosis. It is therefore vital to diagnose oesophageal cancer at an early stage, before the development of symptoms, when treatment can dramatically improve prognosis. Understanding the pathogenesis of these cancers is vital to guide early diagnostic strategies.
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Affiliation(s)
- E L Bird-Lieberman
- MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Hills Road, Cambridge CB22 0XZ, UK
| | - R C Fitzgerald
- MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Hills Road, Cambridge CB22 0XZ, UK
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41
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42
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Abstract
Barrett's esophagus (BE) is a metaplastic premalignant disorder in which the normal stratified squamous epithelium of the lower esophagus is replaced by a columnar lined epithelium with intestinal differentiation. BE generally occurs in the context of chronic gastroesophageal reflux disease and it is the primary risk factor for the development of esophageal adenocarcinoma, with a conversion rate of 0.5% to 1% per annum. The dramatic increase of esophageal adenocarcinoma incidence in the western world over the last two decades justifies the strong interest in BE and its development with the aim to improve preventative and therapeutic clinical strategies.
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43
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Zhang HY, Spechler SJ, Souza RF. Esophageal adenocarcinoma arising in Barrett esophagus. Cancer Lett 2009; 275:170-7. [PMID: 18703277 PMCID: PMC2673195 DOI: 10.1016/j.canlet.2008.07.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2008] [Revised: 07/03/2008] [Accepted: 07/04/2008] [Indexed: 12/20/2022]
Abstract
The major risk factors for esophageal adenocarcinoma are gastroesophageal reflux disease (GERD) and Barrett esophagus, a squamous-to-columnar cell metaplasia that predisposes to malignancy. Adenocarcinomas in Barrett esophagus are thought to arise through a sequence of growth-promoting, genetic alterations that accumulate until the cells have acquired the physiologic hallmarks of cancer proposed by Hanahan and Weinberg. Moreover, GERD and Barrett esophagus are associated with chronic esophagitis, and inflammation is a well known risk factor for cancer formation. The cell that gives rise to Barrett metaplasia is not known. It has been proposed that the metaplasia may arise from a change in the differentiation pattern of stem cells that either reside in the esophagus or are recruited to the esophagus from the bone marrow. Alternatively, it is possible that Barrett metaplasia develops through the conversion of one differentiated cell type into another. Regardless of the cell of origin, Barrett metaplasia ultimately must be sustained by stem cells, which might be identified by intestinal stem cell markers. An emerging concept in tumor biology is that cancer stem cells are responsible for sustaining tumor growth. If Barrett cancers develop from Barrett stem cells, then a therapy targeted at those stem cells might prevent esophageal adenocarcinoma. This report reviews the risk factors for Barrett esophagus and esophageal adenocarcinoma, the mechanisms by which genetic alterations might contribute to carcinogenesis in Barrett esophagus, and the role of stem cells in the development of Barrett metaplasia and adenocarcinoma.
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Affiliation(s)
- Hui Ying Zhang
- Departments of Medicine, VA North Texas Healthcare System, University of Texas Southwestern Medical School, University of Texas Southwestern Medical Center at Dallas, Dallas, TX
| | - Stuart Jon Spechler
- Departments of Medicine, VA North Texas Healthcare System, University of Texas Southwestern Medical School, University of Texas Southwestern Medical Center at Dallas, Dallas, TX
| | - Rhonda F. Souza
- Departments of Medicine, VA North Texas Healthcare System, University of Texas Southwestern Medical School, University of Texas Southwestern Medical Center at Dallas, Dallas, TX
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX
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Abstract
Barrett's oesophagus is a metaplastic change of the lining of the oesophagus, such that the normal squamous epithelium is replaced by specialised or intestinalised columnar epithelium. The disorder seems to be a complication of chronic gastro-oesophageal reflux disease, although asymptomatic individuals might also be affected, and it is a risk factor for the development of oesophageal adenocarcinoma, a cancer with rapidly increasing incidence in developed societies. We review the presentation, epidemiology, and risk factors for this condition. We discuss the molecular changes necessary for the development of Barrett's oesophagus and its progression to cancer, and new strides in both the endoscopic detection of the lesion and the treatment of dysplastic disease. Also, we assess the effectiveness of efforts to screen patients at risk of Barrett's oesophagus, and whether such efforts avert cancer death. We conclude with a discussion of future directions for research, focusing on treatment of early neoplasia, and modifications of current practices to show our evolving understanding of this condition.
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Affiliation(s)
- Nicholas J Shaheen
- Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, NC, USA
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45
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Huang Y, Peters CJ, Fitzgerald RC, Gjerset RA. Progressive silencing of p14ARF in oesophageal adenocarcinoma. J Cell Mol Med 2009; 13:398-409. [PMID: 18410530 PMCID: PMC3098888 DOI: 10.1111/j.1582-4934.2008.00336.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2007] [Accepted: 03/24/2008] [Indexed: 12/31/2022] Open
Abstract
The frequency of oesophageal adenocarcinoma is increasing in Western countries for unknown reasons, and correlates with a corresponding increase in the pre-malignant condition, Barrett's Oesophagus, which raises the risk of adenocarcinoma by some 40- to 125-fold. We have examined how disease progression correlates with changes in expression of the p14ARF (ARF) tumour suppressor, a key regulator of the p53 tumour suppressor pathway that is silenced in some 30% of cancers overall, but for which a role in oesophageal cancer is unclear. We have used quantitative PCR, RT-PCR, methylation-specific PCR and chromatin-immunoprecipitation to examine the regulation and function of ARF in oesophageal adenocarcinoma tissue specimens and cell lines. We find highly significant reductions (P< 0.001) in ARF expression during disease progression from normal oesophageal epithelium to Barrett's Oesophagus to adenocarcinoma, with 57/76 (75%) adenocarcinomas displaying undetectable levels of ARF expression. Retention of ARF expression in adenocarcinoma is a highly significant indicator of increased survival (P< 0.001) and outperforms all clinical variables in a multivariate model. CpG methylation as well as histone H3 methylation of lysines 9 and 27 contribute independently to ARF gene silencing in adenocarcinoma cell lines and can be reversed by 5-aza-2'-deoxycytidine. The results suggest that silencing of ARF is involved in the pathogenesis of oesophageal adenocarcinoma and show that either DNA or histone methylation can provide the primary mechanism for ARF gene silencing. Silencing of ARF could provide a useful marker for increased risk of progression and poor prognosis.
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Affiliation(s)
- Yinghui Huang
- Sidney Kimmel Cancer Center, Cancer Cell Biology, San Diego, CA, USA
- MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, and Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Christopher J Peters
- MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, and Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Rebecca C Fitzgerald
- MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, and Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Ruth A Gjerset
- Sidney Kimmel Cancer Center, Cancer Cell Biology, San Diego, CA, USA
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Abstract
Barrett's esophagus is an important step in the pathway to esophageal adenocarcinoma. Since most patients with Barrett's esophagus are undiagnosed and patients present with advanced adenocarcinoma de novo, prognosis for this disease remains poor. To identify those people with Barrett's esophagus who are at particular risk many new technologies are being developed. In association with these advances in risk stratification, progress is being made in the endoscopic treatment of Barrett's. Chemoprevention is also an area of interest and trials are underway.
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47
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Barber M, Murrell A, Ito Y, Maia AT, Hyland S, Oliveira C, Save V, Carneiro F, Paterson AL, Grehan N, Dwerryhouse S, Lao-Sirieix P, Caldas C, Fitzgerald RC. Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer. J Pathol 2008; 216:295-306. [PMID: 18788075 DOI: 10.1002/path.2426] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2008] [Accepted: 07/31/2008] [Indexed: 12/12/2022]
Abstract
Around 25-40% of cases of hereditary diffuse gastric cancer (HDGC) are caused by heterozygous E-cadherin (CDH1) germline mutations. The mechanisms for loss of the second allele still remain unclear. The aims of this study were to elucidate mechanisms for somatic inactivation of the wild-type CDH1 allele and to seek evidence for cadherin switching. Archival tumour material was analysed from 16 patients with CDH1 germline mutations and seven patients fulfilling HDGC criteria without CDH1 germline mutations. The 16 CDH1 exons were sequenced. E-cadherin promoter methylation was analysed by bisulphite sequencing and pyrosequencing and allele specificity was determined using polymorphic loci. Loss of heterozygosity was analysed using microsatellite markers. Cadherin expression levels were determined by real-time RT-PCR and immunohistochemistry. Six of 16 individuals with germline mutations had at least one second hit mechanism. Two exonic mutations (exon 9 truncating, exon 3 missense) and four intronic mutations which may affect splicing were identified. Tumours from 4/16 individuals had promoter hypermethylation that was restricted to the A allele haplotype in three cases. E-cadherin loss (mRNA and protein) generally correlated with identification of a second hit. In cases without germline E-cadherin mutations there was no evidence for somatic mutation or significant promoter methylation. P-cadherin (>25% cells) was expressed in 7/13 (54%) and 4/5 (80%) with and without germline CDH1 mutations, respectively, independent of complete E-cadherin loss. Overall, inactivation of the second CDH1 allele occurs by mutation and methylation events. Methylation is commonly allele-specific and is uncommon without germline mutations. P-cadherin over-expression commonly occurs in individuals with diffuse type gastric cancer.
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Affiliation(s)
- M Barber
- MRC Cancer Cell Unit, Hutchison/MRC Research Centre and Department of Gastroenterology, Addenbrooke's Hospital, Cambridge CB2 2OZ, UK
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Chao DL, Sanchez CA, Galipeau PC, Blount PL, Paulson TG, Cowan DS, Ayub K, Odze RD, Rabinovitch PS, Reid BJ. Cell proliferation, cell cycle abnormalities, and cancer outcome in patients with Barrett's esophagus: a long-term prospective study. Clin Cancer Res 2008; 14:6988-95. [PMID: 18980994 PMCID: PMC2587072 DOI: 10.1158/1078-0432.ccr-07-5063] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE Elevated cellular proliferation and cell cycle abnormalities, which have been associated with premalignant lesions, may be caused by inactivation of tumor suppressor genes. We measured proliferative and cell cycle fractions of biopsies from a cohort of patients with Barrett's esophagus to better understand the role of proliferation in early neoplastic progression and the association between cell cycle dysregulation and tumor suppressor gene inactivation. EXPERIMENTAL DESIGN Cell proliferative fractions (determined by Ki67/DNA multiparameter flow cytometry) and cell cycle fractions (DNA content flow cytometry) were measured in 853 diploid biopsies from 362 patients with Barrett's esophagus. The inactivation status of CDKN2A and TP53 was assessed in a subset of these biopsies in a cross-sectional study. A prospective study followed 276 of the patients without detectable aneuploidy for an average of 6.3 years with esophageal adenocarcinoma as an end point. RESULTS Diploid S and 4N (G(2)/tetraploid) fractions were significantly higher in biopsies with TP53 mutation and loss of heterozygosity. CDKN2A inactivation was not associated with higher Ki67-positive, diploid S, G(1), or 4N fractions. High Ki67-positive and G(1)-phase fractions were not associated with the future development of esophageal adenocarcinoma (P=0.13 and P=0.15, respectively), whereas high diploid S-phase and 4N fractions were (P=0.03 and P<0.0001, respectively). CONCLUSIONS High Ki67-positive proliferative fractions were not associated with inactivation of CDKN2A and TP53 or future development of cancer in our cohort of patients with Barrett's esophagus. Biallelic inactivation of TP53 was associated with elevated 4N fractions, which have been associated with the future development of esophageal adenocarcinoma.
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Affiliation(s)
- Dennis L Chao
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
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Abstract
The incidence of oesophageal adenocarcinoma has increased dramatically in the Western world over the past two decades. Owing to its dismal 5-year prognosis in advanced stages, early diagnosis is required in order to improve survival rates. Barrett's oesophagus (Barrett's) has been recognised as a pre-cancerous condition generally associated with chronic and severe gastro-oesophageal reflux disease (GORD). Barrett's is defined as the substitution of the normal stratified squamous epithelium of the oesophagus with a columnar cell lining with intestinal-type differentiation; a phenomenon commonly referred to as intestinal metaplasia. Clinical challenges include finding cost-effective ways to identify patients with Barrett's, stratifying them according to their cancer risk and improving the diagnostic potential of endoscopic sampling. Research has generally focused on identifying tissue biomarkers to predict cancer risk in these patients. The oesophagus is easily accessible, making it possible to work with human samples, but most studies have been retrospective and underpowered. Endoscopic surveillance programmes are problematic due to sampling bias and the subjective grading of dysplasia. The lack of an animal model has hampered studies to elucidate markers of the transition from Barrett's to cancer and to test potential therapeutics. However, a number of in vitro model systems are ripe for further development into more physiologically complete systems.
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Affiliation(s)
| | - Christopher J. Peters
- MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Hills Road, Cambridge, CB2 0XZ, UK
| | - Rebecca C. Fitzgerald
- MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Hills Road, Cambridge, CB2 0XZ, UK
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Chen J, Guo L, Peiffer DA, Zhou L, Chan OTM, Bibikova M, Wickham-Garcia E, Lu SH, Zhan Q, Wang-Rodriguez J, Jiang W, Fan JB. Genomic profiling of 766 cancer-related genes in archived esophageal normal and carcinoma tissues. Int J Cancer 2008; 122:2249-54. [PMID: 18241037 DOI: 10.1002/ijc.23397] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We employed the BeadArraytrade mark technology to perform a genetic analysis in 33 formalin-fixed, paraffin-embedded (FFPE) human esophageal carcinomas, mostly squamous-cell-carcinoma (ESCC), and their adjacent normal tissues. A total of 1,432 single nucleotide polymorphisms (SNPs) derived from 766 cancer-related genes were genotyped with partially degraded genomic DNAs isolated from these samples. This directly targeted genomic profiling identified not only previously reported somatic gene amplifications (e.g., CCND1) and deletions (e.g., CDKN2A and CDKN2B) but also novel genomic aberrations. Among these novel targets, the most frequently deleted genomic regions were chromosome 3p (including tumor suppressor genes FANCD2 and CTNNB1) and chromosome 5 (including tumor suppressor gene APC). The most frequently amplified genomic region was chromosome 3q (containing DVL3, MLF1, ABCC5, BCL6, AGTR1 and known oncogenes TNK2, TNFSF10, FGF12). The chromosome 3p deletion and 3q amplification occurred coincidently in nearly all of the affected cases, suggesting a molecular mechanism for the generation of somatic chromosomal aberrations. We also detected significant differences in germline allele frequency between the esophageal cohort of our study and normal control samples from the International HapMap Project for 10 genes (CSF1, KIAA1804, IL2, PMS2, IRF7, FLT3, NTRK2, MAP3K9, ERBB2 and PRKAR1A), suggesting that they might play roles in esophageal cancer susceptibility and/or development. Taken together, our results demonstrated the utility of the BeadArray technology for high-throughput genetic analysis in FFPE tumor tissues and provided a detailed genetic profiling of cancer-related genes in human esophageal cancer.
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Affiliation(s)
- Jing Chen
- Illumina Inc., San Diego, CA 92121, USA
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