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1
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Choi WT, Rabinovitch PS. DNA flow cytometry for detection of genomic instability as a cancer precursor in the gastrointestinal tract. Methods Cell Biol 2024; 186:25-49. [PMID: 38705603 DOI: 10.1016/bs.mcb.2024.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2024]
Abstract
One of the earliest applications of flow cytometry was the measurement of DNA content in cells. This method is based on the ability to stain DNA in a stoichiometric manner (i.e., the amount of stain is directly proportional to the amount of DNA within the cell). For more than 40years, a number of studies have consistently demonstrated the utility of DNA flow cytometry as a potential diagnostic and/or prognostic tool in patients with most epithelial tumors, including pre-invasive lesions (such as dysplasia) in the gastrointestinal tract. However, its availability as a clinical test has been limited to few medical centers due to the requirement for fresh tissue in earlier studies and perceived technical demands. However, more recent studies have successfully utilized formalin-fixed paraffin-embedded (FFPE) tissue to generate high-quality DNA content histograms, demonstrating the feasibility of this methodology. This review summarizes step-by-step methods on how to perform DNA flow cytometry using FFPE tissue and analyze DNA content histograms based on the published consensus guidelines in order to assist in the diagnosis and/or risk stratification of many different epithelial tumors, with particular emphasis on dysplasia associated with Barrett's esophagus and inflammatory bowel disease.
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Affiliation(s)
- Won-Tak Choi
- Department of Pathology, University of California at San Francisco, San Francisco, CA, United States.
| | - Peter S Rabinovitch
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States
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2
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Patil DT, Odze RD. Barrett's Esophagus and Associated Dysplasia. Gastroenterol Clin North Am 2024; 53:1-23. [PMID: 38280743 DOI: 10.1016/j.gtc.2023.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2024]
Abstract
Early detection of dysplasia and effective management are critical steps in halting neoplastic progression in patients with Barrett's esophagus (BE). This review provides a contemporary overview of the BE-related dysplasia, its role in guiding surveillance and management, and discusses emerging diagnostic and therapeutic approaches that might further enhance patient management. Novel, noninvasive techniques for sampling and surveillance, adjunct biomarkers for risk assessment, and their limitations are also discussed.
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Affiliation(s)
- Deepa T Patil
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
| | - Robert D Odze
- Department of Pathology and Lab Medicine, Tufts University School of Medicine, Boston, MA, USA
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3
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Iyer PG, Chak A. Surveillance in Barrett's Esophagus: Challenges, Progress, and Possibilities. Gastroenterology 2023; 164:707-718. [PMID: 36746210 PMCID: PMC10079619 DOI: 10.1053/j.gastro.2023.01.031] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 02/08/2023]
Abstract
Endoscopic surveillance of Barrett's esophagus, aiming to detect prevalent dysplasia and adenocarcinoma, followed by effective endoscopic treatment, is an integral part of the esophageal adenocarcinoma prevention paradigm. However, several limitations, such as the subtle appearance of dysplasia, sampling error (inherent in current surveillance protocols), and noncompliance with surveillance recommendations, lead to missed dysplasia and neoplasia, reducing the effectiveness of surveillance as currently practiced. Careful endoscopic assessment with high-resolution white-light endoscopy, dye-based or electronic chromoendoscopy, and comprehensive sampling of the BE mucosa, remains the cornerstone of endoscopic surveillance. Emerging innovations in this area span the gamut of more efficient sampling methods, advanced imaging tools, artificial intelligence, and molecular marker-powered approaches as adjuncts, to identify prevalent and predict incident dysplasia or adenocarcinoma. Development and implementation of validated quality indicators will allow additional advancement of this critical field. These approaches will hopefully enable efficient and effective cancer prevention and treatment.
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Affiliation(s)
- Prasad G Iyer
- Barrett's Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - Amitabh Chak
- Division of Gastroenterology and Hepatology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio
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4
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Lee C, Hayat U, Song K, Gravely AA, Mesa H, Peltola J, Iwamoto C, Manivel C, Bilal M, Shaheen N, Shaukat A, Hanson BJ. A Consensus Diagnosis Utilizing Surface KI-67 Expression as an Ancillary Marker in Low-Grade Dysplasia Helps Identify Patients at High Risk of Progression to High-Grade Dysplasia and Esophaegal Adenocarcinoma. Dis Esophagus 2023; 36:doac065. [PMID: 36190180 DOI: 10.1093/dote/doac065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 08/12/2022] [Accepted: 08/26/2022] [Indexed: 12/11/2022]
Abstract
Esophageal adenocarcinoma (EAC) develops in a step-wise manner, from low-grade dysplasia (LGD) to high-grade dysplasia (HGD), and ultimately to invasive EAC. However, there remains diagnostic uncertainty about LGD and its risk of progression to HGD/EAC. The aim is to investigate the role of Ki-67, immune-histochemical marker of proliferation, surface expression in patients with confirmed LGD, and risk stratify progression to HGD/EAC. A retrospective cohort study was conducted. Patients with confirmed LGD and indefinite for dysplasia (IND), with a mean follow-up of ≥1 year, were included. Pathology specimens were stained for Ki-67 and analyzed for evidence of surface expression. Our results reveal that 29% of patients with confirmed LGD who stained positive with Ki-67 progressed to HGD/EAC as opposed to none (0%) of the patients who stained negative, a statistically significant result (P = 0.003). Similarly, specimens from patients with IND were stained and analyzed revealing a nonsignificant trend toward a higher rate of progression for Ki-67 positive cases versus Ki-67 negative, 30% versus 21%, respectively. Ki-67 expression by itself can identify patients with LGD at a high risk of progression.
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Affiliation(s)
- Christina Lee
- Department of Medicine, University of Minnesota, MN, USA
| | - Umar Hayat
- Department of Gastroenterology and Hepatology, University of Minnesota & Veterans Administration Health Care System, Minneapolis, MN, USA
| | - Kevin Song
- Department of Gastroenterolgoy, Mayo Clinic, Scottsdale, AZ, USA
| | - Amy A Gravely
- Department of Research, Veterans Administration Health Care System, Minneapolis, MN, USA
| | - Hector Mesa
- Department of Pathology, Indiana University Medical School, Indianapolis, IN, USA
| | - Justin Peltola
- Department of Pathology, Veterans Administration Health Care System, Minneapolis, MN, USA
| | - Carlos Iwamoto
- Department of Pathology, Veterans Administration Health Care System, Minneapolis, MN, USA
| | - Carlos Manivel
- Department of Pathology, Veterans Administration Health Care System, Minneapolis, MN, USA
| | - Mohammad Bilal
- Department of Gastroenterology and Hepatology, University of Minnesota & Veterans Administration Health Care System, Minneapolis, MN, USA
| | - Nicholas Shaheen
- Department of Gastroenteorlogy and Hepatology, University of North Carolina, Chapel Hill, NC, USA
| | - Aasma Shaukat
- Department of Gastroenterology and Hepatology, NYU-Lagone School of Medicine, New York, NY, USA
| | - Brian J Hanson
- Department of Gastroenterology and Hepatology, University of Minnesota & Veterans Administration Health Care System, Minneapolis, MN, USA
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5
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Paulson TG, Galipeau PC, Oman KM, Sanchez CA, Kuhner MK, Smith LP, Hadi K, Shah M, Arora K, Shelton J, Johnson M, Corvelo A, Maley CC, Yao X, Sanghvi R, Venturini E, Emde AK, Hubert B, Imielinski M, Robine N, Reid BJ, Li X. Somatic whole genome dynamics of precancer in Barrett's esophagus reveals features associated with disease progression. Nat Commun 2022; 13:2300. [PMID: 35484108 PMCID: PMC9050715 DOI: 10.1038/s41467-022-29767-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 03/25/2022] [Indexed: 01/08/2023] Open
Abstract
While the genomes of normal tissues undergo dynamic changes over time, little is understood about the temporal-spatial dynamics of genomes in premalignant tissues that progress to cancer compared to those that remain cancer-free. Here we use whole genome sequencing to contrast genomic alterations in 427 longitudinal samples from 40 patients with stable Barrett’s esophagus compared to 40 Barrett’s patients who progressed to esophageal adenocarcinoma (ESAD). We show the same somatic mutational processes are active in Barrett’s tissue regardless of outcome, with high levels of mutation, ESAD gene and focal chromosomal alterations, and similar mutational signatures. The critical distinction between stable Barrett’s versus those who progress to cancer is acquisition and expansion of TP53−/− cell populations having complex structural variants and high-level amplifications, which are detectable up to six years prior to a cancer diagnosis. These findings reveal the timing of common somatic genome dynamics in stable Barrett’s esophagus and define key genomic features specific to progression to esophageal adenocarcinoma, both of which are critical for cancer prevention and early detection strategies. Barrett’s esophagus is a pre-malignant condition that can progress to esophageal cancer. Here, the authors carry out whole genome sequencing of samples from patients who did or did not progress to cancer and find that mutations in many genes occur regardless of progression status, but also find features associated with progressive disease.
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Affiliation(s)
- Thomas G Paulson
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
| | - Patricia C Galipeau
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA
| | - Kenji M Oman
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA
| | - Carissa A Sanchez
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA
| | - Mary K Kuhner
- Department of Genome Sciences, University of Washington, Seattle, WA, 98195-5065, USA.,Brotman Baty Institute for Precision Medicine, Seattle, WA, 98195-5065, USA
| | - Lucian P Smith
- Department of Genome Sciences, University of Washington, Seattle, WA, 98195-5065, USA
| | - Kevin Hadi
- New York Genome Center (NYGC), New York, NY, 10013, USA
| | - Minita Shah
- New York Genome Center (NYGC), New York, NY, 10013, USA
| | - Kanika Arora
- New York Genome Center (NYGC), New York, NY, 10013, USA
| | | | - Molly Johnson
- New York Genome Center (NYGC), New York, NY, 10013, USA
| | - Andre Corvelo
- New York Genome Center (NYGC), New York, NY, 10013, USA
| | - Carlo C Maley
- Arizona Cancer Evolution Center, Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ, 85281, USA
| | - Xiaotong Yao
- New York Genome Center (NYGC), New York, NY, 10013, USA
| | | | | | | | | | - Marcin Imielinski
- New York Genome Center (NYGC), New York, NY, 10013, USA.,Department of Pathology and Laboratory Medicine, Englander Institute for Precision Medicine, Institute for Computational Biomedicine and Meyer Cancer Center, Weill Cornell Medical College, New York, NY, 10065, USA
| | | | - Brian J Reid
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.,Department of Genome Sciences, University of Washington, Seattle, WA, 98195-5065, USA.,Brotman Baty Institute for Precision Medicine, Seattle, WA, 98195-5065, USA.,Department of Medicine, University of Washington, Seattle, WA, 98195, USA
| | - Xiaohong Li
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
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6
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Schmidt M, Hackett RJ, Baker AM, McDonald SAC, Quante M, Graham TA. Evolutionary dynamics in Barrett oesophagus: implications for surveillance, risk stratification and therapy. Nat Rev Gastroenterol Hepatol 2022; 19:95-111. [PMID: 34728819 DOI: 10.1038/s41575-021-00531-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/24/2021] [Indexed: 12/13/2022]
Abstract
Cancer development is a dynamic evolutionary process characterized by marked intratumoural heterogeneity at the genetic, epigenetic and phenotypic levels. Barrett oesophagus, the pre-malignant condition to oesophageal adenocarcinoma (EAC), is an exemplary system to longitudinally study the evolution of malignancy. Evidence has emerged of Barrett oesophagus lesions pre-programmed for progression to EAC many years before clinical detection, indicating a considerable window for therapeutic intervention. In this Review, we explore the mechanisms underlying clonal expansion and contraction that establish the Barrett oesophagus clonal mosaicism over time and space and discuss intrinsic genotypic and extrinsic environmental drivers that direct the evolutionary trajectory of Barrett oesophagus towards a malignant phenotype. We propose that understanding and exploiting the evolutionary dynamics of Barrett oesophagus will identify novel therapeutic targets, improve prognostic tools and offer the opportunity for personalized surveillance programmes geared to prevent progression to EAC.
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Affiliation(s)
- Melissa Schmidt
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany
| | - Richard J Hackett
- Clonal Dynamics in Epithelia Group; Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Ann-Marie Baker
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Stuart A C McDonald
- Clonal Dynamics in Epithelia Group; Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Michael Quante
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany
- Department of Medicine II, Universitaetsklinikum Freiburg, Freiburg, Germany
| | - Trevor A Graham
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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7
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Maslyonkina KS, Konyukova AK, Alexeeva DY, Sinelnikov MY, Mikhaleva LM. Barrett's esophagus: The pathomorphological and molecular genetic keystones of neoplastic progression. Cancer Med 2022; 11:447-478. [PMID: 34870375 PMCID: PMC8729054 DOI: 10.1002/cam4.4447] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/07/2021] [Accepted: 11/09/2021] [Indexed: 02/06/2023] Open
Abstract
Barrett's esophagus is a widespread chronically progressing disease of heterogeneous nature. A life threatening complication of this condition is neoplastic transformation, which is often overlooked due to lack of standardized approaches in diagnosis, preventative measures and treatment. In this essay, we aim to stratify existing data to show specific associations between neoplastic transformation and the underlying processes which predate cancerous transition. We discuss pathomorphological, genetic, epigenetic, molecular and immunohistochemical methods related to neoplasia detection on the basis of Barrett's esophagus. Our review sheds light on pathways of such neoplastic progression in the distal esophagus, providing valuable insight into progression assessment, preventative targets and treatment modalities. Our results suggest that molecular, genetic and epigenetic alterations in the esophagus arise earlier than cancerous transformation, meaning the discussed targets can help form preventative strategies in at-risk patient groups.
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8
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Choi WT, Lauwers GY, Montgomery EA. Utility of ancillary studies in the diagnosis and risk assessment of Barrett's esophagus and dysplasia. Mod Pathol 2022; 35:1000-1012. [PMID: 35260826 PMCID: PMC9314252 DOI: 10.1038/s41379-022-01056-0] [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: 12/15/2021] [Revised: 02/09/2022] [Accepted: 02/13/2022] [Indexed: 12/12/2022]
Abstract
Barrett's esophagus (BE) is a major risk factor for the development of esophageal adenocarcinoma (EAC). BE patients undergo periodic endoscopic surveillance with biopsies to detect dysplasia and EAC, but this strategy is imperfect owing to sampling error and inconsistencies in the diagnosis and grading of dysplasia, which may result in an inaccurate diagnosis or risk assessment for progression to EAC. The desire for more accurate diagnosis and better risk stratification has prompted the investigation and development of potential biomarkers that might assist pathologists and clinicians in the management of BE patients, allowing more aggressive endoscopic surveillance and treatment options to be targeted to high-risk individuals, while avoiding frequent surveillance or unnecessary interventions in those at lower risk. It is known that progression of BE to dysplasia and EAC is accompanied by a host of genetic alterations, and that exploration of these markers could be potentially useful to diagnose/grade dysplasia and/or to risk stratify BE patients. Several biomarkers have shown promise in identifying early neoplastic transformation and thus may be useful adjuncts to histologic evaluation. This review provides an overview of some of the currently available biomarkers and assays, including p53 immunostaining, Wide Area Transepithelial Sampling with Three-Dimensional Computer-Assisted Analysis (WATS3D), TissueCypher, mutational load analysis (BarreGen), fluorescence in situ hybridization, and DNA content abnormalities as detected by DNA flow cytometry.
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Affiliation(s)
- Won-Tak Choi
- University of California at San Francisco, Department of Pathology, San Francisco, CA, 94143, USA.
| | - Gregory Y. Lauwers
- grid.468198.a0000 0000 9891 5233H. Lee Moffitt Cancer Center and Research Institute, Department of Pathology, Tampa, FL 33612 USA
| | - Elizabeth A. Montgomery
- grid.26790.3a0000 0004 1936 8606University of Miami Miller School of Medicine, Department of Pathology and Laboratory Medicine, Miami, FL 33136 USA
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9
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Killcoyne S, Fitzgerald RC. Evolution and progression of Barrett's oesophagus to oesophageal cancer. Nat Rev Cancer 2021; 21:731-741. [PMID: 34545238 DOI: 10.1038/s41568-021-00400-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/12/2021] [Indexed: 02/07/2023]
Abstract
Cancer cells are shaped through an evolutionary process of DNA mutation, cell selection and population expansion. Early steps in this process are driven by a set of mutated driver genes and structural alterations to the genome through copy number gains or losses. Oesophageal adenocarcinoma (EAC) and the pre-invasive tissue, Barrett's oesophagus (BE), provide an ideal example in which to observe and study this evolution. BE displays early genomic instability, specifically in copy number changes that may later be observed in EAC. Furthermore, these early changes result in patterns of progression (that is, 'born bad', gradual or catastrophic) that may help to describe the evolution of EAC. As only a small proportion of patients with BE will go on to develop cancer, a better understanding of these patterns and the resulting genomic changes should improve early detection in EAC and may provide clues for the evolution of cancer more broadly.
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Affiliation(s)
- Sarah Killcoyne
- Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK
| | - Rebecca C Fitzgerald
- Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
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10
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Genomic instability signals offer diagnostic possibility in early cancer detection. Trends Genet 2021; 37:966-972. [PMID: 34218956 DOI: 10.1016/j.tig.2021.06.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/07/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022]
Abstract
Emerging evidence from the large numbers of cancer genomes analyzed in recent years indicates that chromosomal instability (CI), a well-established hallmark of cancer cells, is detectable in precancerous lesions. In this opinion, we discuss the association of this instability with tumor progression and cancer risk. We highlight the opportunity that early genomic instability presents for the diagnosis of esophageal adenocarcinoma (EAC) and its precancerous lesion, Barrett's esophagus (BE). With a growing body of evidence suggesting that only a small pool of cancer-related genes are involved in early tumor development, we argue that general genomic instability may hold greater diagnostic potential for early cancer detection as opposed to the identification of individual mutational biomarkers.
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11
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Unique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneity. Sci Rep 2021; 11:10571. [PMID: 34011996 PMCID: PMC8134446 DOI: 10.1038/s41598-021-90170-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 04/30/2021] [Indexed: 11/08/2022] Open
Abstract
Breast cancers exhibit intratumoral heterogeneity associated with disease progression and therapeutic resistance. To define the sources and the extent of heterogeneity, we performed an in-depth analysis of the genomic architecture of three chemoradiation-naïve breast cancers with well-defined clinical features including variable ER, PR, ERBB2 receptor expression and two distinct pathogenic BRCA2mut genotypes. The latter included a germ line carrier and a patient with a somatic variant. In each case we combined DNA content-based flow cytometry with whole exome sequencing and genome wide copy number variant (CNV) analysis of distinct populations sorted from multiple (4–18) mapped biopsies within the tumors and involved lymph nodes. Interrogating flow-sorted tumor populations from each biopsy provided an objective method to distinguish fixed and variable genomic lesions in each tumor. Notably we show that tumors exploit CNVs to fix mutations and deletions in distinct populations throughout each tumor. The identification of fixed genomic lesions that are shared or unique within each tumor, has broad implications for the study of tumor heterogeneity including the presence of tumor markers and therapeutic targets, and of candidate neoepitopes in breast and other solid tumors that can advance more effective treatment and clinical management of patients with disease.
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12
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Klair JS, Zafar Y, Nagra N, Murali AR, Jayaraj M, Singh D, Rustagi T, Krishnamoorthi R. Outcomes of Radiofrequency Ablation versus Endoscopic Surveillance for Barrett's Esophagus with Low-Grade Dysplasia: A Systematic Review and Meta-Analysis. Dig Dis 2021; 39:561-568. [PMID: 33503615 DOI: 10.1159/000514786] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 01/22/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Endoscopic therapy using radiofrequency ablation (RFA) is a recommended treatment for Barrett's esophagus with high-grade dysplasia (BE-HGD) without a visible lesion which is managed by resection. However, currently, there is no consensus on the management of BE with low-grade dysplasia (BE-LGD) - RFA versus endoscopic surveillance. Hence, we performed a systematic review and meta-analysis of these comparative studies to compare the risk of progression to HGD or esophageal adenocarcinoma (EAC) among patients with BE-LGD treated with RFA versus endoscopic surveillance. METHODS The primary outcome was to compare the risk of progression to HGD or EAC among patients with BE-LGD treated with RFA versus endoscopic surveillance. RESULTS Four comparative studies reporting a total of 543 patients with BE-LGD were included in the meta-analysis (234 in RFA and 309 in endoscopic surveillance). The progression of BE-LGD to either HGD or EAC was significantly lower in patients treated with RFA compared to endoscopic surveillance (OR: 0.17, 95% confidence interval [CI]: 0.04-0.65, p = 0.01). The progression to HGD alone was significantly lower in patients treated with RFA versus endoscopic surveillance (OR: 0.23, 95% CI: 0.08-0.61, p = 0.003). The progression to EAC alone was numerically lower in RFA than endoscopic surveillance without statistical significance (OR: 0.44, 95% CI: 0.17-1.16, p = 0.09). Moderate heterogeneity was noted in the analysis. CONCLUSIONS Based on our meta-analysis, there was a significant reduction in the risk of progression to HGD or EAC among patients with BE-LGD treated with RFA compared with those undergoing endoscopic surveillance. Endoscopic eradication therapy with RFA should be the preferred management approach for BE-LGD.
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Affiliation(s)
- Jagpal Singh Klair
- Digestive Disease Institute, Virginia Mason Medical Center, Seattle, Washington, USA
| | - Yousaf Zafar
- Department of Internal Medicine, Naples Community Healthcare, University of Central Florida, Orlando, Florida, USA
| | - Navroop Nagra
- Digestive Disease Institute, Virginia Mason Medical Center, Seattle, Washington, USA
| | - Arvind R Murali
- Division of Gastroenterology and Hepatology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
| | - Mahendran Jayaraj
- Division of Gastroenterology and Hepatology, University of Nevada Las Vegas, Las Vegas, Nevada, USA
| | - Dhruv Singh
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Tarun Rustagi
- Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, New Mexico, USA
| | - Rajesh Krishnamoorthi
- Digestive Disease Institute, Virginia Mason Medical Center, Seattle, Washington, USA
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13
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Persistent or recurrent Barrett's neoplasia after an endoscopic therapy session is associated with DNA content abnormality and can be detected by DNA flow cytometric analysis of paraffin-embedded tissue. Mod Pathol 2021; 34:1889-1900. [PMID: 34108638 PMCID: PMC8443444 DOI: 10.1038/s41379-021-00832-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 05/03/2021] [Accepted: 05/04/2021] [Indexed: 12/16/2022]
Abstract
Endoscopic therapy is currently the standard of care for the treatment of high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) in patients with Barrett's esophagus (BE). Visible lesions are treated with endoscopic mucosal resection (EMR), which is often coupled with radiofrequency ablation (RFA). However, endoscopic therapy may require multiple sessions (one session every 2-3 months) and does not always assure complete eradication of neoplasia. Furthermore, despite complete eradication, recurrences are not uncommon. This study assesses which potential risk factors can predict a poor response after endoscopic sessions. Forty-five BE patients who underwent at least one endoscopic session (EMR alone or ablation with or without preceding EMR) for the treatment of HGD/IMC, low-grade dysplasia (LGD), or indefinite for dysplasia (IND) were analyzed. DNA flow cytometry was performed on 82 formalin-fixed paraffin-embedded samples from the 45 patients, including 78 HGD/IMC, 2 LGD, and 2 IND. Eight non-dysplastic BE samples were used as controls. Three to four 60-micron thick sections were cut from each tissue block, and the area of HGD/IMC, LGD, or IND was manually dissected. Potential associations between clinicopathologic risk factors and persistent/recurrent HGD/IMC following each endoscopic session were examined using univariate and multivariate Cox models with frailty terms. Sixty (73%) of the 82 specimens showed abnormal DNA content (aneuploidy or elevated 4N fraction). These were all specimens with HGD/IMC (representing 77% of that group). Of these 60 HGD/IMC samples with abnormal DNA content, 42 (70%) were associated with subsequent development of persistent/recurrent HGD/IMC (n = 41) or esophageal adenocarcinoma (EAC; n = 1) within a mean follow-up time of 16 months (range: 1 month to 9.4 years). In contrast, only 6 (27%, all HGD/IMC) of the 22 remaining samples (all with normal DNA content) were associated with persistent/recurrent HGD/IMC. For outcome analysis per patient, 11 (24%) of the 45 patients developed persistent/recurrent HGD/IMC or EAC, despite multiple endoscopic sessions (mean: 3.6, range: 1-11). In a univariate Cox model, the presence of abnormal DNA content (hazard ratio [HR] = 3.8, p = 0.007), long BE segment ≥ 3 cm (HR = 3.4, p = 0.002), endoscopic nodularity (HR = 2.5, p = 0.042), and treatment with EMR alone (HR = 2.9, p = 0.006) were significantly associated with an increased risk for persistent/recurrent HGD/IMC or EAC. However, only abnormal DNA content (HR = 6.0, p = 0.003) and treatment with EMR alone (HR = 2.7, p = 0.047) remained as significant risk factors in a multivariate analysis. Age ≥ 60 years, gender, ethnicity, body mass index (BMI) ≥ 30 kg/m2, presence of hiatal hernia, and positive EMR lateral margin for neoplasia were not significant risk factors for persistent/recurrent HGD/IMC or EAC (p > 0.05). Three-month, 6-month, 1-year, 3-year, and 6-year adjusted probabilities of persistent/recurrent HGD/IMC or EAC in the setting of abnormal DNA content were 31%, 56%, 67%, 79%, and 83%, respectively. The corresponding probabilities in the setting of normal DNA content were 10%, 21%, 28%, 38%, and 43%, respectively. In conclusion, in BE patients with baseline HGD/IMC, both DNA content abnormality and treatment with EMR alone were significantly associated with persistent/recurrent HGD/IMC or EAC following each endoscopic session. DNA content abnormality as detected by DNA flow cytometry identifies HGD/IMC patients at highest risk for persistent/recurrent HGD/IMC or EAC, and it also serves as a diagnostic marker of HGD/IMC with an estimated sensitivity of 77%. The diagnosis of HGD/IMC in the setting of abnormal DNA content may warrant alternative treatment strategies as well as long-term follow-up with shorter surveillance intervals.
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14
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Kumarasinghe MP, Armstrong M, Foo J, Raftopoulos SC. The modern management of Barrett's oesophagus and related neoplasia: role of pathology. Histopathology 2020; 78:18-38. [PMID: 33382493 DOI: 10.1111/his.14285] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 10/14/2020] [Accepted: 10/21/2020] [Indexed: 12/13/2022]
Abstract
Modern management of Barrett's oesophagus and related neoplasia essentially focuses upon surveillance to detect early low-risk neoplastic lesions and offering organ-preserving advanced endoscopic therapies, while traditional surgical treatments of oesophagectomy and lymph node clearance with or without chemoradiation are preserved only for high-risk and advanced carcinomas. With this evolution towards figless invasive therapy, the choice of therapy hinges upon the pathological assessment for risk stratifying patients into those with low risk for nodal metastasis who can continue with less invasive endoscopic therapies and others with high risk for nodal metastasis for which surgery or other forms of treatment are indicated. Detection and confirmation of neoplasia in the first instance depends upon endoscopic and pathological assessment. Endoscopic examination and biopsy sampling should be performed according to the recommended protocols, and endoscopic biopsy interpretation should be performed applying standard criteria using appropriate ancillary studies by histopathologists experienced in the pathology of Barrett's disease. Endoscopic resections (ERs) are both diagnostic and curative and should be performed by clinicians who are skilled with advanced endoscopic techniques. Proper preparation and handling of ERs are essential to assess histological parameters that dictate the curative nature of the procedure. Those parameters are adequacy of resection and risk of lymph node metastasis. The risk of lymph node metastasis is determined by depth invasion and presence of poor differentiation and lymphovascular invasion. Those adenocarcinomas with invasion up to muscularis mucosae (pT1a) and those with superficial submucosal invasion (pT1b) up to 500 µ with no poor differentiation and lymphovascular invasion and negative margins may be considered cured by endoscopic resections.
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Affiliation(s)
- M Priyanthi Kumarasinghe
- PathWest and Clinipath Laboratories and Sir Charles Gairdner Hospital, QEII Medical Centre, Perth, 6009, WA, Australia
| | - Michael Armstrong
- PathWest and Clinipath Laboratories and Sir Charles Gairdner Hospital, QEII Medical Centre, Perth, 6009, WA, Australia
| | - Jonathan Foo
- PathWest and Clinipath Laboratories and Sir Charles Gairdner Hospital, QEII Medical Centre, Perth, 6009, WA, Australia
| | - Spiro C Raftopoulos
- PathWest and Clinipath Laboratories and Sir Charles Gairdner Hospital, QEII Medical Centre, Perth, 6009, WA, Australia
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15
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Lenkiewicz E, Malasi S, Hogenson TL, Flores LF, Barham W, Phillips WJ, Roesler AS, Chambers KR, Rajbhandari N, Hayashi A, Antal CE, Downes M, Grandgenett PM, Hollingsworth MA, Cridebring D, Xiong Y, Lee JH, Ye Z, Yan H, Hernandez MC, Leiting JL, Evans RM, Ordog T, Truty MJ, Borad MJ, Reya T, Von Hoff DD, Fernandez-Zapico ME, Barrett MT. Genomic and Epigenomic Landscaping Defines New Therapeutic Targets for Adenosquamous Carcinoma of the Pancreas. Cancer Res 2020; 80:4324-4334. [PMID: 32928922 DOI: 10.1158/0008-5472.can-20-0078] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 05/07/2020] [Accepted: 07/29/2020] [Indexed: 02/07/2023]
Abstract
Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well-characterized genomic lesions including mutations in TP53 (87%) and KRAS (73%), amplification of MYC (47%), and homozygous deletion of CDKN2A (40%) that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase SMYD2 and the pancreatic cancer stem cell regulator RORC in all three ASCPs, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes in a single ASCP. Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the FGFR1-ERLIN2 fusion-positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provide new strategies for targeting this aggressive subtype of pancreatic cancer. SIGNIFICANCE: These data provide a unique description of the ASCP genomic and epigenomic landscape and identify candidate therapeutic targets for this dismal cancer.
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Affiliation(s)
- Elizabeth Lenkiewicz
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona
| | - Smriti Malasi
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona
| | - Tara L Hogenson
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota
| | - Luis F Flores
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota
| | - Whitney Barham
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota
| | - William J Phillips
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota
| | - Alexander S Roesler
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona
| | - Kendall R Chambers
- Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, California
| | - Nirakar Rajbhandari
- Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, California
| | - Akimasa Hayashi
- The David M. Rubenstein Center for Pancreatic Cancer Research, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Corina E Antal
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California
| | - Michael Downes
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California
| | - Paul M Grandgenett
- Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska
| | - Michael A Hollingsworth
- Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska
| | | | - Yuning Xiong
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.,Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.,Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
| | - Jeong-Heon Lee
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.,Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.,Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
| | - Zhenqing Ye
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.,Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.,Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
| | - Huihuang Yan
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.,Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.,Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
| | | | | | - Ronald M Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California.,Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California
| | - Tamas Ordog
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.,Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.,Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
| | - Mark J Truty
- Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Mitesh J Borad
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona.,Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.,Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona
| | - Tannishtha Reya
- Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, California
| | - Daniel D Von Hoff
- Translational Genomics Research Institute, Phoenix, Arizona.,Virginia G Piper Cancer Center at HonorHealth, Scottsdale, Arizona
| | - Martin E Fernandez-Zapico
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota
| | - Michael T Barrett
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona.
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16
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Hadjinicolaou AV, van Munster SN, Achilleos A, Santiago Garcia J, Killcoyne S, Ragunath K, Bergman JJGHM, Fitzgerald RC, di Pietro M. Aneuploidy in targeted endoscopic biopsies outperforms other tissue biomarkers in the prediction of histologic progression of Barrett's oesophagus: A multi-centre prospective cohort study. EBioMedicine 2020; 56:102765. [PMID: 32460165 PMCID: PMC7251385 DOI: 10.1016/j.ebiom.2020.102765] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/02/2020] [Accepted: 04/08/2020] [Indexed: 02/08/2023] Open
Abstract
Background The cancer risk in Barrett's oesophagus (BO) is difficult to estimate. Histologic dysplasia has strong predictive power, but can be missed by random biopsies. Other clinical parameters have limited utility for risk stratification. We aimed to assess whether a molecular biomarker panel on targeted biopsies can predict neoplastic progression of BO. Methods 203 patients with BO were tested at index endoscopy for 9 biomarkers (p53 and cyclin A expression; aneuploidy and tetraploidy; CDKN2A (p16), RUNX3 and HPP1 hypermethylation; 9p and 17p loss of heterozygosity) on autofluorescence-targeted biopsies and followed-up prospectively. Data comparing progressors to non-progressors were evaluated by univariate and multivariate analyses using survival curves, Cox-proportional hazards and logistic regression models. Findings 127 patients without high-grade dysplasia (HGD) or oesophageal adenocarcinoma (OAC) at index endoscopy were included, of which 42 had evidence of any histologic progression over time. Aneuploidy was the only predictor of progression from non-dysplastic BO (NDBO) to any grade of neoplasia (p = 0.013) and HGD/OAC (p = 0.002). Aberrant p53 expression correlated with risk of short-term progression within 12 months, with an odds ratio of 6.0 (95% CI: 3.1–11.2). A panel comprising aneuploidy and p53 had an area under the receiving operator characteristics curve of 0.68 (95% CI: 0.59–0.77) for prediction of any progression. Interpretation Aneuploidy is the only biomarker that predicts neoplastic progression of NDBO. Aberrant p53 expression suggests prevalent dysplasia, which might have been missed by random biopsies, and warrants early follow up.
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Affiliation(s)
- Andreas V Hadjinicolaou
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, United Kingdom
| | - Sanne N van Munster
- Department of Gastroenterology, Amsterdam University Medical Centre, Meibergdreef 9, 1105 AZ, Amsterdam 22660, the Netherlands
| | - Achilleas Achilleos
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, United Kingdom
| | - Jose Santiago Garcia
- Nottingham Digestive Diseases Biomedical Research Centre, Queens Medical Centre Campus, E Floor, West Block, Derby Road, Nottingham NG7 2UH, United Kingdom
| | - Sarah Killcoyne
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, United Kingdom; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton CB10 1SD, United Kingdom
| | - Krish Ragunath
- Nottingham Digestive Diseases Biomedical Research Centre, Queens Medical Centre Campus, E Floor, West Block, Derby Road, Nottingham NG7 2UH, United Kingdom
| | - Jacques J G H M Bergman
- Department of Gastroenterology, Amsterdam University Medical Centre, Meibergdreef 9, 1105 AZ, Amsterdam 22660, the Netherlands
| | - Rebecca C Fitzgerald
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, United Kingdom
| | - Massimiliano di Pietro
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, United Kingdom.
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17
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Diagnosis, risk stratification, and management of ampullary dysplasia by DNA flow cytometric analysis of paraffin-embedded tissue. Mod Pathol 2019; 32:1291-1302. [PMID: 30976103 PMCID: PMC8549479 DOI: 10.1038/s41379-019-0272-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 02/27/2019] [Accepted: 03/06/2019] [Indexed: 12/20/2022]
Abstract
The limited accuracy of endoscopic biopsy in detecting high-grade dysplasia or adenocarcinoma within ampullary adenoma or dysplasia has been reported. The natural history of ampullary dysplasia is also unclear, and there are no established guidelines to determine which patients with ampullary dysplasia require resection versus surveillance endoscopy. DNA flow cytometry was performed on 47 ampullary biopsies with low-grade dysplasia, 18 high-grade dysplasia, and 23 negative for dysplasia, as well as 11 cases of ampullary adenocarcinoma. Abnormal DNA content (aneuploidy or elevated 4N fraction > 6%) was identified in 9 (82%) of adenocarcinoma, 13 (72%) of high-grade dysplasia, 7 (15%) of low-grade dysplasia, and none (0%) of non-dysplastic mucosa. One-, 2-, and 7-year detection rates of high-grade dysplasia or adenocarcinoma in low-grade dysplasia patients with abnormal DNA content were 57%, 86%, and 88%, respectively, whereas low-grade dysplasia patients in the setting of normal DNA content had 1-, 2-, and 7-year detection rates of 10%, 10%, and 10%, respectively. The univariate and multivariate hazard ratios (HRs) for subsequent detection of high-grade dysplasia or adenocarcinoma in low-grade dysplasia patients with DNA content abnormality were 16.8 (p = <0.01) and 9.8 (p = <0.01), respectively. Among the 13 high-grade dysplasia patients with DNA content abnormality, 5 patients (38%) were subsequently found to have adenocarcinoma within a mean follow-up time of 3 months, whereas only 1 (20%) of the remaining 5 patients in the setting of normal DNA content developed adenocarcinoma in a month (HR = 2.6, p = 0.39). The overall 1- and 2-year detection rates of adenocarcinoma in all high-grade dysplasia patients (regardless of flow cytometric results) were 34% (95% confidence interval = 16-63%) and 47% (95% confidence interval = 23-79%), respectively. In conclusion, the majority of low-grade dysplasia patients (86%) in the setting of abnormal DNA content developed high-grade dysplasia or adenocarcinoma within 2 years and thus may benefit from resection, whereas those with normal DNA content may be followed with surveillance endoscopy. The presence of DNA content abnormality can also confirm a morphologic suspicion of high-grade dysplasia, which should be managed with resection, as nearly 50% of the high-grade dysplasia patients were found to have adenocarcinoma within 2 years.
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18
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Pennathur A, Godfrey TE, Luketich JD. The Molecular Biologic Basis of Esophageal and Gastric Cancers. Surg Clin North Am 2019; 99:403-418. [PMID: 31047032 DOI: 10.1016/j.suc.2019.02.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Esophageal cancer and gastric cancer are leading causes of cancer-related mortality worldwide. In this article, the authors discuss the molecular biology of esophageal and gastric cancer with a focus on esophageal adenocarcinoma. They review data from The Cancer Genome Atlas project and advances in the molecular stratification and classification of esophageal carcinoma and gastric cancer. They also summarize advances in microRNA, molecular staging, gene expression profiling, tumor microenvironment, and detection of circulating tumor DNA. Finally, the authors summarize some of the implications of understanding the molecular basis of esophageal cancer and future directions in the management of esophageal cancer.
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Affiliation(s)
- Arjun Pennathur
- Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, The University of Pittsburgh School of Medicine, University of Pittsburgh, 200 Lothrop St. Suite C-800, Pittsburgh, PA 15213, USA.
| | - Tony E Godfrey
- Department of Surgery, Boston University School of Medicine, 700 Albany St, Boston, MA 02118, USA
| | - James D Luketich
- Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, The University of Pittsburgh School of Medicine, University of Pittsburgh, 200 Lothrop St. Suite C-800, Pittsburgh, PA 15213, USA
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19
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Cholapranee A, Trindade AJ. Challenges in Endoscopic Therapy of Dysplastic Barrett's Esophagus. ACTA ACUST UNITED AC 2019; 17:32-47. [PMID: 30663018 DOI: 10.1007/s11938-019-00215-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
PURPOSE OF REVIEW Barrett's esophagus (BE) is the only known measurable factor associated with esophageal adenocarcinoma. The development of endoscopic eradication therapy (EET) has transformed the way BE is managed. Given the fairly recent development of EET, its role in BE is still evolving. RECENT FINDINGS This paper discusses the challenges that endoscopists face at the preprocedural, intraprocedural, and postprocedural stages of BE management. These include challenges in risk stratification, dysplasia detection, ablation methods and dosimetry, choice of resection technique, and management of refractory disease. Despite the advances in EET in BE, there remain challenges that this review focuses on. Future research into these challenges will optimize ablation techniques and strategies in the future.
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Affiliation(s)
- Aurada Cholapranee
- Division of Gastroenterology, Zucker School of Medicine at Hofstra/Northwell, Northwell Health System, Long Island Jewish Medical Center, 270-05 76th Avenue, New Hyde Park, NY, 11040, USA
| | - Arvind J Trindade
- Division of Gastroenterology, Zucker School of Medicine at Hofstra/Northwell, Northwell Health System, Long Island Jewish Medical Center, 270-05 76th Avenue, New Hyde Park, NY, 11040, USA.
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20
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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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21
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Omstead AN, Kosovec JE, Matsui D, Martin SA, Smith MA, Aaron Guel D, Kolano J, Komatsu Y, Habib F, Lai C, Christopher K, Kelly RJ, Zaidi AH, Jobe BA. Serial Endoscopic Evaluation of Esophageal Disease in a Cancer Model: A Paradigm Shift for Esophageal Adenocarcinoma (EAC) Drug Discovery and Development. Cancer Invest 2018; 36:363-370. [PMID: 30142016 DOI: 10.1080/07357907.2018.1499029] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
A rat model of surgically induced reflux recapitulates the development and progression of human esophageal adenocarcinoma (EAC). In this study, reflux was induced in rats followed by postoperative endoscopy with biopsy, to diagnose and monitor disease progression. Overall, percentage agreement between visual endoscopy and gold standard histology was 95%, with disease-specific classification accuracies of 100% and 75% for Barrett's with dysplasia and EAC, respectively. Additionally, the percentage agreement for biopsy in tumors >4 mm was 75%. Thereby, establishing endoscopic evaluation as a reliable tool to assess disease progression and provide biopsies for downstream correlates in a de novo EAC model.
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Affiliation(s)
- Ashten N Omstead
- a Esophageal and Lung Institute , Allegheny Health Network , Pittsburgh , PA , USA
| | - Juliann E Kosovec
- a Esophageal and Lung Institute , Allegheny Health Network , Pittsburgh , PA , USA
| | - Daisuke Matsui
- b Department of Gastroenterological Surgery , Kanazawa University Hospital , Kanazawa , Ishikawa , Japan
| | - Samantha A Martin
- a Esophageal and Lung Institute , Allegheny Health Network , Pittsburgh , PA , USA
| | - Matthew A Smith
- c Department of Pathology and Laboratory Medicine , Allegheny Health Network , Pittsburgh , PA , USA
| | - D Aaron Guel
- a Esophageal and Lung Institute , Allegheny Health Network , Pittsburgh , PA , USA
| | - Jenna Kolano
- a Esophageal and Lung Institute , Allegheny Health Network , Pittsburgh , PA , USA
| | - Yoshihiro Komatsu
- a Esophageal and Lung Institute , Allegheny Health Network , Pittsburgh , PA , USA
| | - Fahim Habib
- a Esophageal and Lung Institute , Allegheny Health Network , Pittsburgh , PA , USA
| | - Christopher Lai
- a Esophageal and Lung Institute , Allegheny Health Network , Pittsburgh , PA , USA
| | - Kevi Christopher
- a Esophageal and Lung Institute , Allegheny Health Network , Pittsburgh , PA , USA
| | - Ronan J Kelly
- d Department of Oncology, Sidney Kimmel Comprehensive Cancer Center , Johns Hopkins Hospital , Baltimore , MD , USA
| | - Ali H Zaidi
- a Esophageal and Lung Institute , Allegheny Health Network , Pittsburgh , PA , USA
| | - Blair A Jobe
- a Esophageal and Lung Institute , Allegheny Health Network , Pittsburgh , PA , USA
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22
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Abstract
The cost-effectiveness of screening and surveillance for Barrett's esophagus continues to evolve as the incidence of esophageal adenocarcinoma increases, biomarkers enhance the identification of individuals at highest risk for developing cancer, and endoscopic eradication of Barrett's esophagus improves. Screening to detect Barrett's esophagus may be cost-effective in selected high-risk groups based on age, race, sex and other factors such as symptoms of heartburn. Currently, endoscopic eradication therapy for Barrett's esophagus and high-grade dysplasia is a cost-effective intervention, while endoscopic therapy for non-dysplastic Barrett's esophagus is not a cost-effective strategy. As diagnosis of low-grade dysplasia improves, endoscopic eradication therapy may also prove to be a cost-effective intervention.
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Affiliation(s)
- John M Inadomi
- Division of Gastroenterology, Department of Medicine, University of Washington School of Medicine, 1959 NE Pacific Street, Box 356424, Seattle, WA, 98195, USA.
| | - Nina Saxena
- Division of Gastroenterology, Department of Medicine, University of Washington School of Medicine, 1959 NE Pacific Street, Box 356424, Seattle, WA, 98195, USA
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23
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Barrett MT, Lenkiewicz E, Malasi S, Basu A, Yearley JH, Annamalai L, McCullough AE, Kosiorek HE, Narang P, Wilson Sayres MA, Chen M, Anderson KS, Pockaj BA. The association of genomic lesions and PD-1/PD-L1 expression in resected triple-negative breast cancers. Breast Cancer Res 2018; 20:71. [PMID: 29996881 PMCID: PMC6042255 DOI: 10.1186/s13058-018-1004-0] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 06/05/2018] [Indexed: 12/31/2022] Open
Abstract
Background Elevated PD-L1 expression on tumor cells, a context associated with an adaptive immune response, has been linked to the total burden of copy number variants (CNVs) in aneuploid tumors, to microsatellite instability (MSI), and to specific genomic driver lesions, including loss of PTEN, MYC amplification, and activating mutations in driver oncogenes such as KRAS and PIK3CA. Triple-negative breast cancers (TNBCs) typically have high levels of CNVs and diverse driver lesions in their genomes. Thus, there is significant interest in exploiting genomic data to develop predictive immunotherapy biomarkers for patients with TNBC. Methods Whole tissue samples from 55 resected TNBCs were screened by immunohistochemistry (IHC) for PD-1 and PD-L1 by using validated antibodies and established scoring methods for staining of tumor and non-tumor cells. In parallel, we interrogated biopsies from each resection with DNA content flow cytometry and sorted the nuclei of diploid, tetraploid, and aneuploid cell populations. CNVs were mapped with CNV oligonucleotide arrays by using purified (>95%) tumor populations. We generated whole exome data for 12 sorted tumor samples to increase the resolution within loci of interest and to incorporate somatic mutations into our genomic signatures. Results and Conclusions PD-L1 staining was detected on tumor cells in 29 out of 54 (54%) evaluable cases and was associated with increased overall survival (P = 0.0024). High levels of PD-1 and PD-L1 (IHC ≥4) were present in 11 out of 54 (20%) and 20 out of 54 (37%) cases with staining of PD-L1 primarily on tumor cells for 17 out of 20 (85%) cases. The latter included tumors with both high (>50) and low (<20) numbers of CNVs. Notably, homozygous deletion of PTEN (n = 6) or activating mutation in PIK3CA (n = 1) was not associated with increased expression of either immune checkpoint activator in TNBC. In contrast, two treatment-naïve cases with EGFR driver amplicons had high PD-L1 tumor staining. High mutational load and predicted neoepitopes were observed in MSI+ and high CNV burden TNBCs but were not associated with high PD-L1 expression on tumor cells. Our results challenge current models of genomic-based immunotherapy signatures yet suggest that discrete genomic lesions may complement existing biomarkers to advance immune checkpoint therapies for patients with TNBC. Electronic supplementary material The online version of this article (10.1186/s13058-018-1004-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Michael T Barrett
- Division of Hematology and Medical Oncology, Mayo Clinic in Arizona, Scottsdale, AZ, USA.
| | - Elizabeth Lenkiewicz
- Division of Hematology and Medical Oncology, Mayo Clinic in Arizona, Scottsdale, AZ, USA
| | - Smriti Malasi
- Division of Hematology and Medical Oncology, Mayo Clinic in Arizona, Scottsdale, AZ, USA
| | - Anamika Basu
- Division of Hematology and Medical Oncology, Mayo Clinic in Arizona, Scottsdale, AZ, USA
| | | | | | - Ann E McCullough
- Department of Pathology and Laboratory Medicine, Mayo Clinic in Arizona, Scottsdale, AZ, USA
| | - Heidi E Kosiorek
- Division of Hematology and Medical Oncology, Mayo Clinic in Arizona, Scottsdale, AZ, USA
| | - Pooja Narang
- School of Life Sciences, Arizona State University, Tempe, AZ, USA
| | | | - Meixuan Chen
- Biodesign Institute, Arizona State University, Tempe, AZ, USA
| | - Karen S Anderson
- Biodesign Institute, Arizona State University, Tempe, AZ, USA.,Division of Hematology and Medical Oncology, Mayo Clinic in Arizona, Phoenix, AZ, USA
| | - Barbara A Pockaj
- Division of General Surgery, Section of Surgical Oncology, Mayo Clinic in Arizona, Phoenix, AZ, USA
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24
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Choi WT, Tsai JH, Rabinovitch PS, Small T, Huang D, Mattis AN, Kakar S. Diagnosis and risk stratification of Barrett's dysplasia by flow cytometric DNA analysis of paraffin-embedded tissue. Gut 2018. [PMID: 28642331 DOI: 10.1136/gutjnl-2017-313815] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE The diagnosis of dysplasia in Barrett's oesophagus (BO) can be challenging, and reliable ancillary techniques are not available. This study examines if DNA content abnormality detected by flow cytometry can serve as a diagnostic marker of dysplasia and facilitate risk stratification of low-grade dysplasia (LGD) and indefinite for dysplasia (IND) patients using formalin-fixed paraffin-embedded (FFPE) BO samples with varying degrees of dysplasia. DESIGN DNA flow cytometry was performed on 80 FFPE BO samples with high-grade dysplasia (HGD), 38 LGD, 21 IND and 14 negative for dysplasia (ND). Three to four 60-micron thick sections were cut from each tissue block, and the area of interest was manually dissected. RESULTS DNA content abnormality was identified in 76 HGD (95%), 8 LGD (21.1%), 2 IND (9.5%) and 0 ND samples. As a diagnostic marker of HGD, the estimated sensitivity and specificity of DNA content abnormality were 95% and 85%, respectively. For patients with DNA content abnormality detected at baseline LGD or IND, the univariate HRs for subsequent detection of HGD or oesophageal adenocarcinoma (OAC) were 7.0 and 20.0, respectively (p =<0.001). CONCLUSIONS This study demonstrates the promise of DNA flow cytometry using FFPE tissue in the diagnosis and risk stratification of dysplasia in BO. The presence of DNA content abnormality correlates with increasing levels of dysplasia, as 95% of HGD samples showed DNA content abnormality. DNA flow cytometry also identifies a subset of patients with LGD and IND who are at higher risk for subsequent detection of HGD or OAC.
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Affiliation(s)
- Won-Tak Choi
- Department of Pathology, University of California at San Francisco, San Francisco, California, USA
| | - Jia-Huei Tsai
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | | | - Thomas Small
- Department of Pathology, University of Washington, Seattle, Washington, USA
| | - Danning Huang
- Department of Public Health and Preventive Medicine, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Aras N Mattis
- Department of Pathology, University of California at San Francisco, San Francisco, California, USA
| | - Sanjay Kakar
- Department of Pathology, University of California at San Francisco, San Francisco, California, USA
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25
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Eluri S, Klaver E, Duits LC, Jackson SA, Bergman JJ, Shaheen NJ. Validation of a biomarker panel in Barrett's esophagus to predict progression to esophageal adenocarcinoma. Dis Esophagus 2018; 31:4959873. [PMID: 29635420 PMCID: PMC6215490 DOI: 10.1093/dote/doy026] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In a prior study, baseline mutational load (ML) predicted progression to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) in Barrett's esophagus (BE) with an area under the curve (AUC) of 0.95. We aimed to validate the test characteristics of this predictive biomarker panel using crude DNA lysates in a larger well-characterized cohort. We performed a nested case-control study of BE patients from three tertiary referral centers in the Netherlands. Cases had baseline nondysplastic BE (NDBE) and developed HGD/EAC ≥ 2 years later. Controls were matched 2:1, had baseline NDBE, and no progression. Polymerase chain reaction (PCR)-based mutational analysis was performed on crude lysates from formalin-fixed, paraffin-embedded tissue. ML was calculated from loss of heterozygosity (LOH) and microsatellite instability (MSI) at 10 genomic loci. Receiver operator characteristic (ROC) curves were created to assess the diagnostic utility of various cutoffs of ML for progression. Of 159 subjects, 58 were progressors and 101 were nonprogressors, there was no difference in mean ML in preprogression tissue in progressors and nonprogressors (ML = 0.73 ± 0.69 vs. ML = 0.74 ± 0.61, P = 0.93). ROC curves showed poor discrimination of ML in predicting progression with AUC of 0.50 at ML ≥ 1. AUC did not vary with different ML cut-points. The utility of the ML to stratify BE patients for risk of progression was not confirmed in this study. The etiology for discrepancies between this and prior studies showing high predictiveness is likely due to the use of crude lysates in this study, but requires further investigation.
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Affiliation(s)
- S Eluri
- Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina,Address correspondence to: Swathi Eluri, MD, MSCR, Division of Gastroenterology and Hepatology, University of North Carolina, 130 Mason Farm Road CB#7080, Chapel Hill, NC 27599, USA.
| | - E Klaver
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - L C Duits
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - S A Jackson
- Interpace Diagnostics, Pittsburgh, Pennsylvania, USA
| | - J J Bergman
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - N J Shaheen
- Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina
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26
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Management of low-grade dysplasia in Barrett’s esophagus: Ablate or survey? TECHNIQUES IN GASTROINTESTINAL ENDOSCOPY 2018. [DOI: 10.1016/j.tgie.2018.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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27
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Martinez P, Mallo D, Paulson TG, Li X, Sanchez CA, Reid BJ, Graham TA, Kuhner MK, Maley CC. Evolution of Barrett's esophagus through space and time at single-crypt and whole-biopsy levels. Nat Commun 2018; 9:794. [PMID: 29476056 PMCID: PMC5824808 DOI: 10.1038/s41467-017-02621-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 12/13/2017] [Indexed: 12/22/2022] Open
Abstract
The low risk of progression of Barrett's esophagus (BE) to esophageal adenocarcinoma can lead to over-diagnosis and over-treatment of BE patients. This may be addressed through a better understanding of the dynamics surrounding BE malignant progression. Although genetic diversity has been characterized as a marker of malignant development, it is still unclear how BE arises and develops. Here we uncover the evolutionary dynamics of BE at crypt and biopsy levels in eight individuals, including four patients that experienced malignant progression. We assay eight individual crypts and the remaining epithelium by SNP array for each of 6-11 biopsies over 2 time points per patient (358 samples in total). Our results indicate that most Barrett's segments are clonal, with similar number and inferred rates of alterations observed for crypts and biopsies. Divergence correlates with geographical location, being higher near the gastro-esophageal junction. Relaxed clock analyses show that genomic instability precedes and is enhanced by genome doubling. These results shed light on the clinically relevant evolutionary dynamics of BE.
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Affiliation(s)
- Pierre Martinez
- Evolution and Cancer Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon Cedex 08, 69373, France
| | - Diego Mallo
- Biodesign Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, Arizona, 85287, USA
| | - Thomas G Paulson
- Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109-1024, USA
| | - Xiaohong Li
- Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109-1024, USA
| | - Carissa A Sanchez
- Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109-1024, USA
| | - Brian J Reid
- Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109-1024, USA
- Department of Genome Sciences, University of Washington, Seattle, Washington, 98195-5065, USA
| | - Trevor A Graham
- Evolution and Cancer Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Mary K Kuhner
- Department of Genome Sciences, University of Washington, Seattle, Washington, 98195-5065, USA
| | - Carlo C Maley
- Biodesign Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, Arizona, 85287, USA.
- School of Life Sciences, Arizona State University, Tempe, Arizona, 85287, USA.
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28
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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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29
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Clinical study of genomic drivers in pancreatic ductal adenocarcinoma. Br J Cancer 2017; 117:572-582. [PMID: 28720843 PMCID: PMC5558689 DOI: 10.1038/bjc.2017.209] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 05/18/2017] [Accepted: 06/12/2017] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials. METHODS Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples. We profiled biopsies from 68 patients enrolled in two Stand Up to Cancer (SU2C)-sponsored clinical trials. These included 38 resected chemoradiation naïve tumours (SU2C 20206-003) and metastases from 30 patients who progressed on prior therapies (SU2C 20206-001). Patient outcomes including progression-free survival (PFS) and overall survival (OS) were observed. RESULTS We defined: (a) CDKN2A homozygous deletions that included the adjacent MTAP gene, only its' 3' region, or excluded MTAP; (b) SMAD4 homozygous deletions that included ME2; (c) a pancreas-specific MYC super-enhancer region; (d) DNA repair-deficient genomes; and (e) copy number aberrations present in PDA patients with long-term (⩾ 40 months) and short-term (⩽ 12 months) survival after surgical resection. CONCLUSIONS We provide a clinically relevant framework for genomic drivers of PDA and for advancing novel treatments.
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30
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Saxena N, Inadomi JM. Effectiveness and Cost-Effectiveness of Endoscopic Screening and Surveillance. Gastrointest Endosc Clin N Am 2017; 27:397-421. [PMID: 28577764 DOI: 10.1016/j.giec.2017.02.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Guidelines for the screening and surveillance of Barrett's esophagus continue to evolve as the incidence of esophageal adenocarcinoma increases, identification of individuals at highest risk for cancer improves, and management of dysplasia evolves. This article reviews related studies and economic analyses. Advances in diagnosis offer promising strategies to help focus screening efforts on those individuals who are most likely to develop esophageal adenocarcinoma.
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Affiliation(s)
- Nina Saxena
- Division of Gastroenterology, Department of Medicine, University of Washington School of Medicine, 1959 Northeast Pacific Street, Box 356424, Seattle, WA 98195, USA
| | - John M Inadomi
- Division of Gastroenterology, Department of Medicine, University of Washington School of Medicine, 1959 Northeast Pacific Street, Box 356424, Seattle, WA 98195, USA.
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31
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Eluri S, Shaheen NJ. Barrett's esophagus: diagnosis and management. Gastrointest Endosc 2017; 85:889-903. [PMID: 28109913 PMCID: PMC5392444 DOI: 10.1016/j.gie.2017.01.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 01/07/2017] [Indexed: 02/08/2023]
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32
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Altaf K, Xiong JJ, la Iglesia DD, Hickey L, Kaul A. Meta-analysis of biomarkers predicting risk of malignant progression in Barrett's oesophagus. Br J Surg 2017; 104:493-502. [PMID: 28295252 DOI: 10.1002/bjs.10484] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 06/18/2016] [Accepted: 12/08/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Barrett's oesophagus is a precursor to the development of oesophageal adenocarcinoma. This study sought to clarify the role of genetic, chromosomal and proliferation biomarkers that have been the subjects of multiple studies through meta-analysis. METHODS MEDLINE, Embase, PubMed and the Cochrane Library were searched for clinical studies assessing the value of p53, p16, Ki-67 and DNA content abnormalities in Barrett's oesophagus. The main outcome measure was the risk of development of high-grade dysplasia (HGD) or oesophageal adenocarcinoma. RESULTS Some 102 studies, with 12 353 samples, were identified. Mutation (diagnostic odds ratio (DOR) 10·91, sensitivity 47 per cent, specificity 92 per cent, positive likelihood ratio (PLR) 4·71, negative likelihood ratio (NLR) 0·65, area under the curve (AUC) 0·792) and loss (DOR 16·16, sensitivity 31 per cent, specificity 98 per cent, PLR 6·66, NLR 0·41, AUC 0·923) of p53 were found to be superior to the other p53 abnormalities (loss of heterozygosity (LOH) and overexpression). Ki-67 had high sensitivity in identifying high-risk patients (DOR 5·54, sensitivity 82 per cent, specificity 48 per cent, PLR 1·59, NLR 0·42, AUC 0·761). Aneuploidy (DOR 12·08, sensitivity 53 per cent, specificity 87 per cent, PLR 4·26, NLR 0·42, AUC 0·846), tetraploidy (DOR 5·87, sensitivity 46 per cent, specificity 85 per cent, PLR 3·47, NLR 0·65, AUC 0·793) and loss of Y chromosome (DOR 9·23, sensitivity 68 per cent, specificity 80 per cent, PLR 2·67, NLR 0·49, AUC 0·807) also predicted malignant development, but p16 aberrations (hypermethylation, LOH, mutation and loss) failed to demonstrate any advantage over the other biomarkers studied. CONCLUSION Loss and mutation of p53, and raised level of Ki-67 predicted malignant progression in Barrett's oesophagus.
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Affiliation(s)
- K Altaf
- Department of Surgery, Whiston Hospital, St Helen's and Knowsley Hospitals NHS Foundation Trust, Liverpool, UK
| | - J-J Xiong
- Department of Hepato-Biliary-Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - D De la Iglesia
- Department of Gastroenterology and Hepatology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
| | - L Hickey
- Department of Surgery, Whiston Hospital, St Helen's and Knowsley Hospitals NHS Foundation Trust, Liverpool, UK
| | - A Kaul
- Department of Surgery, Whiston Hospital, St Helen's and Knowsley Hospitals NHS Foundation Trust, Liverpool, UK
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33
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Letsolo BT, Jones RE, Rowson J, Grimstead JW, Keith WN, Jenkins GJS, Baird DM. Extensive telomere erosion is consistent with localised clonal expansions in Barrett's metaplasia. PLoS One 2017; 12:e0174833. [PMID: 28362812 PMCID: PMC5375150 DOI: 10.1371/journal.pone.0174833] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 03/15/2017] [Indexed: 12/24/2022] Open
Abstract
Barrett's oesophagus is a premalignant metaplastic condition that predisposes patients to the development of oesophageal adenocarcinoma. However, only a minor fraction of Barrett's oesophagus patients progress to adenocarcinoma and it is thus essential to determine bio-molecular markers that can predict the progression of this condition. Telomere dysfunction is considered to drive clonal evolution in several tumour types and telomere length analysis provides clinically relevant prognostic and predictive information. The aim of this work was to use high-resolution telomere analysis to examine telomere dynamics in Barrett's oesophagus. Telomere length analysis of XpYp, 17p, 11q and 9p, chromosome arms that contain key cancer related genes that are known to be subjected to copy number changes in Barrett's metaplasia, revealed similar profiles at each chromosome end, indicating that no one specific telomere is likely to suffer preferential telomere erosion. Analysis of patient matched tissues (233 samples from 32 patients) sampled from normal squamous oesophagus, Z-line, and 2 cm intervals within Barrett's metaplasia, plus oesophago-gastric junction, gastric body and antrum, revealed extensive telomere erosion in Barrett's metaplasia to within the length ranges at which telomere fusion is detected in other tumour types. Telomere erosion was not uniform, with distinct zones displaying more extensive erosion and more homogenous telomere length profiles. These data are consistent with an extensive proliferative history of cells within Barrett's metaplasia and are indicative of localised clonal growth. The extent of telomere erosion highlights the potential of telomere dysfunction to drive genome instability and clonal evolution in Barrett's metaplasia.
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Affiliation(s)
- Boitelo T. Letsolo
- Division of Cancer & Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
| | - Rhiannon E. Jones
- Division of Cancer & Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
| | - Jan Rowson
- Division of Cancer & Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
| | - Julia W. Grimstead
- Division of Cancer & Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
| | - W. Nicol Keith
- Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Gareth J. S. Jenkins
- GI Cancer Group, School of Medicine, Swansea University, Swansea, United Kingdom
| | - Duncan M. Baird
- Division of Cancer & Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
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Abstract
In The Cancer Genome Atlas the goals were to define how to treat advanced cancers with targeted therapy. However, the challenges facing cancer interception for early detection and prevention include length bias in which current screening and surveillance approaches frequently miss rapidly progressing cancers that then present at advanced stages in the clinic with symptoms (underdiagnosis). In contrast, many early detection strategies detect benign conditions that may never progress to cancer during a lifetime, and the patient dies of unrelated causes (overdiagnosis). This challenge to cancer interception is believed to be due to the speed at which the neoplasm evolves, called length bias sampling; rapidly progressing cancers are missed by current early detection strategies. In contrast, slowly or non-progressing cancers or their precursors are selectively detected. This has led to the concept of cancer interception, which can be defined as active interception of a biological process that drives cancer development before the patient presents in the clinic with an advanced, symptomatic cancer. The solutions needed to advance strategies for cancer interception require assessing the rate at which the cancer evolves over time and space. This is an essential challenge that needs to be addressed by robust study designs including normal and non-progressing controls when known to be appropriate.
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Affiliation(s)
- Brian J. Reid
- Correspondence Address correspondence to: Brian J. Reid, MD, PhD, 1100 Fairview Avenue N, C1-157, PO Box 19024, Seattle, Washington 98109-1024. fax: (206) 667-6192.1100 Fairview Avenue N, C1-157, PO Box 19024SeattleWashington 98109-1024
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35
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Ohshima S, Seyama A. Establishment of Proliferative Tetraploid Cells from Nontransformed Human Fibroblasts. J Vis Exp 2017. [PMID: 28117785 DOI: 10.3791/55028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Polyploid (mostly tetraploid) cells are often observed in preneoplastic lesions of human tissues and their chromosomal instability has been considered to be responsible for carcinogenesis in such tissues. Although proliferative polyploid cells are requisite for analyzing chromosomal instability of polyploid cells, creating such cells from nontransformed human cells is rather challenging. Induction of tetraploidy by chemical agents usually results in a mixture of diploid and tetraploid populations, and most studies employed fluorescence-activated cell sorting or cloning by limiting dilution to separate tetraploid from diploid cells. However, these procedures are time-consuming and laborious. The present report describes a relatively simple protocol to induce proliferative tetraploid cells from normal human fibroblasts with minimum contamination by diploid cells. Briefly, the protocol is comprised of the following steps: arresting cells in mitosis by demecolcine (DC), collecting mitotic cells after shaking off, incubating collected cells with DC for an additional 3 days, and incubating cells in drug-free medium (They resume proliferation as tetraploid cells within several days). Depending on cell type, the collection of mitotic cells by shaking off might be omitted. This protocol provides a simple and feasible method to establish proliferative tetraploid cells from normal human fibroblasts. Tetraploid cells established by this method could be a useful model for studying chromosome instability and the oncogenic potential of polyploid human cells.
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Affiliation(s)
- Susumu Ohshima
- Division of Morphological Science, Biomedical Research Center, Saitama Medical University;
| | - Atsushi Seyama
- Department of Pathology, International Medical Center, Saitama Medical University
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Wani S, Rubenstein JH, Vieth M, Bergman J. Diagnosis and Management of Low-Grade Dysplasia in Barrett's Esophagus: Expert Review From the Clinical Practice Updates Committee of the American Gastroenterological Association. Gastroenterology 2016; 151:822-835. [PMID: 27702561 DOI: 10.1053/j.gastro.2016.09.040] [Citation(s) in RCA: 106] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The purpose of this clinical practice update expert review is to define the key principles in the diagnosis and management of low-grade dysplasia (LGD) in Barrett's esophagus patients. The best practices outlined in this review are based on relevant publications, including systematic reviews and expert opinion (when applicable). Practice Advice 1: The extent of Barrett's esophagus should be defined using a standardized grading system documenting the circumferential and maximal extent of the columnar lined esophagus (Prague classification) with a clear description of landmarks and visible lesions (nodularity, ulceration) when present. Practice Advice 2: Given the significant interobserver variability among pathologists, the diagnosis of Barrett's esophagus with LGD should be confirmed by an expert gastrointestinal pathologist (defined as a pathologist with a special interest in Barrett's esophagus-related neoplasia who is recognized as an expert in this field by his/her peers). Practice Advice 3: Expert pathologists should report audits of their diagnosed cases of LGD, such as the frequency of LGD diagnosed among surveillance patients and/or the difference in incidence of neoplastic progression among patients diagnosed with LGD vs nondysplastic Barrett's esophagus. Practice Advice 4: Patients in whom the diagnosis of LGD is downgraded to nondysplastic Barrett's esophagus should be managed as nondysplastic Barrett's esophagus. Practice Advice 5: In Barrett's esophagus patients with confirmed LGD (based on expert gastrointestinal pathology review), repeat upper endoscopy using high-definition/high-resolution white-light endoscopy should be performed under maximal acid suppression (twice daily dosing of proton pump inhibitor therapy) in 8-12 weeks. Practice Advice 6: Under ideal circumstances, surveillance biopsies should not be performed in the presence of active inflammation (erosive esophagitis, Los Angeles grade C and D). Pathologists should be informed if biopsies are obtained in the setting of erosive esophagitis and if pathology findings suggest LGD, or if no biopsies are obtained, surveillance biopsies should be repeated after the anti-reflux regimen has been further intensified. Practice Advice 7: Surveillance biopsies should be performed in a four-quadrant fashion every 1-2 cm with target biopsies obtained from visible lesions taken first. Practice Advice 8: Patients with a confirmed histologic diagnosis of LGD should be referred to an endoscopist with expertise in managing Barrett's esophagus-related neoplasia practicing at centers equipped with high-definition endoscopy and capable of performing endoscopic resection and ablation. Practice Advice 9: Endoscopic resection should be performed in Barrett's esophagus patients with LGD with endoscopically visible abnormalities (no matter how subtle) in order to accurately assess the grade of dysplasia. Practice Advice 10: In patients with confirmed Barrett's esophagus with LGD by expert GI pathology review that persists on a second endoscopy, despite intensification of acid-suppressive therapy, risks and benefits of management options of endoscopic eradication therapy (specifically adverse events associated with endoscopic resection and ablation), and ongoing surveillance should be discussed and documented. Practice Advice 11: Endoscopic eradication therapy should be considered in patients with confirmed and persistent LGD with the goal of achieving complete eradication of intestinal metaplasia. Practice Advice 12: Patients with LGD undergoing surveillance rather than endoscopic eradication therapy should undergo surveillance every 6 months times 2, then annually unless there is reversion to nondysplastic Barrett's esophagus. Biopsies should be obtained in 4-quadrants every 1-2 cm and of any visible lesions. Practice Advice 13: In patients with Barrett's esophagus-related LGD undergoing ablative therapy, radiofrequency ablation should be used. Practice Advice 14: Patients completing endoscopic eradication therapy should be enrolled in an endoscopic surveillance program. Patients who have achieved complete eradication of intestinal metaplasia should undergo surveillance every year for 2 years and then every 3 years thereafter to detect recurrent intestinal metaplasia and dysplasia. Patients who have not achieved complete eradication of intestinal metaplasia should undergo surveillance every 6 months for 1 year after the last endoscopy, then annually for 2 years, then every 3 years thereafter. Practice Advice 15: Following endoscopic eradication therapy, the biopsy protocol of obtaining biopsies in 4 quadrants every 2 cm throughout the length of the original Barrett's esophagus segment and any visible columnar mucosa is suggested. Practice Advice 16: Endoscopists performing endoscopic eradication therapy should report audits of their rates of complete eradication of dysplasia and intestinal metaplasia and adverse events in clinical practice.
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Affiliation(s)
- Sachin Wani
- University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Joel H Rubenstein
- Veterans Affairs Center for Clinical Management Research, Ann Arbor, Michigan; University of Michigan Medical School, Ann Arbor, Michigan
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Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer. Oncotarget 2016; 6:26483-93. [PMID: 26317899 PMCID: PMC4694916 DOI: 10.18632/oncotarget.4494] [Citation(s) in RCA: 106] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 06/22/2015] [Indexed: 12/16/2022] Open
Abstract
We used DNA content flow cytometry followed by oligonucleotide array based comparative genomic hybridization to survey the genomes of 326 tumors, including 41 untreated surgically resected triple negative breast cancers (TNBC). A high level (log2ratio ≥ 1) 9p24 amplicon was found in TNBC (12/41), glioblastomas (2/44), and colon carcinomas (2/68). The shortest region of overlap for the amplicon targets 9p24.1 and includes the loci for PD-L1, PD-L2, and JAK2 (PDJ amplicon). In contrast this amplicon was absent in ER+ (0/8) and HER2+ (0/15) breast tumors, and in pancreatic ductal adenocarcinomas (0/150). The PDJ amplicon in TNBCs was correlated with clinical outcomes in group comparisons by two-sample t-tests for continuous variables and chi-squared tests for categorical variables. TNBC patients with the PDJ amplicon had a worse outcome with worse disease-free and overall survival. Quantitative RT-PCR confirmed that the PDJ amplicon in TNBC is associated with elevated expression of JAK2 and of the PD-1 ligands. These initial findings demonstrate that the PDJ amplicon is enriched in TNBC, targets signaling pathways that activate the PD-1 mediated immune checkpoint, and identifies patients with a poor prognosis.
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Abstract
The article by Banerjee and colleagues published in this issue of the journal involving a randomized control prevention trial of ursodeoxycholic acid (UDCA) in Barrett esophagus reported a null outcome despite being well designed and executed. Possible reasons for this null outcome are discussed focusing on use of surrogate endpoints in the trial. The trial is especially topical because it comes at a time when there are calls for a Pre-Cancer Genome Atlas (PCGA) for "understanding the earliest molecular and cellular events associated with cancer initiation…" This commentary discusses current concepts in prevention research including branched evolution that leads to therapeutic resistance. Length bias sampling postulates underdiagnosis is due to rapidly progressing disease that is difficult to detect by screening because it progresses to cancer too rapidly and that overdiagnosis is the result of very slowly or nonprogressing disease that is easy to detect by screening because it persists for a lifetime and the patient dies of unrelated causes. Finally, it also explores study designs, including surrogate endpoints in Barrett esophagus trials, and opportunities and pitfalls for a PCGA in the context of high levels of over and underdiagnosis of Barrett esophagus as well as many other cancers and their precursors. Cancer Prev Res; 9(7); 512-7. ©2016 AACRSee related article by Banerjee, et al., p. 528.
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Affiliation(s)
- Brian J Reid
- Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Departments of Genome Sciences and Medicine, University of Washington, Seattle, Washington.
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Management of Barrett's esophagus: Screening to newer treatments. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2016. [DOI: 10.1016/j.rgmxen.2016.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Thoguluva Chandrasekar V, Vennalaganti P, Sharma P. Management of Barrett's esophagus: From screening to newer treatments. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2016; 81:91-102. [PMID: 26964773 DOI: 10.1016/j.rgmx.2015.07.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 07/15/2015] [Indexed: 02/07/2023]
Abstract
Barrett's esophagus is a premalignant condition of the esophagus in which the squamous epithelium of the lower end of the esophagus is replaced with columnar epithelium. Since the incidence of esophageal adenocarcinoma is on the rise, the major gastroenterology societies have come up with their recommendations for screening and surveillance. Specific factors like obesity, white race, age over 50 years, early age of onset of GERD, smoking and hiatal hernia have been identified as increasing the risk of Barrett's esophagus and adenocarcinoma. The diagnosis requires both endoscopic identification of columnar-lined mucosa and histological confirmation with biopsy. Most medical societies recommend screening people with GERD and other risk factors with endoscopy, but other alternatives employing less invasive methods are currently being studied. Surveillance strategies vary depending on the endoscopic findings and the Seattle biopsy protocol with random 4-quadrant sampling is recommended. Biomarkers have shown promising results, but more studies are needed in the future. White light endoscopy is the standard practice, but other advanced imaging modalities have shown variable results and hence more studies are awaited for further validation. Endoscopic eradication techniques, including both resection and ablation, have shown good but variable results for treating dysplastic lesions confined to the mucosa. Resection procedures to remove visible lesions followed by ablation of the dysplastic mucosa have shown the best results with higher eradication rates and lower recurrence rates. Surgical management is reserved for lesions with sub-mucosal invasion and lymph node spread with increased risk of metastasis.
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Affiliation(s)
| | - P Vennalaganti
- Department of Gastroenterology, Hepatology and Motility, University of Kansas Medical Center, Kansas city, Missouri, EE. UU
| | - P Sharma
- Department of Gastroenterology, Hepatology and Motility, University of Kansas Medical Center, Kansas city, Missouri, EE. UU..
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Ohshima S, Seyama A. Establishment of proliferative tetraploid cells from telomerase-immortalized normal human fibroblasts. Genes Chromosomes Cancer 2016; 55:522-30. [PMID: 26917432 DOI: 10.1002/gcc.22354] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 02/22/2016] [Accepted: 02/22/2016] [Indexed: 12/15/2022] Open
Abstract
Aneuploidy is observed in the majority of human cancers and is considered to be causally related to carcinogenesis. Although malignant aneuploid cells are suggested to develop from polyploid cells formed in precancerous lesions, the mechanisms of this process remain elusive. This is partly because no experimental model is available where nontransformed polyploid human cells propagate in vitro. We previously showed that proliferative tetraploid cells can be established from normal human fibroblasts by treatment with the spindle poison demecolcine (DC). However, the limited lifespan of these cells hampered detailed analysis of a link between chromosomal instability and the oncogenic transformation of polyploid cells. Here, we report the establishment of proliferative tetraploid cells from the telomerase-immortalized normal human fibroblast cell line TIG-1. Treatment of immortalized diploid cells with DC for 4 days resulted in proliferation of cells with tetraploid DNA content and near-tetraploid/tetraploid chromosome counts. Established tetraploid cells had functional TP53 despite growing at almost the same rate as diploid cells. The frequency of clonal and sporadic chromosome aberrations in tetraploid cells was higher than in diploid cells and in one experiment, gradually increased with repeated subculture. This study suggests that tetraploid cells established from telomerase-immortalized normal human fibroblasts can be a valuable model for studying chromosomal instability and the oncogenic potential of polyploid cells. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Susumu Ohshima
- Division of Morphological Science, Biomedical Research Center, Saitama Medical University, Morohongo, Moroyama, Iruma, Saitama, Japan
| | - Atsushi Seyama
- Department of Pathology, International Medical Center, Saitama Medical University, Yamane, Hidaka, Saitama, Japan
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Findlay JM, Middleton MR, Tomlinson I. Genetic Biomarkers of Barrett's Esophagus Susceptibility and Progression to Dysplasia and Cancer: A Systematic Review and Meta-Analysis. Dig Dis Sci 2016; 61:25-38. [PMID: 26445852 PMCID: PMC4700058 DOI: 10.1007/s10620-015-3884-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 09/11/2015] [Indexed: 01/01/2023]
Abstract
Barrett's esophagus (BE) is a common and important precursor lesion of esophageal adenocarcinoma (EAC). A third of patients with BE are asymptomatic, and our ability to predict the risk of progression of metaplasia to dysplasia and EAC (and therefore guide management) is limited. There is an urgent need for clinically useful biomarkers of susceptibility to both BE and risk of subsequent progression. This study aims to systematically identify, review, and meta-analyze genetic biomarkers reported to predict both. A systematic review of the PubMed and EMBASE databases was performed in May 2014. Study and evidence quality were appraised using the revised American Society of Clinical Oncology guidelines, and modified Recommendations for Tumor Marker Scores. Meta-analysis was performed for all markers assessed by more than one study. A total of 251 full-text articles were reviewed; 52 were included. A total of 33 germline markers of susceptibility were identified (level of evidence II-III); 17 were included. Five somatic markers of progression were identified; meta-analysis demonstrated significant associations for chromosomal instability (level of evidence II). One somatic marker of progression/relapse following photodynamic therapy was identified. However, a number of failings of methodology and reporting were identified. This is the first systematic review and meta-analysis to evaluate genetic biomarkers of BE susceptibility and risk of progression. While a number of limitations of study quality temper the utility of those markers identified, some-in particular, those identified by genome-wide association studies, and chromosomal instability for progression-appear plausible, although robust validation is required.
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Affiliation(s)
- John M Findlay
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
- Oxford OesophagoGastric Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation trust, Oxford, OX3 7LJ, UK.
- NIHR Oxford Biomedical Research Centre, The Joint Research Office, Churchill Hospital, Oxford, OX3 7LE, UK.
| | - Mark R Middleton
- NIHR Oxford Biomedical Research Centre, The Joint Research Office, Churchill Hospital, Oxford, OX3 7LE, UK
- Department of Oncology, Old Road Campus Research Building, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, UK
| | - Ian Tomlinson
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK
- NIHR Oxford Biomedical Research Centre, The Joint Research Office, Churchill Hospital, Oxford, OX3 7LE, UK
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ACG Clinical Guideline: Diagnosis and Management of Barrett's Esophagus. Am J Gastroenterol 2016; 111:30-50; quiz 51. [PMID: 26526079 DOI: 10.1038/ajg.2015.322] [Citation(s) in RCA: 1038] [Impact Index Per Article: 115.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 08/28/2015] [Indexed: 12/11/2022]
Abstract
Barrett's esophagus (BE) is among the most common conditions encountered by the gastroenterologist. In this document, the American College of Gastroenterology updates its guidance for the best practices in caring for these patients. These guidelines continue to endorse screening of high-risk patients for BE; however, routine screening is limited to men with reflux symptoms and multiple other risk factors. Acknowledging recent data on the low risk of malignant progression in patients with nondysplastic BE, endoscopic surveillance intervals are attenuated in this population; patients with nondysplastic BE should undergo endoscopic surveillance no more frequently than every 3-5 years. Neither routine use of biomarker panels nor advanced endoscopic imaging techniques (beyond high-definition endoscopy) is recommended at this time. Endoscopic ablative therapy is recommended for patients with BE and high-grade dysplasia, as well as T1a esophageal adenocarcinoma. Based on recent level 1 evidence, endoscopic ablative therapy is also recommended for patients with BE and low-grade dysplasia, although endoscopic surveillance continues to be an acceptable alternative. Given the relatively common recurrence of BE after ablation, we suggest postablation endoscopic surveillance intervals. Although many of the recommendations provided are based on weak evidence or expert opinion, this document provides a pragmatic framework for the care of the patient with BE.
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Abstract
Beginning in the 1980s, an alarming rise in the incidence of esophageal adenocarcinoma (EA) led to screening of patients with reflux to detect Barrett's esophagus (BE) and surveillance of BE to detect early EA. This strategy, based on linear progression disease models, resulted in selective detection of BE that does not progress to EA over a lifetime (overdiagnosis) and missed BE that rapidly progresses to EA (underdiagnosis). Here we review the historical thought processes that resulted in this undesired outcome and the transformation in our understanding of genetic and evolutionary principles governing neoplastic progression that has come from application of modern genomic technologies to cancers and their precursors. This new synthesis provides improved strategies for prevention and early detection of EA by addressing the environmental and mutational processes that can determine "windows of opportunity" in time to detect rapidly progressing BE and distinguish it from slowly or nonprogressing BE.
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Affiliation(s)
- Brian J. Reid
- Division of Human Biology, FredHutch, Seattle WA,Division of Public Health Sciences, FredHutch, Seattle WA,Department of Genome Sciences, University of Washington,Department of Medicine, University of Washington,Corresponding author Brian J. Reid, M.D., Ph.D. 1100 Fairview Ave N., C1-157 P.O. Box 19024 Seattle, WA 98109-1024 206-667-4073 (phone) 206-667-6192 (FAX)
| | | | - Xiaohong Li
- Division of Human Biology, FredHutch, Seattle WA
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Kim SY, Im K, Park SN, Kwon J, Kim JA, Choi Q, Hwang SM, Han SH, Kwon S, Oh IH, Lee DS. Asymmetric aneuploidy in mesenchymal stromal cells detected by in situ karyotyping and fluorescence in situ hybridization: suggestions for reference values for stem cells. Stem Cells Dev 2015; 24:77-92. [PMID: 25019198 DOI: 10.1089/scd.2014.0137] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cytogenetic testing is important to ensure patient safety before therapeutic application of mesenchymal stromal cells (MSCs). However, the standardized methods and criteria for the screening of chromosomal abnormalities of MSCs have not yet been determined. We investigated the frequency of cytogenetic aberrations in MSCs using G-banding and fluorescence in situ hybridization (FISH) and suggest reference values for aneuploidy in MSCs. Cytogenetic analysis was performed on 103 consecutive cultures from 68 MSCs (25 adipose-origin, 20 bone marrow-origin, 18 cord blood-origin, and 5 neural stem cells; 8 from adipose tissue of patients with breast cancer and 60 from healthy donors). We compared the MSC aneuploidy patterns with those of hematological malignancies and benign hematological diseases. Interphase FISH showed variable aneuploid clone proportions (1%-20%) in 68 MSCs. The aneuploidy patterns were asymmetric, and aneuploidy of chromosomes 16, 17, 18, and X occurred most frequently. Clones with polysomy were significantly more abundant than those with monosomy. The cutoff value of maximum polysomy rates (upper 95th percentile value) was 13.0%. By G-banding, 5 of the 61 MSCs presented clonal chromosomal aberrations. Aneuploidy was asymmetric in the malignant hematological diseases, while it was symmetric in the benign hematological diseases. We suggest an aneuploidy cutoff value of 13%, and FISH for aneuploidy of chromosomes 16, 17, 18, and X would be informative to evaluate the genetic stability of MSCs. Although it is unclear whether the aneuploid clones might represent the senescent cell population or transformed cells, more attention should be focused on the safety of MSCs, and G-banding combined with FISH should be performed.
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Affiliation(s)
- Seon Young Kim
- 1 Department of Laboratory Medicine, Seoul National University College of Medicine , Seoul, Republic of Korea
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Srivastava A, Golden KL, Sanchez CA, Liu K, Fong PY, Li X, Cowan DS, Rabinovitch PS, Reid BJ, Blount PL, Odze RD. High Goblet Cell Count Is Inversely Associated with Ploidy Abnormalities and Risk of Adenocarcinoma in Barrett's Esophagus. PLoS One 2015; 10:e0133403. [PMID: 26230607 PMCID: PMC4521918 DOI: 10.1371/journal.pone.0133403] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Accepted: 06/25/2015] [Indexed: 12/13/2022] Open
Abstract
Purpose Goblet cells may represent a potentially successful adaptive response to acid and bile by producing a thick mucous barrier that protects against cancer development in Barrett's esophagus (BE). The aim of this study was to determine the relationship between goblet cells (GC) and risk of progression to adenocarcinoma, and DNA content flow cytometric abnormalities, in BE patients. Experimental Design Baseline mucosal biopsies (N=2988) from 213 patients, 32 of whom developed cancer during the follow up period, enrolled in a prospective dynamic cohort of BE patients were scored in a blinded fashion, for the total number (#) of GC, mean # of GC/crypt (GC density), # of crypts with ≥ 1 GC, and the proportion of crypts with ≥1 GC, in both dysplastic and non-dysplastic epithelium separately. The relationship between these four GC parameters and DNA content flow cytometric abnormalities and adenocarcinoma outcome was compared, after adjustment for age, gender, and BE segment length. Results High GC parameters were inversely associated with DNA content flow cytometric abnormalities, such as aneuploidy, ploidy >2.7N, and an elevated 4N fraction > 6%, and with risk of adenocarcinoma. However, a Kaplan-Meier analysis showed that the total # of GC and the total # crypts with ≥1 GC were the only significant GC parameters (p<0.001 and 0.003, respectively). Conclusions The results of this study show, for the first time, an inverse relationship between high GC counts and flow cytometric abnormalities and risk of adenocarcinoma in BE. Further studies are needed to determine if GC depleted foci within esophageal columnar mucosa are more prone to neoplastic progression or whether loss of GC occurs secondary to underlying genetic abnormalities.
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Affiliation(s)
- Amitabh Srivastava
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts, United States of America
| | - Kevin L. Golden
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts, United States of America
| | - Carissa A. Sanchez
- Department of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Karen Liu
- Department of Vaccine Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Pui Yee Fong
- Department of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Xiaohong Li
- Department of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - David S. Cowan
- Department of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Peter S. Rabinovitch
- Department of Pathology, University of Washington, Seattle, Washington, United States of America
| | - Brian J. Reid
- Department of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| | - Patricia L. Blount
- Department of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Robert D. Odze
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts, United States of America
- * E-mail:
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Li X, Paulson TG, Galipeau PC, Sanchez CA, Liu K, Kuhner MK, Maley CC, Self SG, Vaughan TL, Reid BJ, Blount PL. Assessment of Esophageal Adenocarcinoma Risk Using Somatic Chromosome Alterations in Longitudinal Samples in Barrett's Esophagus. Cancer Prev Res (Phila) 2015; 8:845-56. [PMID: 26130253 DOI: 10.1158/1940-6207.capr-15-0130] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 06/15/2015] [Indexed: 12/20/2022]
Abstract
Cancers detected at a late stage are often refractory to treatments and ultimately lethal. Early detection can significantly increase survival probability, but attempts to reduce mortality by early detection have frequently increased overdiagnosis of indolent conditions that do not progress over a lifetime. Study designs that incorporate biomarker trajectories in time and space are needed to distinguish patients who progress to an early cancer from those who follow an indolent course. Esophageal adenocarcinoma is characterized by evolution of punctuated and catastrophic somatic chromosomal alterations and high levels of overall mutations but few recurrently mutated genes aside from TP53. Endoscopic surveillance of Barrett's esophagus for early cancer detection provides an opportunity for assessment of alterations for cancer risk in patients who progress to esophageal adenocarcinoma compared with nonprogressors. We investigated 1,272 longitudinally collected esophageal biopsies in a 248 Barrett's patient case-cohort study with 20,425 person-months of follow-up, including 79 who progressed to early-stage esophageal adenocarcinoma. Cancer progression risk was assessed for total chromosomal alterations, diversity, and chromosomal region-specific alterations measured with single-nucleotide polymorphism arrays in biopsies obtained over esophageal space and time. A model using 29 chromosomal features was developed for cancer risk prediction (area under receiver operator curve, 0.94). The model prediction performance was robust in two independent esophageal adenocarcinoma sets and outperformed TP53 mutation, flow cytometric DNA content, and histopathologic diagnosis of dysplasia. This study offers a strategy to reduce overdiagnosis in Barrett's esophagus and improve early detection of esophageal adenocarcinoma and potentially other cancers characterized by punctuated and catastrophic chromosomal evolution.
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Affiliation(s)
- Xiaohong Li
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Thomas G Paulson
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Patricia C Galipeau
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Carissa A Sanchez
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Karen Liu
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Mary K Kuhner
- Department of Genome Sciences, University of Washington, Seattle, Washington
| | - Carlo C Maley
- Center for Evolution and Cancer, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. School of Life Sciences, Arizona State University, Tempe, Arizona
| | - Steven G Self
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Thomas L Vaughan
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Epidemiology, University of Washington, Seattle, Washington
| | - Brian J Reid
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Genome Sciences, University of Washington, Seattle, Washington. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Medicine, University of Washington, Seattle, Washington.
| | - Patricia L Blount
- Department of Medicine, University of Washington, Seattle, Washington
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Gall A, Fero J, McCoy C, Claywell BC, Sanchez CA, Blount PL, Li X, Vaughan TL, Matsen FA, Reid BJ, Salama NR. Bacterial Composition of the Human Upper Gastrointestinal Tract Microbiome Is Dynamic and Associated with Genomic Instability in a Barrett's Esophagus Cohort. PLoS One 2015; 10:e0129055. [PMID: 26076489 PMCID: PMC4468150 DOI: 10.1371/journal.pone.0129055] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 05/04/2015] [Indexed: 12/19/2022] Open
Abstract
Background The incidence of esophageal adenocarcinoma (EAC) has increased nearly five-fold over the last four decades in the United States. Barrett’s esophagus, the replacement of the normal squamous epithelial lining with a mucus-secreting columnar epithelium, is the only known precursor to EAC. Like other parts of the gastrointestinal (GI) tract, the esophagus hosts a variety of bacteria and comparisons among published studies suggest bacterial communities in the stomach and esophagus differ. Chronic infection with Helicobacter pylori in the stomach has been inversely associated with development of EAC, but the mechanisms underlying this association remain unclear. Methodology The bacterial composition in the upper GI tract was characterized in a subset of participants (n=12) of the Seattle Barrett’s Esophagus Research cohort using broad-range 16S PCR and pyrosequencing of biopsy and brush samples collected from squamous esophagus, Barrett’s esophagus, stomach corpus and stomach antrum. Three of the individuals were sampled at two separate time points. Prevalence of H. pylori infection and subsequent development of aneuploidy (n=339) and EAC (n=433) was examined in a larger subset of this cohort. Results/Significance Within individuals, bacterial communities of the stomach and esophagus showed overlapping community membership. Despite closer proximity, the stomach antrum and corpus communities were less similar than the antrum and esophageal samples. Re-sampling of study participants revealed similar upper GI community membership in two of three cases. In this Barrett’s esophagus cohort, Streptococcus and Prevotella species dominate the upper GI and the ratio of these two species is associated with waist-to-hip ratio and hiatal hernia length, two known EAC risk factors in Barrett’s esophagus. H. pylori-positive individuals had a significantly decreased incidence of aneuploidy and a non-significant trend toward lower incidence of EAC.
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Affiliation(s)
- Alevtina Gall
- Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, United States of America
- Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Jutta Fero
- Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Connor McCoy
- Divisions of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Brian C. Claywell
- Divisions of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Carissa A. Sanchez
- Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Patricia L. Blount
- Divisions of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Xiaohong Li
- Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Divisions of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Thomas L. Vaughan
- Divisions of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Epidemiology, University of Washington, Seattle, Washington, United States of America
| | - Frederick A. Matsen
- Divisions of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Brian J. Reid
- Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Divisions of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| | - Nina R. Salama
- Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America
- * E-mail:
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Runge TM, Abrams JA, Shaheen NJ. Epidemiology of Barrett's Esophagus and Esophageal Adenocarcinoma. Gastroenterol Clin North Am 2015; 44:203-31. [PMID: 26021191 PMCID: PMC4449458 DOI: 10.1016/j.gtc.2015.02.001] [Citation(s) in RCA: 154] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Barrett's esophagus (BE) is the precursor to esophageal adenocarcinoma (EAC), a disease with increasing burden in the Western world, especially in white men. Risk factors for BE include obesity, tobacco smoking, and gastroesophageal reflux disease (GERD). EAC is the most common form of esophageal cancer in the United States. Risk factors include GERD, tobacco smoking, and obesity, whereas nonsteroidal antiinflammatory drugs and statins may be protective. Factors predicting progression from nondysplastic BE to EAC include dysplastic changes on esophageal histology and length of the involved BE segment. Biomarkers have shown promise, but none are approved for clinical use.
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Affiliation(s)
- Thomas M. Runge
- University of North Carolina at Chapel Hill, Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, Chapel Hill, NC
| | - Julian A. Abrams
- Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY
| | - Nicholas J. Shaheen
- University of North Carolina at Chapel Hill, Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, Chapel Hill, NC
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Abstract
There is substantial interest in identifying patients with premalignant conditions such as Barrett's esophagus (BE), to improve outcomes of subjects with esophageal adenocarcinoma. However, there is limited consensus on the rationale for screening, the appropriate target population, and optimal screening modality. Recent progress in the development and validation of minimally invasive tools for BE screening has reinvigorated interest in BE screening. BE risk scores combining clinical, anthropometric, and laboratory variables are being developed that may allow more precise targeting of screening to high-risk individuals. This article reviews and summarizes data on recent progress and challenges in screening for BE.
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Affiliation(s)
- Milli Gupta
- Division of Gastroenterology and Hepatology, University of Calgary, 2500 University Dr NW, Calgary, Alberta T2N 1N4, Canada
| | - Prasad G Iyer
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
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