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Alteration of protein expression and spliceosome pathway activity during Barrett's carcinogenesis. J Gastroenterol 2021; 56:791-807. [PMID: 34227026 PMCID: PMC8370908 DOI: 10.1007/s00535-021-01802-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 06/18/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Barrett's esophagus (BE) is a known precursor lesion and the strongest risk factor for esophageal adenocarcinoma (EAC), a common and lethal type of cancer. Prediction of risk, the basis for efficient intervention, is commonly solely based on histologic examination. This approach is challenged by problems such as inter-observer variability in the face of the high heterogeneity of dysplastic tissue. Molecular markers might offer an additional way to understand the carcinogenesis and improve the diagnosis-and eventually treatment. In this study, we probed significant proteomic changes during dysplastic progression from BE into EAC. METHODS During endoscopic mucosa resection, epithelial and stromal tissue samples were collected by laser capture microdissection from 10 patients with normal BE and 13 patients with high-grade dysplastic/EAC. Samples were analyzed by mass spectrometry-based proteomic analysis. Expressed proteins were determined by label-free quantitation, and gene set enrichment was used to find differentially expressed pathways. The results were validated by immunohistochemistry for two selected key proteins (MSH6 and XPO5). RESULTS Comparing dysplastic/EAC to non-dysplastic BE, we found in equal volumes of epithelial tissue an overall up-regulation in terms of protein abundance and diversity, and determined a set of 226 differentially expressed proteins. Significantly higher expressions of MSH6 and XPO5 were validated orthogonally and confirmed by immunohistochemistry. CONCLUSIONS Our results demonstrate that disease-related proteomic alterations can be determined by analyzing minute amounts of cell-type-specific collected tissue. Further analysis indicated that alterations of certain pathways associated with carcinogenesis, such as micro-RNA trafficking, DNA damage repair, and spliceosome activity, exist in dysplastic/EAC.
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Grady WM, Yu M, Markowitz SD, Chak A. Barrett's Esophagus and Esophageal Adenocarcinoma Biomarkers. Cancer Epidemiol Biomarkers Prev 2020; 29:2486-2494. [PMID: 33093162 DOI: 10.1158/1055-9965.epi-20-0223] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/31/2020] [Accepted: 10/15/2020] [Indexed: 12/20/2022] Open
Abstract
Esophageal adenocarcinoma is a major cause of cancer-related morbidity and mortality in Western countries. The incidences of esophageal adenocarcinoma and its precursor Barrett's esophagus have increased substantially in the last four decades. Current care guidelines recommend that endoscopy be used for the early detection and monitoring of patients with Barrett's esophagus; however, the efficacy of this approach is unclear. To prevent the increasing morbidity and mortality from esophageal adenocarcinoma, there is a tremendous need for early detection and surveillance biomarker assays that are accurate, low-cost, and clinically feasible to implement. The last decade has seen remarkable advances in the development of minimally invasive molecular biomarkers, an effort led in large part by the Early Detection Research Network (EDRN). Advances in multi-omics analysis, the development of swallowable cytology collection devices, and emerging technology have led to promising assays that are likely to be implemented into clinical care in the next decade. In this review, an updated overview of the molecular pathology of Barrett's esophagus and esophageal adenocarcinoma and emerging molecular biomarker assays, as well as the role of EDRN in biomarker discovery and validation, will be discussed.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."
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Affiliation(s)
- William M Grady
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington. .,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Ming Yu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Sanford D Markowitz
- Oncology Division, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | - Amitabh Chak
- Gastroenterology Division, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio
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Wang Z, Kambhampati Thiruvengadam S, Cheng Y, Ma K, Simsek C, Tieu AH, Abraham JM, Liu X, Prasath V, Duncan M, Stark A, Trick A, Tsai HL, Wang H, He Y, Khashab MA, Ngamruengphong S, Shin EJ, Wang TH, Meltzer SJ. Methylation Biomarker Panel Performance in EsophaCap Cytology Samples for Diagnosing Barrett's Esophagus: A Prospective Validation Study. Clin Cancer Res 2019; 25:2127-2135. [PMID: 30670490 PMCID: PMC6594757 DOI: 10.1158/1078-0432.ccr-18-3696] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 12/28/2018] [Accepted: 01/17/2019] [Indexed: 12/19/2022]
Abstract
PURPOSE Barrett's esophagus is the only known precursor of esophageal adenocarcinoma (EAC). Although endoscopy and biopsy are standard methods for Barrett's esophagus diagnosis, their high cost and risk limit their use as a screening modality. Here, we sought to develop a Barrett's esophagus detection method based on methylation status in cytology samples captured by EsophaCap using a streamlined sensitive technique, methylation on beads (MOB). EXPERIMENTAL DESIGN We conducted a prospective cohort study on 80 patients (52 in the training set; 28 in the test set). We used MOB to extract and bisulfite-convert DNA, followed by quantitative methylation-specific PCR to assess methylation levels of 8 previously selected candidate markers. Lasso regression was applied to establish a prediction model in the training set, which was then tested on the independent test set. RESULTS In the training set, five of eight candidate methylation biomarkers (p16, HPP1, NELL1, TAC1, and AKAP12) were significantly higher in Barrett's esophagus patients than in controls. We built a four-biomarker-plus-age lasso regression model for Barrett's esophagus diagnosis. The AUC was 0.894, with sensitivity 94.4% [95% confidence interval (CI), 71%-99%] and specificity 62.2% (95% CI, 44.6%-77.3%) in the training set. This model also performed with high accuracy for Barrett's esophagus diagnosis in an independent test set: AUC = 0.929 (P < 0.001; 95% CI, 0.810%-1%), with sensitivity=78.6% (95% CI, 48.8%-94.3%) and specificity = 92.8% (95% CI, 64.1%-99.6%). CONCLUSIONS EsophaCap, in combination with an epigenetic biomarker panel and the MOB method, is a promising, well-tolerated, low-cost esophageal sampling strategy for Barrett's esophagus diagnosis. This approach merits further prospective studies in larger populations.
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Affiliation(s)
- Zhixiong Wang
- Gastrointestinal Surgical Center, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Center of Gastric Cancer, Sun Yat-Sen University, Guangzhou, China
| | - Swetha Kambhampati Thiruvengadam
- Division of Hematology/Oncology, Department of Medicine, Helen Diller Family Comprehensive Cancer Center, UCSF Medical Center, San Francisco, California
- Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland
| | - Yulan Cheng
- Division of Gastroenterology, Department of Medicine and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ke Ma
- Division of Gastroenterology, Department of Medicine and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Cem Simsek
- Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Alan H Tieu
- Division of Gastroenterology, Department of Medicine and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - John M Abraham
- Division of Gastroenterology, Department of Medicine and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Xi Liu
- Department of Pathology, the First Affiliated Hospital of Xi' an Jiaotong University, Xi' an, Shaanxi, China
| | - Vishnu Prasath
- Department of Surgery, Johns Hopkins University, Baltimore, Maryland
| | - Mark Duncan
- Department of Surgery, Johns Hopkins University, Baltimore, Maryland
| | - Alejandro Stark
- Departments of Mechanical Engineering and Biomedical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland
| | - Alexander Trick
- Departments of Mechanical Engineering and Biomedical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland
| | - Hua-Ling Tsai
- Division of Biostatistics, Department of Oncology, Department of Medicine and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hao Wang
- Division of Biostatistics, Department of Oncology, Department of Medicine and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Yulong He
- Gastrointestinal Surgical Center, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Center of Gastric Cancer, Sun Yat-Sen University, Guangzhou, China
- Gastrointestinal Surgical Center, Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Mouen A Khashab
- Division of Gastroenterology, Department of Medicine and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Saowanee Ngamruengphong
- Division of Gastroenterology, Department of Medicine and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Eun J Shin
- Division of Gastroenterology, Department of Medicine and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Tza-Huei Wang
- Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland
| | - Stephen J Meltzer
- Division of Gastroenterology, Department of Medicine and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Murao T, Shiotani A, Fujita Y, Yamanaka Y, Kamada T, Manabe N, Hata J, Nishio K, Haruma K. Overexpression of CD55 from Barrett's esophagus is associated with esophageal adenocarcinoma risk. J Gastroenterol Hepatol 2016. [PMID: 26202380 DOI: 10.1111/jgh.13055] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIM Although several molecular biomarkers for esophageal adenocarcinoma (EAC) have been shown to be useful disease indicators, none has been established as a reliable indicator for risk of EAC or have progressed to routine use. The aim was to identify biomarkers of high risk for EAC in patients with Barrett's esophagus (BE). METHODS Following endoscopic observation by magnified endoscopy with narrow band imaging (ME-NBI), brushing was followed by obtaining biopsy samples from columnar-lined esophagus (CLE) and from EAC lesions of EAC patients, and from age- and sex-matched non-EAC controls with BE. Total RNA was extracted for microarray analysis using Affymetrix GeneChip Human Genome U133 plus 2.0 Array. Real-time-PCR analysis of identified candidate genes was used to confirm the results. RESULTS Overall, 9 EAC patients and 50 patients with BE were studied. Seventy-nine candidate genes were identified by microarray analysis based on a proportional hazards model (P < 0.005). Six genes exhibited significantly differential expressions in both BE and cancer lesions of the EAC group compared to BE of the controls. In the brushing samples, median CD55 relative expression levels in cancer lesions were highest and decreased in BE of EAC group and BE of the controls, in that order (P < 0.001). CONCLUSION Over expression of CD55 in brushing samples taken from BE may be associated with the risk of EAC.
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Affiliation(s)
- Takahisa Murao
- Division of Gastroenterology, Department of Internal Medicine, Japan
| | - Akiko Shiotani
- Division of Gastroenterology, Department of Internal Medicine, Japan
| | - Yoshihiko Fujita
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan
| | | | - Tomoari Kamada
- Division of Gastroenterology, Department of Internal Medicine, Japan
| | - Noriaki Manabe
- Department of Clinical Pathology and Laboratory Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Jiro Hata
- Department of Clinical Pathology and Laboratory Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Kazuto Nishio
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan
| | - Ken Haruma
- Division of Gastroenterology, Department of Internal Medicine, Japan
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Varghese S, Newton R, Ross-Innes CS, Lao-Sirieix P, Krishnadath KK, O'Donovan M, Novelli M, Wernisch L, Bergman J, Fitzgerald RC. Analysis of dysplasia in patients with Barrett's esophagus based on expression pattern of 90 genes. Gastroenterology 2015; 149:1511-1518.e5. [PMID: 26248086 DOI: 10.1053/j.gastro.2015.07.053] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 07/03/2015] [Accepted: 07/19/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Diagnoses of dysplasia, based on histologic analyses, dictate management decisions for patients with Barrett's esophagus (BE). However, there is much intra- and inter-observer variation in identification of dysplasia-particularly low-grade dysplasia. We aimed to identify a biomarker that could be used to assign patients with low-grade dysplasia to a low- or high-risk group. METHODS We performed a stringent histologic assessment of 150 frozen esophageal tissues samples collected from 4 centers in the United Kingdom (from 2000 through 2006). The following samples with homogeneous diagnoses were selected for gene expression profiling: 28 from patients with nondysplastic BE, 10 with low-grade dysplasia, 13 with high-grade dysplasia (HGD), and 8 from patients with esophageal adenocarcinoma. A leave-one-out cross-validation analysis was used identify a gene expression signature associated with HGD vs nondysplastic BE. Functional pathways associated with gene signature sets were identified using the MetaCore analysis. Gene expression signature sets were validated using gene expression data on BE and esophageal adenocarcinoma accessed through National Center for Biotechnology Information Gene Expression Omnibus, as well as a separate set of samples (n = 169) collected from patients who underwent endoscopy in the United Kingdom or the Netherlands and analyzed histologically. RESULTS We identified an expression pattern of 90 genes that could separate nondysplastic BE tissues from those with HGD (P < .0001). Genes in a pathway regulated by retinoic acid-regulated nuclear protein made the largest contribution to this gene set (P < .0001); the transcription factor MYC regulated at least 30% of genes within the signature (P < .0001). In the National Center for Biotechnology Information Gene Expression Omnibus validation set, the signature separated nondysplastic BE samples from esophageal adenocarcinoma samples (P = .0012). In the UK and Netherlands validation cohort, the signature identified dysplastic tissues with an area under the curve value of 0.87 (95% confidence interval: 0.82-0.93). Of samples with low-grade dysplasia (LGD), 64% were considered high risk according to the 90-gene signature; these patients had a higher rate of disease progression than those with a signature categorized as low risk (P = .047). CONCLUSIONS We identified an expression pattern of 90 genes in esophageal tissues of patients with BE that was associated with low- or high-risk for disease progression. This pattern might be used in combination with histologic analysis of biopsy samples to stratify patients for treatment. It would be most beneficial for analysis of patients without definitive evidence of HGD but for whom early endoscopic intervention is warranted.
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Affiliation(s)
- Sibu Varghese
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom
| | | | - Caryn S Ross-Innes
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom
| | - Pierre Lao-Sirieix
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom
| | | | - Maria O'Donovan
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom
| | - Marco Novelli
- GI Services, University College Hospital, NHS Foundation Trust, London, United Kingdom
| | | | | | - Rebecca C Fitzgerald
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom.
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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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8
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Abstract
BACKGROUND There is need for the application of biomarkers in a clinical setting in order to improve patient care. Current surveillance methods are costly for health care systems and invasive for patients, and subjective methodology leads to frequent misdiagnosis. This review summarises the most advanced recent and relevant literature in the field of biomarker development in the context of Barrett's esophagus and comments on their potential application. Studies included roughly correlate with Early Detection Research Network phases three and four. RECENT FINDINGS A number of individual candidate and panels of biomarkers have been investigated recently. These include: gene-specific mutations such as loss of heterozygosity, copy number alterations (in particular aneuploidy) methylation panels, altered gene expression, and glycosylation assayed by lectin binding, as well as genetic and clonal diversity measures. Immunostaining for p53 is the only candidate biomarker deemed "ready for prime time." This has been recommended for use clinically as an adjunct to histological diagnosis of dysplastic Barrett's esophagus in the 2014 British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's esophagus. CONCLUSIONS Progress is being made but in many cases further prospective validation studies are required before clinical application can take place. Limitations to furthering these studies include the large patient cohorts required for prospective validation studies, costs associated with studies, and reproducibility of methods across laboratories. Continued research in this area is strongly recommended as, in the long run, biomarker application has the potential to significantly improve patient care.
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Affiliation(s)
- Eleanor M Gregson
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Biomedical Campus, Box 197, Cambridge, CB2 0XZ, UK,
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9
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di Pietro M, Chan D, Fitzgerald RC, Wang KK. Screening for Barrett's Esophagus. Gastroenterology 2015; 148:912-23. [PMID: 25701083 PMCID: PMC4703087 DOI: 10.1053/j.gastro.2015.02.012] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 02/04/2015] [Accepted: 02/04/2015] [Indexed: 12/20/2022]
Abstract
The large increase in the incidence of esophageal adenocarcinoma in the West during the past 30 years has stimulated interest in screening for Barrett's esophagus (BE), a precursor to esophageal cancer. Effective endoscopic treatments for dysplasia and intramucosal cancer, coupled with screening programs to detect BE, could help reverse the increase in the incidence of esophageal cancer. However, there are no accurate, cost-effective, minimally invasive techniques available to screen for BE, reducing the enthusiasm of gastroenterologists. Over the past 5 years, there has been significant progress in the development of screening technologies. We review existing and developing technologies, new minimally invasive imaging techniques, nonendoscopic devices for cell collection, and biomarkers that can be measured in blood or stool samples. We discuss the status of these approaches, data from clinical studies of their effects, and their anticipated strengths and weaknesses in screening. The area is rapidly evolving, and new tools will soon be ready for prime time.
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Affiliation(s)
| | - Daniel Chan
- Barrett's Esophagus Unit, Mayo Clinic, Rochester, Minnesota
| | | | - Kenneth K Wang
- Barrett's Esophagus Unit, Mayo Clinic, Rochester, Minnesota.
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10
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Fouad YM, Mostafa I, Yehia R, El-Khayat H. Biomarkers of Barrett's esophagus. World J Gastrointest Pathophysiol 2014; 5:450-456. [PMID: 25400988 PMCID: PMC4231509 DOI: 10.4291/wjgp.v5.i4.450] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 07/02/2014] [Accepted: 07/17/2014] [Indexed: 02/06/2023] Open
Abstract
Barrett's esophagus is the strongest risk for esophageal adenocarcinoma (EAC). Metaplasia in patients with BE may progress to dysplasia and then invasive carcinoma. Well-defined diagnostic, progressive, predictive, and prognostic biomarkers are needed to identify the presence of the disease, estimate the risk of malignant transformation, and predict the therapeutic outcome and survival of EAC patients. There are many predictive and prognostic markers that lack substantial validation, and do not allow stratification of patients with gastroesophageal reflux disease in clinical practice for outcome and effectiveness of therapy. In this short review we summarize the current knowledge regarding possible biomarkers, focusing on the pathophysiologic mechanisms to improve prognostic and therapeutic approaches.
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11
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Davelaar AL, Calpe S, Lau L, Timmer MR, Visser M, Ten Kate FJ, Parikh KB, Meijer SL, Bergman JJ, Fockens P, Krishnadath KK. Aberrant TP53 detected by combining immunohistochemistry and DNA-FISH improves Barrett's esophagus progression prediction: a prospective follow-up study. Genes Chromosomes Cancer 2014; 54:82-90. [PMID: 25284618 DOI: 10.1002/gcc.22220] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 09/05/2014] [Indexed: 12/13/2022] Open
Abstract
Barrett's esophagus (BE) goes through a sequence of low grade dysplasia (LGD) and high grade dysplasia (HGD) to esophageal adenocarcinoma (EAC). The current gold standard for BE outcome prediction, histopathological staging, can be unreliable. TP53 abnormalities may serve as prognostic biomarkers. TP53 protein accumulation detected by immunohistochemistry (IHC) indirectly assesses TP53 mutations. DNA fluorescent in situ hybridization (FISH) on brush cytology specimens directly evaluates gene locus loss. We evaluated if IHC and FISH are complementary tools to assess TP53 abnormalities and tested their prognostic value in a long-term prospective follow-up of a BE cohort. TP53 IHC on tissue sections and FISH on brush cytology specimens were evaluated for 116 BE patients with respect to the different histological stages. The TP53 abnormalities were further studied in a panel of cell lines representative of the Barrett's carcinogenic sequence. For 91patients, the predictive value of TP53 abnormalities with respect to progression to HGD/EAC was tested after long term follow-up. The frequency of IHC and FISH TP53 abnormalities increased significantly with increasing histological stage (P < 0.001, Chi(2) -test). Combining the techniques detected TP53 abnormalities in 100% of patients with LGD, HGD, and EAC. Multivariate analysis showed that IHC (hazard ratio: 17, 95% CI: 3.2-96, P = 0.001) and FISH (hazard ratio: 7.3, 95% CI: 1.3-41, P = 0.02) were both independent significant predictors of progression. Combining FISH and IHC in assessing TP53 abnormalities leads to an increased detection rate of TP53 aberrations and improved accuracy for predicting BE progression.
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Affiliation(s)
- Akueni L Davelaar
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands
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di Pietro M, Alzoubaidi D, Fitzgerald RC. Barrett's esophagus and cancer risk: how research advances can impact clinical practice. Gut Liver 2014; 8:356-70. [PMID: 25071900 PMCID: PMC4113043 DOI: 10.5009/gnl.2014.8.4.356] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 04/15/2014] [Indexed: 12/18/2022] Open
Abstract
Barrett’s esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), whose incidence has increased sharply in the last 4 decades. The annual conversion rate of BE to cancer is significant, but small. The identification of patients at a higher risk of cancer therefore poses a clinical conundrum. Currently, endoscopic surveillance is recommended in BE patients, with the aim of diagnosing either dysplasia or cancer at early stages, both of which are curable with minimally invasive endoscopic techniques. There is a large variation in clinical practice for endoscopic surveillance, and dysplasia as a marker of increased risk is affected by sampling error and high interobserver variability. Screening programs have not yet been formally accepted, mainly due to the economic burden that would be generated by upper gastrointestinal endoscopy. Screening programs have not yet been formally accepted, mainly due to the economic burden that would be generated by widespread indication to upper gastrointestinal endoscopy. In fact, it is currently difficult to formulate an accurate algorithm to confidently target the population at risk, based on the known clinical risk factors for BE and EAC. This review will focus on the clinical and molecular factors that are involved in the development of BE and its conversion to cancer and on how increased knowledge in these areas can improve the clinical management of the disease.
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Affiliation(s)
| | - Durayd Alzoubaidi
- Department of Gastroenterology, Basildon and Thurrock University Hospital, Basildon, UK
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Affiliation(s)
- Maikel P Peppelenbosch
- Department of Gastroenterology & Hepatology, Erasmus University Medical Center Rotterdam, , Rotterdam, The Netherlands
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Timmer MR, Sun G, Gorospe EC, Leggett CL, Lutzke L, Krishnadath KK, Wang KK. Predictive biomarkers for Barrett's esophagus: so near and yet so far. Dis Esophagus 2013; 26:574-81. [PMID: 23316980 PMCID: PMC4466900 DOI: 10.1111/dote.12015] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Barrett's esophagus (BE) is the strongest risk factor for the development of esophageal adenocarcinoma. However, the risk of cancer progression is difficult to ascertain in individuals, as a significant number of patients with BE do not necessarily progress to esophageal adenocarcinoma. There are several issues with the current strategy of using dysplasia as a marker of disease progression. It is subject to sampling error during biopsy acquisition and interobserver variability among gastrointestinal pathologists. Ideal biomarkers with high sensitivity and specificity are needed to accurately detect high-risk BE patients for early intervention and appropriate cost-effective surveillance. To date, there are no available molecular tests in routine clinical practice despite known genetic and epigenetic aberrations in the Barrett's epithelium. In this review, we present potential biomarkers for the prediction of malignant progression in BE. These include markers of genomic instability, tumor suppressor loci abnormalities, epigenetic changes, proliferation markers, cell cycle predictors, and immunohistochemical markers. Further work in translating biomarkers for routine clinical use may eventually lead to accurate risk stratification.
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Affiliation(s)
- M. R. Timmer
- Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA,Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - G. Sun
- Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA,Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China
| | - E. C. Gorospe
- Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - C. L. Leggett
- Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - L. Lutzke
- Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - K. K. Krishnadath
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - K. K. Wang
- Barrett’s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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15
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Tänzer M, Liebl M, Quante M. Molecular biomarkers in esophageal, gastric, and colorectal adenocarcinoma. Pharmacol Ther 2013; 140:133-47. [PMID: 23791941 DOI: 10.1016/j.pharmthera.2013.06.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Accepted: 06/06/2013] [Indexed: 02/06/2023]
Abstract
Cancers of the esophagus, stomach and colon contribute to a major health burden worldwide and over 20% of all cancer deaths. Biomarkers that should indicate pathogenic process and are measureable in an objective manner for these tumors are rare and not established in the clinical setting. In general biomarkers can be very useful for cancer management as they can improve clinical decision-making regarding diagnosis, surveillance, and therapy. Biomarkers can be different types of molecular entities (such as DNA, RNA or proteins), which can be detected, in different tissues or body fluids. However, more important is the type of biomarker itself, which allows diagnostic, prognostic or predictive analyses for different clinical problems. This review aims to systematically summarize the recent findings of genetic and epigenetic markers for gastrointestinal tumors within the last decade. While many biomarkers seem to be very promising, especially if used as panels, further development is urgently needed to address practical considerations of biomarkers in cancer treatment.
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Affiliation(s)
- Marc Tänzer
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany
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GERD-Barrett-Adenocarcinoma: Do We Have Suitable Prognostic and Predictive Molecular Markers? Gastroenterol Res Pract 2013; 2013:643084. [PMID: 23573078 PMCID: PMC3615572 DOI: 10.1155/2013/643084] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 02/18/2013] [Indexed: 02/07/2023] Open
Abstract
Due to unfavorable lifestyle habits (unhealthy diet and tobacco abuse) the incidence of gastroesophageal reflux disease (GERD) in western countries is increasing. The GERD-Barrett-Adenocarcinoma sequence currently lacks well-defined diagnostic, progressive, predictive, and prognostic biomarkers (i) providing an appropriate screening method identifying the presence of the disease, (ii) estimating the risk of evolving cancer, that is, the progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC), (iii) predicting the response to therapy, and (iv) indicating an overall survival—prognosis for EAC patients. Based on histomorphological findings, detailed screening and therapeutic guidelines have been elaborated, although epidemiological studies could not support the postulated increasing progression rates of GERD to BE and EAC. Additionally, proposed predictive and prognostic markers are rather heterogeneous by nature, lack substantial proofs, and currently do not allow stratification of GERD patients for progression, outcome, and therapeutic effectiveness in clinical practice. The aim of this paper is to discuss the current knowledge regarding the GERD-BE-EAC sequence mainly focusing on the disputable and ambiguous status of proposed biomarkers to identify promising and reliable markers in order to provide more detailed insights into pathophysiological mechanisms and thus to improve prognostic and predictive therapeutic approaches.
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Booth CL, Thompson KS. Barrett's esophagus: A review of diagnostic criteria, clinical surveillance practices and new developments. J Gastrointest Oncol 2012; 3:232-42. [PMID: 22943014 DOI: 10.3978/j.issn.2078-6891.2012.028] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Accepted: 04/18/2012] [Indexed: 12/25/2022] Open
Abstract
Barrett's esophagus is defined by metaplastic glandular changes to the distal esophagus and is linked to an increased risk of esophageal adenocarcinoma. Controversy exists whether the definition should be limited to intestinal type glands with goblet cells or should be expanded to include non-goblet cell columnar epithelium. Barrett's esophagus may be asymptomatic in a large proportion of the population but screening should be considered for those with certain clinical findings. The diagnosis of Barrett's should be based on the combination of careful endoscopic evaluation and histologic review of the biopsy material. Continued surveillance biopsies may be necessary in cases of indeterminate or low grade dysplasia. Clinical follow-up of patients with high grade dysplasia should be tailored to the individual patient. Development of newer endoscopy techniques including chemoendoscopy, chromoendoscopy and use of biomarkers on frozen tissue have shown some promise of identifying patients at risk for malignancy.
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Affiliation(s)
- Cassie L Booth
- Department of Pathology and Laboratory Medicine, Loma Linda University Medical Center, Loma Linda, California, USA
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Varghese S, Lao-Sirieix P, Fitzgerald RC. Identification and clinical implementation of biomarkers for Barrett's esophagus. Gastroenterology 2012; 142:435-441.e2. [PMID: 22266150 DOI: 10.1053/j.gastro.2012.01.013] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Sibu Varghese
- MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, UK
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Kadri S, Lao-Sirieix P, Fitzgerald RC. Developing a nonendoscopic screening test for Barrett's esophagus. Biomark Med 2011; 5:397-404. [PMID: 21657849 DOI: 10.2217/bmm.11.40] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Barrett's esophagus (BE) arises as a complication of chronic gastro-esophageal reflux disease and is the precursor lesion for esophageal adenocarcinoma. The prevalence of esophageal adenocarcinoma has been increasing in Western countries and the overall prognosis from this cancer remains dismal. Surveillance for BE is highly controversial since although early cancer detection through surveillance programs benefits individuals, surveillance has not been proven to reduce population mortality from the disease. One factor contributing to this apparent paradox is that an estimated >80% cases of BE are undiagnosed and, therefore, do not have the benefit of surveillance. Some form of screening modality is required to achieve more comprehensive detection of BE, which in turn, may lead to early detection of cancerous lesions and early intervention in order to reduce progression to invasive and symptomatic cancer. The advent of endoscopic therapy makes this paradigm attractive. A number of methods could be considered for screening. These include a nonendoscopic sampling method using a Cytosponge that needs to be coupled with a biomarker to obtain required levels of sensitivity and specificity. For screening to be recommended consideration needs to be given to the point of delivery, cost and acceptability to patients.
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Affiliation(s)
- Sudarshan Kadri
- MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, UK
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SPECHLER STUARTJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ. American Gastroenterological Association technical review on the management of Barrett's esophagus. Gastroenterology 2011; 140:e18-52; quiz e13. [PMID: 21376939 PMCID: PMC3258495 DOI: 10.1053/j.gastro.2011.01.031] [Citation(s) in RCA: 799] [Impact Index Per Article: 57.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Melton SD, Genta RM, Souza RF. Biomarkers and molecular diagnosis of gastrointestinal and pancreatic neoplasms. Nat Rev Gastroenterol Hepatol 2010; 7:620-8. [PMID: 20924366 PMCID: PMC3197699 DOI: 10.1038/nrgastro.2010.153] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Standard protocols for the diagnosis of neoplasms in the gastrointestinal tract are based on histopathologic analysis in combination with clinical information. With the completion of the Human Genome Project in 2003, our understanding of the contribution of genetics to human disease has increased exponentially. This knowledge is gradually being incorporated into clinical decision-making. However, the rate at which molecular biomarkers are validated for use in mainstream clinical applications has lagged far behind that of biomarker discovery. Nevertheless, a number of molecular biomarkers are available for use in the diagnosis and management of gastrointestinal tract neoplasms. This article reviews the most common molecular biomarkers currently available for neoplasms of the luminal gastrointestinal tract and pancreas. In neoplasms of the esophagus, for which no biomarkers are currently used in routine clinical practice, those that have shown the most promise in early clinical validation studies are discussed.
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Affiliation(s)
- Shelby D. Melton
- Departments of Pathology and Laboratory Medicine, University of Texas Southwestern Medical Center, Dallas, TX, VA North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, TX
| | - Robert M. Genta
- Departments of Pathology and Laboratory Medicine, University of Texas Southwestern Medical Center, Dallas, TX, VA North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, TX, Caris Research Institute, Irving, TX
| | - Rhonda F. Souza
- Department of Medicine, VA North Texas Health Care System & University of Texas Southwestern Medical Center, Dallas, TX, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX
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Maltby EL, Dyson MJ, Wheeler MR, Thomson M, Sethuraman C, Cohen MC. Molecular abnormalities in pediatric barrett esophagus: can we test for potential of neoplastic progression? Pediatr Dev Pathol 2010; 13:310-7. [PMID: 20053129 DOI: 10.2350/09-08-0700-oa.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Barrett esophagus (BE) is a preneoplastic condition that predisposes to esophageal adenocarcinoma and is a consequence of prolonged gastroesophageal reflux disease. The condition is mainly seen in adults and is thought to be a complex disease in which individual genetic predisposition interacts with environmental stimuli. The aim of our study was to investigate whether genetic biomarkers of potential disease progression are the same in the rare situation of pediatric BE, as described in adults. We performed fluorescence in situ hybridization with probes from Abbott Vysis Corporation on 4-micron sections taken from 48 paraffin-embedded sequential biopsies of 10 cases of BE. The 4 probe sets were specific for HER2 at 17q12/17 centromere/4 centromere, p16 at 9p21/9 centromere, TP53 at 17p13/17 centromere/6 centromere, and CCND1 at 11q13/11 centromere. The probe sets were validated on 10 cases of adult Barrett adenocarcinoma. Of the 10 cases, 6 biopsies in 5 cases were informative. Two had gain of HER2 detected in 1 biopsy each (1 also had gain of chromosome 17) and 4 separate cases showed p16 deletion in 1 biopsy of each (1 also had gain of chromosome 9). The genetic markers informative in 50% of our cases were also identified in adult patients with Barrett adenocarcinoma. The importance of this study is that even at the pediatric level, BE can show genetic changes associated with neoplastic progression.
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Affiliation(s)
- Edna L Maltby
- Cytogenetics Department, Sheffield Children's NHS Foundation Trust, Western Bank, Sheffield, United Kingdom
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Prasad GA, Bansal A, Sharma P, Wang KK. Predictors of progression in Barrett's esophagus: current knowledge and future directions. Am J Gastroenterol 2010; 105:1490-1502. [PMID: 20104216 PMCID: PMC3408387 DOI: 10.1038/ajg.2010.2] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Barrett's esophagus (BE) is the strongest risk factor for esophageal adenocarcinoma (EAC), a malignancy with persistently poor long-term outcomes. EAC is thought to develop through progression of metaplasia to dysplasia to invasive carcinoma. Identification of factors predicting progression to EAC would help in focusing surveillance, chemoprevention, or ablation for those deemed to be at highest risk of progression. We performed a comprehensive review of the literature and summarized current evidence on risk factors for progression in subjects with known BE. Clinical and demographic factors (age, male gender, length of BE segment) are associated with modestly increased odds of progression to EAC in some studies. Biomarkers such as aneuploidy and p53 loss of heterozygosity have been associated with increased risk of progression to high-grade dysplasia and/or EAC in single-center prospective cohort studies. Promising newer techniques and markers have been recently reported with the potential to help risk stratify BE subjects. Development of a comprehensive BE risk progression score comprised of both clinical and biomarker variables should be the ultimate goal and can be achieved by multicenter prospective collaborative efforts. Although it would be challenging, creation of such a score has the potential to improve outcomes and make the management of patients with BE more cost-effective.
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Affiliation(s)
- Ganapathy A. Prasad
- Division of Gastroenterology and Hepatology, Barrett’s Esophagus Unit, Mayo Clinic, Rochester, Minnesota, USA
| | - Ajay Bansal
- Division of Gastroenterology, Veterans Affairs Medical Center & University of Kansas School of Medicine, Kansas City, Missouri, USA.
| | - Prateek Sharma
- Division of Gastroenterology, Veterans Affairs Medical Center & University of Kansas School of Medicine, Kansas City, Missouri, USA.
| | - Kenneth K. Wang
- Division of Gastroenterology and Hepatology, Barrett’s Esophagus Unit, Mayo Clinic, Rochester, Minnesota, USA
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Abstract
Biomarkers are needed to screen multiple stages in the clinical pathway of Barrett's oesophagus patients; from disease diagnosis to risk stratification and predicting response to therapy. Routes to the identification of biomarkers have been recognized by known molecular features of the disease and more recently through transcriptomic, methylation and proteomic screening approaches. The majority of Barrett's oesophagus patients remain undiagnosed in the general population. In order to develop a tool to screen for Barrett's oesophagus in the primary care setting, minimally invasive sampling methods coupled with immunocytology-based biomarkers are currently being assessed. Biomarkers may also have utility in surveillance programmes by allowing endoscopic interval to be adjusted according to individual neoplastic risk. Many individual biomarkers have been proposed in this regard, but have frequently been assessed in studies of limited power, or have lacked sufficient sensitivity or specificity when assessed in wider population-based studies. Biomarker panels may provide a route forward. In this regard, a panel of methylation markers has shown promise in a multicentre, double-blind, validation study. Biomarkers are also being developed to improve detection of high-grade dysplasia and oesophageal adenocarcinoma, utilizing brush cytology combined with FISH (fluorescence in situ hybridization), and to assess therapeutic success and risk of complication during photodynamic therapy. Finally, we outline progress in identifying alternative sources of biomarkers for this condition.
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Souza RF. The molecular basis of carcinogenesis in Barrett's esophagus. J Gastrointest Surg 2010; 14:937-40. [PMID: 20094816 PMCID: PMC2873060 DOI: 10.1007/s11605-009-1145-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2009] [Accepted: 12/14/2009] [Indexed: 01/31/2023]
Affiliation(s)
- Rhonda F. Souza
- Department of Medicine, VA North Texas Health Care System, The University of Texas Southwestern Medical School, Dallas, TX, USA, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA, Department of GI, MC# 111B1, Dallas VA Medical Center, 4500 South Lancaster Road, Dallas, TX 75216, USA,
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Souza RF. Biomarkers in Barrett's Esophagus. TECHNIQUES IN GASTROINTESTINAL ENDOSCOPY 2010; 12:116-1212. [PMID: 20657812 DOI: 10.1016/j.tgie.2010.02.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Biomarkers are substances that can be used to indicate normal or diseased states. In clinical settings, the term biomarker generally refers to a molecular marker produced by tissues whose detection heralds a diseased state. For patients with Barrett's esophagus, there are at least three clinical settings in which the use of molecular biomarkers has been proposed including 1) stratifying the risk of neoplastic progression, 2) serving as an adjunct to aid in the diagnosis of dysplasia, and 3) predicting response to ablative therapies. Although the routine clinical use of biomarkers in any of these clinical settings is not yet recommended, it seems reasonable to assume that biomarker validation studies will be carried out in the coming years and that movement into the clinics will be inevitable. This article reviews the current progress in using biomarkers in each of the clinical settings described above with a focus on the molecular biomarkers which have advanced the farthest toward use in routine clinical practice.
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Affiliation(s)
- Rhonda F Souza
- Departments of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, and the Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
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Cheung PY, Deng W, Man C, Tse WW, Srivastava G, Law S, Tsao SW, Cheung ALM. Genetic alterations in a telomerase-immortalized human esophageal epithelial cell line: implications for carcinogenesis. Cancer Lett 2010; 293:41-51. [PMID: 20092939 DOI: 10.1016/j.canlet.2009.12.015] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2009] [Revised: 12/18/2009] [Accepted: 12/23/2009] [Indexed: 02/04/2023]
Abstract
Ectopic expression of viral oncoproteins disrupts cellular functions and limits the value of many existing immortalization models as models for carcinogenesis, especially for cancers without definitive viral etiology. Our newly established telomerase-immortalized human esophageal epithelial cell line, NE2-hTERT, retained nearly-diploid and non-tumorigenic characteristics, but exhibited genetic and genomic alterations commonly found in esophageal cancer, including progressive loss of the p16(INK4a) alleles, upregulation of anti-apoptotic proteins, epithelial-mesenchymal transition, whole-chromosome 7 gain and duplicated 5q arm. Our data also revealed a novel positive regulation of p16(INK4a) on cyclin D1. These findings probably represent early crucial events and mechanisms in esophageal carcinogenesis.
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Affiliation(s)
- Pak Yan Cheung
- Cancer Biology Group, Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
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Kissel HD, Galipeau PC, Li X, Reid BJ. Translation of an STR-based biomarker into a clinically compatible SNP-based platform for loss of heterozygosity. Cancer Biomark 2009; 5:143-58. [PMID: 19407369 DOI: 10.3233/cbm-2009-0618] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Loss of heterozygosity (LOH) has been shown to be a promising biomarker of cancer risk in patients with premalignant conditions. In this study we describe analytical validation in clinical biopsy samples of a SNP-based pyrosequencing panel targeting regions of LOH on chromosomes 17p and 9p including TP53 and CDKN2A tumor suppressor genes. Assays were tested for analytic specificity, sensitivity, efficiency, and reproducibility. Accuracy was evaluated by comparing SNP-based LOH results to those obtained by previously well-studied short tandem repeat polymorphisms (STRs) in DNA derived from different tissue sources including fresh-frozen endoscopic biopsies, samples from surgical resections, and formalin-fixed paraffin-embedded sections. A 17p/9p LOH panel comprised of 43 SNPs was designed to amplify with universal assay conditions in a two-step PCR and sequence-by-synthesis reaction that can be completed in two hours and 10 minutes. The methods presented can be a model for developing a SNP-based LOH approach targeted to any chromosomal region of interest for other premalignant conditions and this panel could be incorporated as part of a biomarker for cancer risk prediction, early detection, or as entry criteria for randomized trials.
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Affiliation(s)
- Heather D Kissel
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Abstract
Barrett's esophagus is an important step in the pathway to esophageal adenocarcinoma. Since most patients with Barrett's esophagus are undiagnosed and patients present with advanced adenocarcinoma de novo, prognosis for this disease remains poor. To identify those people with Barrett's esophagus who are at particular risk many new technologies are being developed. In association with these advances in risk stratification, progress is being made in the endoscopic treatment of Barrett's. Chemoprevention is also an area of interest and trials are underway.
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Rossi E, Grisanti S, Villanacci V, Della Casa D, Cengia P, Missale G, Minelli L, Buglione M, Cestari R, Bassotti G. HER-2 overexpression/amplification in Barrett's oesophagus predicts early transition from dysplasia to adenocarcinoma: a clinico-pathologic study. J Cell Mol Med 2008. [PMID: 19292734 DOI: 10.1111/j.1582-4934.2008.00517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Barrett's oesophagus (BO) is the primary precursor lesion for oesophageal adenocarcinoma (ADC). The natural history of metaplasia-dysplasia-carcinoma sequence remains largely unknown. HER2/neu oncogene results overexpressed/amplified in preneoplastic lesions and in ADC of the oesophagus and it has been associated with poor prognosis. Our aim was to evaluate the role of HER2 overexpression/amplification in predicting the conversion from precursor lesions to ADC. We retrospectively evaluated by univariate analysis of single variables clinical records and histological specimens of 21 patients with a confirmed diagnosis of BO and/or oesophageal dysplasia. Clinical variables included age, gender, alcohol and smoking intake, presence of symptoms (pyrosis, disphagia) and endoscopic features (length). HER2 status was studied by immunohistochemistry and fluorescence in situ hybridization (FISH) on paraffin-embedded tissue. The end-points were the occurrence of progression and the time-to-progression (TTP) from the initial histologic lesion to the worst pathological pattern. Median age at diagnosis was 63 years (range 37-84). BO median length was 4.5 cm. Progression occurred in 11 of 21 patients and median TTP was 24 months. HER2 was overexpressed/amplified in 8 of 21 (38%) patients. HER2 overexpression/ amplification and the presence of dysplasia were statistically associated with progression (P= 0.038). This study provides evidence for a possible role of HER2 in the transition from dysplasia to ADC of the oesophagus. This fact could help in identifying patients at high risk of malignant transformation.
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Affiliation(s)
- Elisa Rossi
- 2nd Department of Pathology, Spedali Civili, Brescia, Italy
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Rossi E, Grisanti S, Villanacci V, Della Casa D, Cengia P, Missale G, Minelli L, Buglione M, Cestari R, Bassotti G. HER-2 overexpression/amplification in Barrett's oesophagus predicts early transition from dysplasia to adenocarcinoma: a clinico-pathologic study. J Cell Mol Med 2008; 13:3826-33. [PMID: 19292734 PMCID: PMC4516530 DOI: 10.1111/j.1582-4934.2008.00517.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Barrett’s oesophagus (BO) is the primary precursor lesion for oesophageal adenocarcinoma (ADC). The natural history of metaplasia-dysplasia-carcinoma sequence remains largely unknown. HER2/neu oncogene results overexpressed/amplified in preneoplastic lesions and in ADC of the oesophagus and it has been associated with poor prognosis. Our aim was to evaluate the role of HER2 overexpression/amplification in predicting the conversion from precursor lesions to ADC. We retrospectively evaluated by univariate analysis of single variables clinical records and histological specimens of 21 patients with a confirmed diagnosis of BO and/or oesophageal dysplasia. Clinical variables included age, gender, alcohol and smoking intake, presence of symptoms (pyrosis, disphagia) and endoscopic features (length). HER2 status was studied by immunohistochemistry and fluorescence in situ hybridization (FISH) on paraffin-embedded tissue. The end-points were the occurrence of progression and the time-to-progression (TTP) from the initial histologic lesion to the worst pathological pattern. Median age at diagnosis was 63 years (range 37–84). BO median length was 4.5 cm. Progression occurred in 11 of 21 patients and median TTP was 24 months. HER2 was overexpressed/amplified in 8 of 21 (38%) patients. HER2 overexpression/ amplification and the presence of dysplasia were statistically associated with progression (P= 0.038). This study provides evidence for a possible role of HER2 in the transition from dysplasia to ADC of the oesophagus. This fact could help in identifying patients at high risk of malignant transformation.
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Affiliation(s)
- Elisa Rossi
- 2nd Department of Pathology, Spedali Civili, Brescia, Italy
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