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Qureshi S, Abbasi WA, Qureshi MA, Jalil HA, Quraishy MS. Identification of PGC as a Potential Biomarker for Progression from Barrett's Esophagus to Esophageal Adenocarcinoma: A Comprehensive Bioinformatic Analysis. Diagnostics (Basel) 2024; 14:2863. [PMID: 39767224 PMCID: PMC11675858 DOI: 10.3390/diagnostics14242863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 11/28/2024] [Accepted: 12/04/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Barrett's esophagus (BE), with metaplastic columnar epithelium in the lower esophagus, predisposes patients to esophageal adenocarcinoma (EAC). Despite extensive research, mechanisms underlying BE progression to EAC remain unclear, and no validated biomarkers are available for clinical use. Progastricsin/Pepsinogen-C (PGC), an aspartic proteinase linked to maintaining normal epithelial morphology, is often absent in advanced gastrointestinal malignancies. This study comprehensively investigates PGC expression across cancers, particularly in esophageal cancer (ESCA), to clarify its role in BE progression to EAC. Methods: We utilized multiple bioinformatic platforms (TIMER, UALCAN, cBioPortal, GEPIA, STRING, Metascape, and GEO database) to assess PGC expression, genomic alterations, and correlations with clinicopathological features, survival, and immune infiltration. Additionally, using the GEO dataset, we compared non-dysplastic Barrett's esophagus (NDBE) patients with those who progressed to malignancy, identifying differentially expressed genes (DEGs), their interactions, and potential roles in progression. Results: PGC was notably upregulated in various cancers, especially in adjacent normal tissues of ESCA. Genomic amplifications of PGC were linked to improved survival in EAC patients, particularly those with high PGC expression, suggesting a protective role. Moreover, PGC expression positively correlated with favorable immune infiltration, notably B cells and CD8+ T cells. Enrichment analysis of downregulated DEGs revealed significant involvement in key biological processes, specifically in extracellular matrix organization. Among the downregulated DEGs, we identified PGC among the top 10 hub genes, underscoring its role in tissue homeostasis. Conclusions: These findings suggest that PGC could serve as a promising biomarker for predicting the high-risk transformation from BE to EAC, offering new insights into EAC progression and future therapeutic targets.
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Mejza M, Małecka-Wojciesko E. Diagnosis and Management of Barrett's Esophagus. J Clin Med 2023; 12:jcm12062141. [PMID: 36983142 PMCID: PMC10057256 DOI: 10.3390/jcm12062141] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/07/2023] [Accepted: 03/07/2023] [Indexed: 03/30/2023] Open
Abstract
Barrett's esophagus is a metaplastic change of esophageal mucosa, which can be characterized by its salmon-colored lining and the presence of columnar epithelium with goblet cells. It is a well-established precancerous state of esophageal adenocarcinoma, a tumor with very poor survival rates, which incidence is rapidly growing. Despite numerous research, the debate about its diagnosis and management is still ongoing. This article aims to provide an overview of the current recommendations and new discoveries regarding the subject.
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Affiliation(s)
- Maja Mejza
- Department of Digestive Tract Diseases, Medical University, 90-153 Lodz, Poland
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Abstract
Barrett's esophagus is the precursor lesion for esophageal adenocarcinoma. The goals of endoscopic surveillance are to detect dysplasia and early esophageal adenocarcinoma in order to improve patient outcomes. Despite the ongoing debate regarding the efficacy of surveillance, all current gastrointestinal societies recommend surveillance at this time. Optimal surveillance technique includes adequate inspection time, evaluation using high-definition white light and chromoendoscopy, appropriate documentation of the metaplastic segment using the Prague C & M criteria as well as the Paris classification should lesions be found, utilization of the Seattle biopsy protocol, and endoscopic resection of visible lesions.
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Affiliation(s)
- Joseph R. Triggs
- Clinical Instructor, Division of Gastroenterology. Hospital of the University of Pennsylvania. University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Gary W. Falk
- Professor of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania. University of Pennsylvania Perelman School of Medicine Pennsylvania, Philadelphia, PA, USA
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Endoscopic Eradication Therapy for Barrett's Neoplasia: Where Do We Stand a Decade Later? Curr Gastroenterol Rep 2020; 22:61. [PMID: 33277663 DOI: 10.1007/s11894-020-00799-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), a cancer associated with increasing incidence and poor survival. Early identification and effective treatment of BE-related neoplasia prior to the development of invasive adenocarcinoma are essential to limiting the morbidity and mortality associated with this cancer. In this review, we summarized the recent evidence guiding endoscopic eradication therapies (EET) for neoplastic BE. RECENT FINDINGS New sampling technologies and the application of artificial intelligence (AI) systems have potential to revolutionize early neoplasia detection in BE. EET for BE are safe and effective in achieving complete eradication of intestinal metaplasia (CE-IM) and reducing the progression to EAC, a practice endorsed by all GI society guidelines. EET should be considered in patients with high-grade dysplasia (HGD), intramucosal carcinoma (IMC), and select cases with low-grade dysplasia (LGD). The increasing use of endoscopic submucosal dissection (ESD) in the West may allow EET of select cases with submucosal EAC. Post-EET surveillance strategies will continue to evolve as knowledge of specific risk factors and long-term neoplasia recurrence rates improve. In the last decade, major advancements in EET for neoplastic BE have been achieved. These now represent the standard of care in the management of BE-related dysplasia and intramucosal cancer.
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Abstract
PURPOSE OF REVIEW Barrett's oesophagus is the only identifiable precursor lesion to oesophageal adenocarcinoma. The stepwise progression of Barrett's oesophagus to dysplasia and invasive carcinoma provides the opportunity to intervene and reduce the morbidity and mortality associated with this lethal cancer. Several studies have demonstrated the efficacy and safety of endoscopic eradication therapy (EET) for the management of Barrett's oesophagus related neoplasia. The primary goal of EET is to achieve complete eradication of intestinal metaplasia (CE-IM) followed by enrolment of patients in surveillance protocols to detect recurrence of Barrett's oesophagus and Barrett's oesophagus related neoplasia. RECENT FINDINGS EET depends on early and accurate detection and diagnosis of Barrett's oesophagus related neoplasia. All visible lesions should be resected followed by ablation of the remaining Barrett's epithelium. After treatment, patients should be enrolled in endoscopic surveillance programmes. For nondysplastic Barrett's oesophagus, surveillance alone is recommended. For low-grade dysplasia, both surveillance and ablation are reasonable options and should be decided on an individual basis according to patient risk factors and preferences. EET is preferred for high-grade dysplasia and intramucosal carcinoma. For T1b oesophageal adenocarcinoma, esophagectomy remains the standard of care, but endoscopic therapy can be considered in select cases. SUMMARY EET is now standard of care and endorsed by societal guidelines for the treatment of Barrett's oesophagus related neoplasia. Future studies should focus on risk stratification models using a combination of clinical data and biomarkers to identify ideal candidates for EET, and to predict recurrence. Optimal therapy for T1b cancer and surveillance strategy after CE-IM are topics that require further study.
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Fassan M, Realdon S, Cascione L, Hahne JC, Munari G, Guzzardo V, Arcidiacono D, Lampis A, Brignola S, Dal Santo L, Agostini M, Bracon C, Maddalo G, Scarpa M, Farinati F, Zaninotto G, Valeri N, Rugge M. Circulating microRNA expression profiling revealed miR-92a-3p as a novel biomarker of Barrett's carcinogenesis. Pathol Res Pract 2020; 216:152907. [PMID: 32131978 DOI: 10.1016/j.prp.2020.152907] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/24/2020] [Accepted: 02/27/2020] [Indexed: 12/20/2022]
Abstract
The main intent of secondary prevention strategies for Barrett's esophagus (BE) patients relies in the prompt identification of patients with dysplasia (or intra-epithelial neoplasia; IEN) and early-stage adenocarcinoma (Barrett's adenocarcinoma; BAc). Despite the adequate characterization of the molecular landscape characterizing Barrett's carcinogenesis, no tissue and/or circulating biomarker has been approved for clinical use. A series of 25 serum samples (12 BE, 5 HG-IEN and 8 BAc) were analyzed for comprehensive miRNA profiling and ten miRNAs were found to be significantly dysregulated. In particular seven were upregulated (i.e. miR-92a-3p, miR-151a-5p, miR-362-3p, miR-345-3p, miR-619-3p, miR-1260b, and miR-1276) and three downregulated (i.e. miR-381-3p, miR-502-3p, and miR-3615) in HG-IEN/BAc samples in comparison to non-dysplastic BE. All the identified miRNAs showed significant ROC curves in discriminating among groups with AUC values range of 0.75-0.83. Validation of the results were performed by droplet digital PCR in two out of three tested miRNAs. To understand the cellular source of circulating miR-92a-3p, we analyzed its expression in endoscopy biopsy samples by both qRT-PCR and ISH analyses. As observed in serum samples, miR-92a-3p was over-expressed in HG-IEN/BAc samples in comparison to naïve esophageal squamous mucosa and BE and was mainly localized within the epithelial cells, supporting neoplastic cells as the main source of the circulating miRNA. Our data further demonstrated that circulating miRNAs are a promising mini-invasive diagnostic tool in the secondary follow-up and management of BE patients. Larger multi-Institutional studies should validate and investigate the most adequate miRNAs profile in discriminating BE patients in specific risk classes.
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Affiliation(s)
- Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy.
| | | | - Luciano Cascione
- Institute of Oncology Research (IOR), Università della Svizzera italiana (USI), Bellinzona, Switzerland; SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Jens C Hahne
- Division of Molecular Pathology, Institute of Cancer Research, London, UK; Centre for Molecular Pathology, Royal Marsden Hospital, London, UK
| | - Giada Munari
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy; Istituto Oncologico Veneto - IOV-IRCCS, Padua, Italy
| | - Vincenza Guzzardo
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
| | | | - Andrea Lampis
- Division of Molecular Pathology, Institute of Cancer Research, London, UK; Centre for Molecular Pathology, Royal Marsden Hospital, London, UK
| | - Stefano Brignola
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
| | - Luca Dal Santo
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
| | - Marco Agostini
- Department of Surgical Oncology and Gastroenterology Sciences (DiSCOG), Surgery Unit, University of Padua, Padua, Italy
| | - Chiara Bracon
- Beatson West of Scotland Cancer Centre, Glasgow, UK; University of Glasgow, Glasgow, UK
| | - Gemma Maddalo
- Department of Surgical Oncology and Gastroenterology Sciences (DiSCOG), Gastroenterology Unit, University of Padua, Padua, Italy
| | - Marco Scarpa
- General Surgery Unit, University Hospital of Padua, Padua, Italy
| | - Fabio Farinati
- Department of Surgical Oncology and Gastroenterology Sciences (DiSCOG), Gastroenterology Unit, University of Padua, Padua, Italy
| | | | - Nicola Valeri
- Division of Molecular Pathology, Institute of Cancer Research, London, UK; Centre for Molecular Pathology, Royal Marsden Hospital, London, UK.
| | - Massimo Rugge
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy; Veneto Cancer Registry, Padua, Italy
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Neutrophil-Lymphocyte Ratio as a Marker of Progression from Non-Dysplastic Barrett's Esophagus to Esophageal Adenocarcinoma: a Cross-Sectional Retrospective Study. J Gastrointest Surg 2020; 24:8-18. [PMID: 31745889 DOI: 10.1007/s11605-019-04456-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 10/29/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Immune imbalance and inflammation have been suggested as key factors of Barrett's esophagus (BE) pathway towards adenocarcinoma. The neutrophil-lymphocyte ratio (NLR) indirectly reflects the relation between innate and adaptive immune systems and has been studied in premalignant conditions as a biomarker for cancer diagnosis. Our aim was to investigate if increasing values of NLR correlated with advancing stages of BE progression to dysplasia and neoplasia. METHODS We retrospectively analyzed data of patients with biopsies reporting BE between 2013 and 2017 and with a complete blood count within 6 months from the endoscopy, as well as patients with esophageal adenocarcinoma (EAC). NLR was calculated as neutrophil count/lymphocyte count. Cases (n = 113) were classified as non-dysplastic BE (NDBE, n = 72), dysplastic BE (DBE, n = 11) and EAC (n = 30). RESULTS NLR progressively increased across groups (NDBE, 1.92 ± 0.7; DBE, 2.92 ± 1.1; EAC 4.54 ± 2.9), with a significant correlation between its increasing value and the presence of dysplasia or neoplasia (r = 0.53, p < 0.001). NLR > 2.27 was able to diagnose EAC with 80% sensitivity and 71% specificity (area under the curve = 0.8). CONCLUSION NLR correlates with advancing stages of BE progression, a finding that reinforces the role of immune imbalance in EAC carcinogenesis and suggests a possible use of this marker for risk stratification on surveillance strategies.
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Dugalic P, Djuranovic S, Pavlovic-Markovic A, Dugalic V, Tomasevic R, Gluvic Z, Obradovic M, Bajic V, Isenovic ER. Proton Pump Inhibitors and Radiofrequency Ablation for Treatment of Barrett's Esophagus. Mini Rev Med Chem 2020; 20:975-987. [PMID: 31644405 DOI: 10.2174/1389557519666191015203636] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 06/04/2019] [Accepted: 06/25/2019] [Indexed: 02/07/2023]
Abstract
Gastroesophageal Reflux Disease (GERD) is characterized by acid and bile reflux in the distal oesophagus, and this may cause the development of reflux esophagitis and Barrett's oesophagus (BE). The natural histological course of untreated BE is non-dysplastic or benign BE (ND), then lowgrade (LGD) and High-Grade Dysplastic (HGD) BE, with the expected increase in malignancy transfer to oesophagal adenocarcinoma (EAC). The gold standard for BE diagnostics involves high-resolution white-light endoscopy, followed by uniform endoscopy findings description (Prague classification) with biopsy performance according to Seattle protocol. The medical treatment of GERD and BE includes the use of proton pump inhibitors (PPIs) regarding symptoms control. It is noteworthy that long-term use of PPIs increases gastrin level, which can contribute to transfer from BE to EAC, as a result of its effects on the proliferation of BE epithelium. Endoscopy treatment includes a wide range of resection and ablative techniques, such as radio-frequency ablation (RFA), often concomitantly used in everyday endoscopy practice (multimodal therapy). RFA promotes mucosal necrosis of treated oesophagal region via high-frequency energy. Laparoscopic surgery, partial or total fundoplication, is reserved for PPIs and endoscopy indolent patients or in those with progressive disease. This review aims to explain distinct effects of PPIs and RFA modalities, illuminate certain aspects of molecular mechanisms involved, as well as the effects of their concomitant use regarding the treatment of BE and prevention of its transfer to EAC.
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Affiliation(s)
- Predrag Dugalic
- Department of Gastroenterology and Hepatology, University Clinical-Hospital Centre Zemun-Belgrade, Belgrade, Serbia
| | - Srdjan Djuranovic
- Clinical Centre of Serbia, Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Aleksandra Pavlovic-Markovic
- Clinical Centre of Serbia, Clinic for Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Vladimir Dugalic
- Clinical Centre of Serbia, Clinic for Surgery, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Ratko Tomasevic
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Belgrade, University Clinical-Hospital Centre Zemun-Belgrade, Belgrade, Serbia
| | - Zoran Gluvic
- Department of Endocrinology and Diabetes, Faculty of Medicine, University of Belgrade, University Clinical-Hospital Centre Zemun-Belgrade, Belgrade, Serbia
| | - Milan Obradovic
- Department of Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinca, University of Belgrade, Belgrade, Serbia
| | - Vladan Bajic
- Department of Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinca, University of Belgrade, Belgrade, Serbia
| | - Esma R Isenovic
- Department of Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinca, University of Belgrade, Belgrade, Serbia
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Porter RJ, Murray GI, Brice DP, Petty RD, McLean MH. Novel biomarkers for risk stratification of Barrett's oesophagus associated neoplastic progression-epithelial HMGB1 expression and stromal lymphocytic phenotype. Br J Cancer 2019; 122:545-554. [PMID: 31831860 PMCID: PMC7028982 DOI: 10.1038/s41416-019-0685-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 10/30/2019] [Accepted: 11/28/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The incidence of oesophageal adenocarcinoma is increasing globally. Barrett's oesophagus (BO) is a pre-malignant condition with no biomarker to risk stratify those at highest risk of dysplasia and malignant transformation. METHODS Subcellular epithelial protein (HMGB1, p53, RUNX3) expression, alongside expression of CD20, CD4, CD8 and Foxp3 to characterise stromal B lymphocyte, and helper, cytotoxic and regulatory T-lymphocyte cell infiltrate, respectively, was assessed by immunohistochemistry in 218 human tissue samples including normal oesophageal/gastric biopsies (n = 39), BO (non-dysplasia, dysplasia, non-dysplastic background from progressors to dysplasia or cancer, n = 121) and oesophageal adenocarcinoma (n = 58). RESULTS There is a dynamic subcellular epithelial expression of HMGB1 (loss of nuclear, emergence of cytoplasmic), associated with epithelial p53 expression and differential immune cell phenotype in oesophageal neoplastic progression. We identify a protein signature and lymphocyte infiltrate in non-dysplastic BO when progressive disease (dysplasia or adenocarcinoma) is present but not histologically represented in the biopsied field. There is a dynamic stromal lymphocytic infiltrate in oesophageal neoplastic progression. CONCLUSIONS This data reveals novel insights into the microenvironment of BO and progression towards cancer and identifies a novel high-risk biomarker of disease progression to aid surveillance strategies to identify early progression and impact future incidence of oesophageal cancer.
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Affiliation(s)
- Ross J Porter
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
| | - Graeme I Murray
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
| | - Daniel P Brice
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
| | - Russell D Petty
- Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, DD1 1GZ, UK
| | - Mairi H McLean
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
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McDaniel M, Conran RM. Educational Case: Barrett Esophagus. Acad Pathol 2019; 6:2374289519848089. [PMID: 31192298 PMCID: PMC6543786 DOI: 10.1177/2374289519848089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 04/02/2019] [Accepted: 04/09/2019] [Indexed: 11/17/2022] Open
Abstract
The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, seehttp://journals.sagepub.com/doi/10.1177/2374289517715040.
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Steele D, Baig KKK, Peter S. Evolving screening and surveillance techniques for Barrett's esophagus. World J Gastroenterol 2019; 25:2045-2057. [PMID: 31114132 PMCID: PMC6506582 DOI: 10.3748/wjg.v25.i17.2045] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 03/26/2019] [Accepted: 04/11/2019] [Indexed: 02/06/2023] Open
Abstract
Barrett’s esophagus (BE) is a change in the esophageal lining and is known to be the major precursor lesion for most cases of esophageal adenocarcinoma (EAC). Despite an understanding of its association with BE for many years and the falling incidence rates of squamous cell carcinoma of the esophagus, the incidence for EAC continues to rise exponentially. In association with this rising incidence, if the delay in diagnosis of EAC occurs after the onset of symptoms, then the mortality at 5 years is greater than 80%. Appropriate diagnosis and surveillance strategies are therefore vital for BE. Multiple novel optical technologies and other advanced approaches are being utilized to assist in making screening and surveillance more cost effective. We review the current guidelines and evolving techniques that are currently being evaluated.
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Affiliation(s)
- David Steele
- Basil Hirschowitz Endoscopic Centre of Endoscopic Excellence, Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, AL 35294, United Sates
| | - Kondal Kyanam Kabir Baig
- Basil Hirschowitz Endoscopic Centre of Endoscopic Excellence, Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, AL 35294, United Sates
| | - Shajan Peter
- Basil Hirschowitz Endoscopic Centre of Endoscopic Excellence, Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, AL 35294, United Sates
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Lv J, Guo L, Wang JH, Yan YZ, Zhang J, Wang YY, Yu Y, Huang YF, Zhao HP. Biomarker identification and trans-regulatory network analyses in esophageal adenocarcinoma and Barrett's esophagus. World J Gastroenterol 2019; 25:233-244. [PMID: 30670912 PMCID: PMC6337015 DOI: 10.3748/wjg.v25.i2.233] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 12/10/2018] [Accepted: 12/15/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Esophageal adenocarcinoma (EAC) is an aggressive disease with high mortality and an overall 5-year survival rate of less than 20%. Barrett's esophagus (BE) is the only known precursor of EAC, and patients with BE have a persistent and excessive risk of EAC over time. Individuals with BE are up to 30-125 times more likely to develop EAC than the general population. Thus, early detection of EAC and BE could significantly improve the 5-year survival rate of EAC. Due to the limitations of endoscopic surveillance and the lack of clinical risk stratification strategies, molecular biomarkers should be considered and thoroughly investigated. AIM To explore the transcriptome changes in the progression from normal esophagus (NE) to BE and EAC. METHODS Two datasets from the Gene Expression Omnibus (GEO) in NCBI Database (https://www.ncbi.nlm.nih.gov/geo/) were retrieved and used as a training and a test dataset separately, since NE, BE, and EAC samples were included and the sample sizes were adequate. This study identified differentially expressed genes (DEGs) using the R/Bioconductor project and constructed trans-regulatory networks based on the Transcriptional Regulatory Element Database and Cytoscape software. Enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) terms was identified using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources. The diagnostic potential of certain DEGs was assessed in both datasets. RESULTS In the GSE1420 dataset, the number of up-regulated DEGs was larger than that of down-regulated DEGs when comparing EAC vs NE and BE vs NE. Among these DEGs, five differentially expressed transcription factors (DETFs) displayed the same trend in expression across all the comparison groups. Of these five DETFs, E2F3, FOXA2, and HOXB7 were up-regulated, while PAX9 and TFAP2C were down-regulated. Additionally, the majority of the DEGs in trans-regulatory networks were up-regulated. The intersection of these potential DEGs displayed the same direction of changes in expression when comparing the DEGs in the GSE26886 dataset to the DEGs in trans-regulatory networks above. The receiver operating characteristic curve analysis was performed for both datasets and found that TIMP1 and COL1A1 could discriminate EAC from NE tissue, while REG1A, MMP1, and CA2 could distinguish BE from NE tissue. DAVID annotation indicated that COL1A1 and MMP1 could be potent biomarkers for EAC and BE, respectively, since they participate in the majority of the enriched KEGG and GO terms that are important for inflammation and cancer. CONCLUSION After the construction and analyses of the trans-regulatory networks in EAC and BE, the results indicate that COL1A1 and MMP1 could be potential biomarkers for EAC and BE, respectively.
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Affiliation(s)
- Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Lei Guo
- Department of Spinal Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Ji-Han Wang
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Yu-Zhu Yan
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Jun Zhang
- Department of Gastroenterology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Yang-Yang Wang
- The Tenth Research Institute of Telecommunications Technology, Xi’an 710000, Shaanxi Province, China
| | - Yan Yu
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Yun-Fei Huang
- Department of Spinal Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - He-Ping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
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Espinoza JA, Riquelme I, Sagredo EA, Rosa L, García P, Bizama C, Apud-Bell M, Leal P, Weber H, Benavente F, Vargas S, Romero D, Kalergis AM, Roa JC. Mucin 5B, carbonic anhydrase 9 and claudin 18 are potential theranostic markers of gallbladder carcinoma. Histopathology 2018; 74:597-607. [PMID: 30565710 DOI: 10.1111/his.13797] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 11/19/2018] [Indexed: 02/06/2023]
Abstract
AIMS Gallbladder cancer (GBC) is an aggressive tumour that is usually diagnosed at advanced stages and is characterised by a poor prognosis. Using public data of normal human tissues, we found that mRNA and protein levels of mucin 5B (MUC5B) and carbonic anhydrase 9 (CA9) were highly increased in gallbladder tissues. In addition, previous evidence has shown that claudin 18 (CLDN18) protein expression is higher in GBC. The aim of this study was to perform an analysis of these cell surface proteins during the histological progression of GBC in order to identify their theranostic potential. METHODS AND RESULTS MUC5B expression, CA9 expression and CLDN18 expression were examined by immunohistochemistry in a series of 179 chronic cholecystitis (including 16 metaplastic tissues), 15 dysplasia and 217 GBC samples by the use of tissue microarray analysis. A composite staining score was calculated from staining intensity and percentage of positive cells. Immunohistochemical analysis showed high expression of MUC5B and CA9 among normal epithelium, metaplastic tissues, and dysplastic tissues. However, expression of both proteins was observed in roughly 50% of GBC samples. In contrast, CLDN18 was absent in normal epithelium, but its expression was higher in metaplastic cells. Among GBC cases, approximately half showed high CLDN18 expression. No associations were found between MUC5B, CA9 and CLDN18 expression and any clinicopathological features. CONCLUSIONS CLDN18 is a new metaplasia marker in gallbladder tissues, and is conserved in approximately half of GBC cases. MUC5B and CA9 are highly conserved during GBC histological progression. The three markers are potential theranostic markers, in particular CA9 and CLDN18, for which there are already targeted therapies available.
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Affiliation(s)
- Jaime A Espinoza
- SciLifeLab, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Stockholm, Sweden
| | - Ismael Riquelme
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Temuco, Chile
| | - Eduardo A Sagredo
- Centro de Investigación y Tratamiento del Cáncer, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Lorena Rosa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Patricia García
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - María Apud-Bell
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pamela Leal
- Centre of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de la Frontera, Temuco, Chile
| | - Helga Weber
- Centre of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de la Frontera, Temuco, Chile
| | - Felipe Benavente
- Departamento de Procesos Diagnósticos y Evaluación, Facultad de Ciencias de la Salud, Universidad Católica de Temuco, Temuco, Chile
| | - Sergio Vargas
- Department of Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Diego Romero
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis M Kalergis
- Department of Molecular Genetics and Microbiology, Millennium Institute of Immunology and Immunotherapy, Faculty of Biological Sciences, Santiago, Chile.,Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Molecular Genetics and Microbiology, Millennium Institute of Immunology and Immunotherapy, Faculty of Biological Sciences, Santiago, Chile
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Ex vivo drug sensitivity testing as a means for drug repurposing in esophageal adenocarcinoma. PLoS One 2018; 13:e0203173. [PMID: 30212533 PMCID: PMC6136712 DOI: 10.1371/journal.pone.0203173] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 08/15/2018] [Indexed: 12/13/2022] Open
Abstract
Background Esophageal cancer remains one of the hardest cancers to treat with rising incidence rates, low overall survival and high levels of treatment resistance. The lack of clinically available biomarkers hinder diagnosis and treatment stratification. While large scale sequencing approaches have uncovered a number of molecular makers, little has translated in the routine treatment of esophageal cancer patients. Material and methods We evaluate the treatment response towards a panel of 215 FDA-approved and 163 epigenetic compounds of 4 established and 2 patient-derived esophageal cancer cell lines. Cell viability was evaluated after 72h of treatment using cell titer glow. The drug sensitivity testing results for gemcitabine and cisplatin were validated using clonogenic assays. Results The tested cell lines display different drug sensitivity profiles, although we found compounds that display efficacy in all of the tested established or patient-derived cell lines. Clonogenic assays confirmed the validity of the drug sensitivity testing results. Using the epigenetic library, we observed high sensitivity towards a number of epigenetic modifiers. Discussion Ex vivo drug sensitivity testing may present a viable option for the treatment stratification of esophageal cancer patients and holds the potential to greatly improve patient outcome while reducing treatment toxicity.
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