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Wullweber A, Strick R, Lange F, Sikic D, Taubert H, Wach S, Wullich B, Bertz S, Weyerer V, Stoehr R, Breyer J, Burger M, Hartmann A, Strissel PL, Eckstein M. Bladder Tumor Subtype Commitment Occurs in Carcinoma In Situ Driven by Key Signaling Pathways Including ECM Remodeling. Cancer Res 2021; 81:1552-1566. [PMID: 33472889 DOI: 10.1158/0008-5472.can-20-2336] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/24/2020] [Accepted: 01/13/2021] [Indexed: 11/16/2022]
Abstract
Basal and luminal subtypes of invasive bladder tumors have significant prognostic and predictive impacts for patients. However, it remains unclear whether tumor subtype commitment occurs in noninvasive urothelial lesions or in carcinoma in situ (CIS) and which gene pathways are important for bladder tumor progression. To understand the timing of this commitment, we used gene expression and protein analysis to create a global overview of 36 separate tissues excised from a whole bladder encompassing urothelium, noninvasive urothelial lesions, CIS, and invasive carcinomas. Additionally investigated were matched CIS, noninvasive urothelial lesions, and muscle-invasive bladder cancers (MIBC) from 22 patients. The final stage of subtype commitment to either a luminal or basal MIBC occurred at the CIS transition. For all tissues combined, hierarchical clustering of subtype gene expression revealed three subtypes: "luminal," "basal," and a "luminal p53-/extracellular matrix (ECM)-like" phenotype of ECM-related genes enriched in tumor-associated urothelium, noninvasive urothelial lesions, and CIS, but rarely invasive, carcinomas. A separate cohort of normal urothelium from noncancer patients showed significantly lower expression of ECM-related genes compared with tumor-associated urothelium, noninvasive urothelial lesions, and CIS. A PanCancer Progression Panel of 681 genes unveiled pathways specific for the luminal p53-/ECM-like cluster, for example, ECM remodeling, angiogenesis, epithelial-to-mesenchymal transition, cellular discohesion, cell motility involved in tumor progression, and cell proliferation and oncogenic ERBB2/ERBB3 signaling for invasive carcinomas. In conclusion, this study provides insights into bladder cancer subtype commitment and associated signaling pathways, which could help predict therapy response and enhance our understanding of therapy resistance. SIGNIFICANCE: This study demonstrates that CIS is the stage of commitment for determining MIBC tumor subtype, which is relevant for patient prognosis and therapy response.
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Affiliation(s)
- Adrian Wullweber
- Department of Internal Medicine, Evangelisches Krankenhaus Düsseldorf, Düsseldorf, Germany.,Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Reiner Strick
- Translational Research Centre (TRC), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.,Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Fabienne Lange
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Danijel Sikic
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Helge Taubert
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Sven Wach
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Bernd Wullich
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Simone Bertz
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Veronika Weyerer
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Robert Stoehr
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Johannes Breyer
- Department of Urology, Caritas Hospital St. Josef, University of Regensburg, Regensburg, Germany
| | - Maximilian Burger
- Department of Urology, Caritas Hospital St. Josef, University of Regensburg, Regensburg, Germany
| | - Arndt Hartmann
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Pamela L Strissel
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.,Translational Research Centre (TRC), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Markus Eckstein
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
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Santos LL, Santos J, Gouveia MJ, Bernardo C, Lopes C, Rinaldi G, Brindley PJ, da Costa JMC. Urogenital Schistosomiasis-History, Pathogenesis, and Bladder Cancer. J Clin Med 2021; 10:jcm10020205. [PMID: 33429985 PMCID: PMC7826813 DOI: 10.3390/jcm10020205] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 12/21/2022] Open
Abstract
Schistosomiasis is the most important helminthiasis worldwide in terms of morbidity and mortality. Most of the infections occurs in Africa, which about two thirds are caused by Schistosoma haematobium. The infection with S. haematobium is considered carcinogenic leading to squamous cell carcinoma (SCC) and urothelial carcinoma of the urinary bladder. Additionally, it is responsible for female genital schistosomiasis leading to infertility and higher risk of human immunodeficiency virus (HIV) transmission. Remarkably, a recent outbreak in Corsica (France) drew attention to its potential re-mergence in Southern Europe. Thus far, little is known related to host-parasite interactions that trigger carcinogenesis. However, recent studies have opened new avenues to understand mechanisms on how the parasite infection can lead cancer and other associated pathologies. Here, we present a historical perspective of schistosomiasis, and review the infection-associated pathologies and studies on host-parasite interactions that unveil tentative mechanisms underlying schistosomiasis-associated carcinogenesis.
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Affiliation(s)
- Lúcio Lara Santos
- Experimental Pathology and Therapeutics, Research Centre, Portuguese Oncology Institute—Porto (IPO-Porto), 4200-072 Porto, Portugal; (L.L.S.); (C.L.)
- Department of Surgical Oncology, Portuguese Oncology Institute—Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
- Urology Department, Hospital Américo Boavida, Luanda 00200, Angola;
| | - Júlio Santos
- Urology Department, Hospital Américo Boavida, Luanda 00200, Angola;
| | - Maria João Gouveia
- Center for the Study in Animal Science (CECA/ICETA), University of Porto, Rua de D. Manuel II, Apt 55142, 4051-401 Porto, Portugal;
- Centre for Parasite Biology and Immunology, Department of Infectious Diseases, National Institute of Health Dr. Ricardo Jorge, Rua Alexandre Herculano 321, 4000-055 Porto, Portugal
| | - Carina Bernardo
- Hormones and Cancer Lab, Institute of Biomedicine, iBiMED, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal;
| | - Carlos Lopes
- Experimental Pathology and Therapeutics, Research Centre, Portuguese Oncology Institute—Porto (IPO-Porto), 4200-072 Porto, Portugal; (L.L.S.); (C.L.)
- Department of Surgical Oncology, Portuguese Oncology Institute—Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
| | - Gabriel Rinaldi
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK;
| | - Paul J. Brindley
- Department of Microbiology, Immunology & Tropical Medicine, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA;
- Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA
| | - José M. Correia da Costa
- Center for the Study in Animal Science (CECA/ICETA), University of Porto, Rua de D. Manuel II, Apt 55142, 4051-401 Porto, Portugal;
- Centre for Parasite Biology and Immunology, Department of Infectious Diseases, National Institute of Health Dr. Ricardo Jorge, Rua Alexandre Herculano 321, 4000-055 Porto, Portugal
- Correspondence:
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Knüchel-Clarke R, Gaisa NT. [Preneoplastic lesions and precursors of urothelial cancer]. DER PATHOLOGE 2016; 37:33-9. [PMID: 26811248 DOI: 10.1007/s00292-015-0130-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
As even a mere thickening of the urothelium can harbor genetic changes identical to that of low grade papillary urothelial tumors, it is not always possible to clearly recognize a precursor lesion of urothelial carcinoma by routine histological diagnostics. Complementary immunohistochemical and molecular diagnostic methods assist the recognition of these entities. These methods especially help to identify clinically important genetically unstable cells as the hallmark of carcinoma in situ (CIS). Little is known about the clinical significance of the morphological subtypes of CIS, which range from large cell to micropapillary variants. For a better understanding of special types of bladder cancer (e.g. adenocarcinoma and squamous cell carcinoma), it seems to be important to define the phenotype and the molecular pattern of non-urothelial lesions, such as intestinal metaplasia and squamous metaplasia, better and more precisely.
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Affiliation(s)
- R Knüchel-Clarke
- Institut für Pathologie, Uniklinik RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Deutschland.
| | - N T Gaisa
- Institut für Pathologie, Uniklinik RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Deutschland
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Mir R, Masroor M, Javid J, Ahamad I, Farooq S, Yadav P, Zuberi M, Lone M, Ray PC, Saxena A. Clinical implications of cytosine deletion of exon 5 of P53 gene in non small cell lung cancer patients. South Asian J Cancer 2016; 5:33-36. [PMID: 27169122 PMCID: PMC4845608 DOI: 10.4103/2278-330x.179701] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
AIM Lung cancer is considered to be the most common cancer in the world. In humans, about 50% or more cancers have a mutated tumor suppressor p53 gene thereby resulting in accumulation of p53 protein and losing its function to activate the target genes that regulate the cell cycle and apoptosis. Extensive research conducted in murine cancer models with activated p53, loss of p53, or p53 missense mutations have facilitated researchers to understand the role of this key protein. Our study was aimed to evaluate the frequency of cytosine deletion in nonsmall cell lung cancer (NSCLC) patients. METHODS One hundred NSCLC patients were genotyped for P53 (exon5, codon168) cytosine deletion leading to loss of its function and activate the target genes by allele-specific polymerase chain reaction. The P53 cytosine deletion was correlated with all the clinicopathological parameters of the patients. RESULTS AND ANALYSIS 59% cases were carrying P53 cytosine deletion. Similarly, the significantly higher incidence of cytosine deletion was reported in current smokers (75%) in comparison to exsmoker and nonsmoker. Significantly higher frequency of cytosine deletion was reported in adenocarcinoma (68.08%) than squamous cell carcinoma (52.83%). Also, a significant difference was reported between p53 cytosine deletion and metastasis (64.28%). Further, the majority of the cases assessed for response carrying P53 cytosine deletion were found to show faster disease progression. CONCLUSION The data suggests that there is a significant association of the P53 exon 5 deletion of cytosine in codon 168 with metastasis and staging of the disease.
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Affiliation(s)
- Rashid Mir
- Prince Fahd Bin Sultan Research Chair Cancer Molecular Genetics, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Saudi Arabia, KSA
| | - Mirza Masroor
- Cancer Genetic Lab, Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi, India
| | - Jamsheed Javid
- Prince Fahd Bin Sultan Research Chair Cancer Molecular Genetics, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Saudi Arabia, KSA
| | - Imtiyaz Ahamad
- Cancer Genetic Lab, Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi, India
| | - Shazia Farooq
- Cancer Genetic Lab, Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi, India
| | - Prasant Yadav
- Cancer Genetic Lab, Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi, India
| | - Mariyam Zuberi
- Cancer Genetic Lab, Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi, India
| | - Maqbool Lone
- Department of Radiation oncology, SKIMS, Jammu and Kashmir, India
| | - P. C Ray
- Cancer Genetic Lab, Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi, India
| | - Alpana Saxena
- Cancer Genetic Lab, Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi, India
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Warrick JI, Hovelson DH, Amin A, Liu CJ, Cani AK, McDaniel AS, Yadati V, Quist MJ, Weizer AZ, Brenner JC, Feng FY, Mehra R, Grasso CS, Tomlins SA. Tumor evolution and progression in multifocal and paired non-invasive/invasive urothelial carcinoma. Virchows Arch 2015; 466:297-311. [PMID: 25502898 PMCID: PMC4936404 DOI: 10.1007/s00428-014-1699-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Revised: 10/21/2014] [Accepted: 11/24/2014] [Indexed: 10/24/2022]
Abstract
Although multifocal tumors and non-invasive/invasive components are commonly encountered in surgical pathology, their genetic relationship is often poorly characterized. We used next-generation sequencing (NGS) to characterize somatic alterations in a patient with five spatially distinct, high-grade papillary urothelial carcinomas (UCs), with one tumor harboring an underlying invasive component. NGS of 409 cancer-related genes was performed on DNA isolated from formalin-fixed paraffin-embedded (FFPE) blocks representing each papillary tumor (n = 5), the invasive component of one tumor, and matched normal tissue. We identified nine unique non-synonymous somatic mutations across the six UC samples, including five present in each carcinoma sample, consistent with clonal origin and limited intertumoral heterogeneity. Copy number and loss of heterogeneity (LOH) profiles were similar in all six carcinomas; however, the invasive carcinoma component uniquely showed focal CDKN2A loss and chromosome 9 LOH and did not harbor gains of chromosomes 5p or X that were present in the other tumor samples. Phylogenetic analysis supported the invasive component arising from a shared progenitor prior to the outgrowth of cells in the non-invasive tumors. Results were extended to three additional cases of upper tract UC with paired non-invasive/invasive components, which identified driving alterations exclusive to both non-invasive and invasive components. Lastly, we performed targeted RNA sequencing (RNAseq) using a custom bladder cancer panel, which confirmed gene expression signature differences between paired non-invasive/invasive components. The results and approaches presented here may be useful in understanding the clonal relationships in multifocal cancers or paired non-invasive/invasive components from routine FFPE specimens.
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Affiliation(s)
- Joshua I. Warrick
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI
| | - Daniel H. Hovelson
- Department of Computational Medicine & Bioinformatics, University of Michigan Medical School, Ann Arbor, MI
| | - Anmol Amin
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI
| | - Chia-Jen Liu
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI
| | - Andi K. Cani
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI
| | - Andrew S. McDaniel
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI
| | - Venkata Yadati
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI
| | - Michael J. Quist
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI
- Department of Pathology, Oregon Health & Sciences University, Portland, OR
| | - Alon Z. Weizer
- Department of Urology, University of Michigan Medical School, Ann Arbor, MI
- Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI
| | - J. Chad Brenner
- Department of Otolaryngology, University of Michigan Medical School, Ann Arbor, MI
| | - Felix Y. Feng
- Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI
- Department of Urology, University of Michigan Medical School, Ann Arbor, MI
| | - Rohit Mehra
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI
| | - Catherine S. Grasso
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI
- Department of Pathology, Oregon Health & Sciences University, Portland, OR
| | - Scott A. Tomlins
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI
- Department of Urology, University of Michigan Medical School, Ann Arbor, MI
- Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI
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6
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Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 2015; 15:25-41. [PMID: 25533674 DOI: 10.1038/nrc3817] [Citation(s) in RCA: 889] [Impact Index Per Article: 88.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Urothelial carcinoma of the bladder comprises two long-recognized disease entities with distinct molecular features and clinical outcome. Low-grade non-muscle-invasive tumours recur frequently but rarely progress to muscle invasion, whereas muscle-invasive tumours are usually diagnosed de novo and frequently metastasize. Recent genome-wide expression and sequencing studies identify genes and pathways that are key drivers of urothelial cancer and reveal a more complex picture with multiple molecular subclasses that traverse conventional grade and stage groupings. This improved understanding of molecular features, disease pathogenesis and heterogeneity provides new opportunities for prognostic application, disease monitoring and personalized therapy.
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Affiliation(s)
- Margaret A Knowles
- Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK
| | - Carolyn D Hurst
- Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK
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8
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RUNX3 methylation in normal surrounding urothelium of patients with non-muscle-invasive bladder cancer: Potential role in the prediction of tumor progression. Eur J Surg Oncol 2012; 38:1095-100. [DOI: 10.1016/j.ejso.2012.07.116] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Revised: 06/06/2012] [Accepted: 07/19/2012] [Indexed: 12/15/2022] Open
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Gaisa NT, Graham TA, McDonald SAC, Cañadillas-Lopez S, Poulsom R, Heidenreich A, Jakse G, Tadrous PJ, Knuechel R, Wright NA. The human urothelium consists of multiple clonal units, each maintained by a stem cell. J Pathol 2011; 225:163-71. [PMID: 21744343 DOI: 10.1002/path.2945] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2011] [Revised: 05/24/2011] [Accepted: 05/25/2011] [Indexed: 11/08/2022]
Abstract
Little is known about the clonal architecture of human urothelium. It is likely that urothelial stem cells reside within the basal epithelial layer, yet lineage tracing from a single stem cell as a means to show the presence of a urothelial stem cell has never been performed. Here, we identify clonally related cell areas within human bladder mucosa in order to visualize epithelial fields maintained by a single founder/stem cell. Sixteen frozen cystectomy specimens were serially sectioned. Patches of cells deficient for the mitochondrially encoded enzyme cytochrome c oxidase (CCO) were identified using dual-colour enzyme histochemistry. To show that these patches represent clonal proliferations, small CCO-proficient and -deficient areas were individually laser-capture microdissected and the entire mitochondrial genome (mtDNA) in each area was PCR amplified and sequenced to identify mtDNA mutations. Immunohistochemistry was performed for the different cell layers of the urothelium and adjacent mesenchyme. CCO-deficient patches could be observed in normal urothelium of all cystectomy specimens. The two-dimensional length of these negative patches varied from 2-3 cells (about 30 µm) to 4.7 mm. Each cell area within a CCO-deficient patch contained an identical somatic mtDNA mutation, indicating that the patch was a clonal unit. Patches contained all the mature cell differentiation stages present in the urothelium, suggesting the presence of a stem cell. Our results demonstrate that the normal mucosa of human bladder contains stem cell-derived clonal units that actively replenish the urothelium during ageing. The size of the clonal unit attributable to each stem cell was broadly distributed, suggesting replacement of one stem cell clone by another.
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Affiliation(s)
- Nadine T Gaisa
- Institute of Pathology RWTH Aachen University, Aachen, Germany.
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Stief C, Zaak D, Stöckle M, Studer U, Knuechel R, Rödel C, Sauer R, Rubben H. [Standards and perspectives in diagnosis and therapy of bladder carcinoma]. Urologe A 2009; 45 Suppl 4:90-6. [PMID: 16896761 DOI: 10.1007/s00120-006-1134-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
MESH Headings
- Administration, Intravesical
- Antineoplastic Agents/administration & dosage
- Carcinoma, Papillary/diagnosis
- Carcinoma, Papillary/mortality
- Carcinoma, Papillary/pathology
- Carcinoma, Papillary/therapy
- Carcinoma, Transitional Cell/diagnosis
- Carcinoma, Transitional Cell/mortality
- Carcinoma, Transitional Cell/pathology
- Carcinoma, Transitional Cell/therapy
- Combined Modality Therapy
- Cystectomy
- Cystoscopy
- Disease-Free Survival
- Germany
- Hematoporphyrin Photoradiation
- Humans
- Immunotherapy
- Neoplasm Staging
- Prognosis
- Quality Assurance, Health Care/standards
- Reference Standards
- Urinary Bladder/pathology
- Urinary Bladder Neoplasms/diagnosis
- Urinary Bladder Neoplasms/mortality
- Urinary Bladder Neoplasms/pathology
- Urinary Bladder Neoplasms/therapy
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Affiliation(s)
- C Stief
- Urologische Klinik und Poliklinik, Klinikum der Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377 München.
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11
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Abstract
Urothelial carcinoma comprise a heterogenous group of diseases with very different clinical outcome: 70%-80% of urothelial carcinoma are genetically stable and associated with a favorable prognosis, while 20%-30% are genetically unstable and have a high progression rate. Therefore, the current WHO Classification (2004) reduces the histologic grade to simply 'low grade' and 'high grade'. In addition to TNM classification and histologic grade, genetic factors such as p53 mutations, fibroblast growth factor receptor 3 (FGFR3) and phosphatidylinositol-3-kinase (PIC(3)CA) are relevant in a patient's prognosis.
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Rouprêt M. Anatomical location of urothelial carcinomas of the urinary tract leads to perspectives of specific treatment. Future Oncol 2007; 3:595-9. [DOI: 10.2217/14796694.3.6.595] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Morgan Rouprêt
- Academic Urology Department, Hopital Pitié, Assistance Publique Hôpitaux de Paris, University Paris 6, 47–83 bvd de l’Hopital, 75013 Paris, France
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Höglund M. On the origin of syn- and metachronous urothelial carcinomas. Eur Urol 2006; 51:1185-93; discussion 1193. [PMID: 17123702 DOI: 10.1016/j.eururo.2006.11.025] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2006] [Accepted: 11/09/2006] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To evaluate existing models for the origin of meta- and synchronous urothelial carcinomas in light of the accumulated genetic data. METHODS Published studies on the clonal origin and genetic relationships of syn- and metachronous tumors, genetic aberrations in normal and premalignant urothelial lesions, as well as histologic and genetic mapping studies of cystectomized bladder samples are reviewed. RESULTS The most common models for the origin of syn- and metachronous tumors are found to conform less well to the accumulated genetic data. A new model is proposed, the field-first-tumor-later model, in which aberrant cells with a stem cell, or stem cell-like, origin spread in the urothelium by cellular displacement, creating fields of premalignant cells. Tumor growth is suggested to be initiated by critical genetic events occurring in individual cells in such fields. Hence, recurring tumors are proposed to originate from a shared field of premalignant cells and not from previous overt tumors. CONCLUSIONS The proposed model can better account for the existing genetic and histological data on syn- and metachronous urothelial carcinomas.
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Affiliation(s)
- Mattias Höglund
- Department of Clinical Genetics, Lund University Hospital, Lund SE-221 85, Sweden.
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15
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Burger M, Denzinger S, Hammerschmied C, Tannapfel A, Maderstorfer A, Wieland WF, Hartmann A, Stoehr R. Mitogen-Activated Protein Kinase Signaling is Activated in Prostate Tumors but not Mediated by B-RAF Mutations. Eur Urol 2006; 50:1102-9; discussion 1109-10. [PMID: 16413100 DOI: 10.1016/j.eururo.2005.11.031] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2005] [Revised: 11/05/2005] [Accepted: 11/23/2005] [Indexed: 11/30/2022]
Abstract
OBJECTIVES A dysregulated mitogen-activated protein kinase (MAPK) pathway plays an important role in various malignancies and is often mediated by mutations in several oncogenes (eg, RAF, RAS). B-RAF mutations, predominantly the specific V600E mutation and additional alterations in exons 11 and 15, were frequently detected in malignant melanomas, papillary thyroid tumors, and colorectal cancers with microsatellite instability (MSI). The present study investigated B-RAF mutations, MSI status, and activation of MAPK signaling in prostate tumors. METHODS The V600E mutation of the B-RAF gene was analyzed using allele-specific polymerase chain reaction in 79 archival prostatic adenocarcinomas (pT1aG1 to pT3cG3, median Gleason score 6); exons 11 and 15 were sequenced. MSI status was determined using the National Cancer Institute consensus panel for hereditary nonpolyposis colorectal carcinoma (HNPCC) detection. Active MAPK signaling was investigated using immunohistochemistry for p44/ERK1 and p42/ERK2. RESULTS No B-RAF mutations could be detected. Six of 79 tumors showed MSI positivity. Active MAPK signaling was detected in 51% of the analyzed tumors. No correlation was found between MAPK activity and histopathologic/clinical characteristics. CONCLUSION The most frequent B-RAF gene alterations are not involved in prostate carcinogenesis. MSI is infrequent in prostate cancer and is not linked to B-RAF mutations. MAPK signaling is frequently activated in prostate tumors and might be suitable for a therapeutic approach.
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Abstract
Urothelial carcinomas are well known to feature multifocal development in the urinary tract, both synchronously and asynchronously. This phenomenon can be explained by either seeding of cancer cells in the urinary tract or field cancerization. As there are two characteristic morphological patterns of urothelial carinomas, papillary and nodular, published papers were here reviewed to understand the development and progression of urothelial carcinoma regarding multifocality due to seeding or field changes with reference to the type of urothelial carcinoma. From animal experiments using rats, mice and dogs treated with N-butyl-N-(4-hydoroxybutyl) nitrosamine, and from pathological observation of human cystectomy specimens on step-sectioning and molecular analysis, nodular carcinomas appear to either develop via papillary carcinomas or de novo. Clinical aspects of multifocal tumor development are outside of the scope of this review, although an understanding of the mechanisms underlying multifocality and the papillary/nodular morphological relationship is important to determine follow-up strategies for patients treated for primary urothelial carcinomas and for reconstruction of the urinary tract after cystectomy.
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Affiliation(s)
- Tadao Kakizoe
- National Cancer Center, Tsukiji 5-1-1, Tokyo 104-0045, Japan.
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17
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Höglund M. Bladder cancer, a two phased disease? Semin Cancer Biol 2006; 17:225-32. [PMID: 16574430 DOI: 10.1016/j.semcancer.2006.02.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2006] [Revised: 02/16/2006] [Accepted: 02/17/2006] [Indexed: 10/25/2022]
Abstract
The processes of intraepithelial migration, intraluminal seeding, and field cancerization as models for initiation, spread, and recurrences of urothelial cell carcinoma (UCC) are reviewed in light of recent molecular investigations. The accumulated molecular data on synchronous and metachronous tumors indicate that the majority of recurrent and multiple tumors are monoclonal. Molecular data has also shown the presence of chromosomal and genetic changes in precursor lesions as well as in normal urothelial cells. Genetic-histological mapping of cystectomized bladders has shown that overt tumors occur as local events in areas of genetically altered urothelium. A model is put forward in which the tumor process is initiated by genetically altered but histologically normal cells that produce fields of altered cells by intraepithelial displacement. By the accumulation of further genetic changes the fields of altered urothelium reaches a state of criticality, which locally may produce frank tumors.
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Affiliation(s)
- Mattias Höglund
- Department of Clinical Genetics, Lund University Hospital, Lund SE-221 81, Sweden.
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18
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Denzinger S, Mohren K, Knuechel R, Wild PJ, Burger M, Wieland WF, Hartmann A, Stoehr R. Improved clonality analysis of multifocal bladder tumors by combination of histopathologic organ mapping, loss of heterozygosity, fluorescence in situ hybridization, and p53 analyses. Hum Pathol 2006; 37:143-51. [PMID: 16426913 DOI: 10.1016/j.humpath.2005.10.014] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2005] [Revised: 10/21/2005] [Accepted: 10/21/2005] [Indexed: 11/29/2022]
Abstract
The clonality status of multifocal bladder tumors is still controversially discussed with experimental evidence for both monoclonality and field cancerization. Methodologically, loss of heterozygosity (LOH) and genomic sequencing analyses are widely used in clonality analysis of malignant tumors. In the present study, we used LOH analysis and genomic sequencing in combination with fluorescence in situ hybridization (FISH) and extensive histopathologic whole-organ mapping to determine the clonal relationship of multifocal bladder cancer disease. Tissue sections (1 cm(2)) covering the entire urothelial lining were systematically dissected from 2 cystectomy specimens (cystectomy 1, no urothelial lesions, bladder infiltration by a leiomyosarcoma of the vaginal wall; cystectomy 2, multifocal pT3G3 tumors). The location of each sample was documented (bladder mapping). Urothelial cells were microdissected for LOH (chromosomes 9, 17p) and FISH analysis (CDKI2 (9p21), FACC (9q22), p53 (17p13.1), and centromeric probes for corresponding chromosome). Exons 5 to 9 of the p53 gene were sequenced in all tumor samples. No chromosomal alterations were detected in the cystectomy specimen without urothelial malignancies. The tumor-bearing bladder showed an increasing frequency of deletions with increasing malignancy of the investigated lesions. LOH analysis detected deletions only on chromosomes 9p and 17p. In contrast, FISH analysis revealed deletions of all investigated genes at chromosomes 9p, 9q, and 17p in all samples analyzed (preneoplastic and neoplastic tissue). An identical p53 mutation in codon 281 was found in all 7 analyzable tumor samples. Combination of molecular data with histopathologic bladder mapping suggested a monoclonal development of the multifocal lesions mostly via intraurothelial migration. Our data strengthen the results from recently published studies that patients with advanced urothelial carcinoma seem to have a monoclonal panurothelial disease in most cases. FISH showed a much higher sensitivity for detection of chromosomal losses than classical LOH analysis, especially in preneoplastic and small lesions. Combining 3 molecular approaches together with histopathologic organ mapping presents a valuable tool to determine the clonality status of multifocal bladder tumors.
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19
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Habuchi T. Origin of multifocal carcinomas of the bladder and upper urinary tract: molecular analysis and clinical implications. Int J Urol 2005; 12:709-16. [PMID: 16174043 DOI: 10.1111/j.1442-2042.2005.01155.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The simultaneous or metachronous development of multifocal tumors with identical or variable histological features in the urothelial tract in a single patient is a well-known characteristic of urothelial cancer. To explain this phenomenon, two distinct concepts have been proposed: the 'field defect' hypothesis according to which urothelial cells in patients are primed to undergo transformation by previous carcinogenic insults and the 'single progenitor cell' hypothesis, which asserts that the multifocal development is caused by the seeding or intraepithelial spread of transformed cells. Results of recent molecular genetic studies support the 'single progenitor cell' hypothesis, and indicate that the genetic and phenotypic diversity observed in multifocal urothelial tumors is a consequence of clonal evolution from a single transformed cell. An understanding of the mechanism of the heterotopic recurrence of urothelial cancer may provide new prospects for early molecular detection and prevention of heterotopic recurrence of urothelial cancer.
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Affiliation(s)
- Tomonori Habuchi
- Department of Urology, Akita University School of Medicine, Akita, Japan.
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20
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Ahmed HU, Arya M, Patel HRH. Bladder carcinoma: understanding advanced and metastatic disease with potential molecular therapeutic targets. Expert Rev Anticancer Ther 2005; 5:1011-1022. [PMID: 16336092 DOI: 10.1586/14737140.5.6.1011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
This article is an expert review of bladder cancer genetics focusing on genetic changes and their significance in the pathogenesis and progression of bladder transitional cell carcinoma, in particular, muscle-invasive disease. Alongside the relevant genetic markers and their products, new therapeutic targets and agents that are being developed are presented.
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21
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Junker K, Stoehr R, Hartmann A. Reply by the authors:. Urology 2004. [DOI: 10.1016/j.urology.2004.01.055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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22
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Duggan BJ, Gray SB, McKnight JJ, Watson CJ, Johnston SR, Williamson KE. Oligoclonality in bladder cancer: the implication for molecular therapies. J Urol 2004; 171:419-25. [PMID: 14665946 DOI: 10.1097/01.ju.0000100105.27708.6c] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE There is conflicting evidence in the published literature regarding the clonal or oligoclonal origin of bladder cancer. MATERIALS AND METHODS A MEDLINE search of articles on the clonality, genetic, epigenetic and tumor microenvironment of bladder cancer cells was done. Laboratory and clinical studies were included and relevant articles were selected if tumor cell clonality was part of the study. We reviewed this published evidence. RESULTS Current thinking proposes 2 main theories. 1) In the clonogenic theory multifocal and recurrent tumors evolve from a single transformed cell and, hence, all progeny share a number of identical genetic mutations. 2) The field change theory assumes a global change in the urothelium with multiple transformed cells evolving into mature tumors independently. The evidence for and against each theory is compelling. Of equal importance are the parallel epigenetic modifications and changes in the cellular microenvironment that permit tumor evolution. CONCLUSIONS The presence of oligoclonality has implications for the potential efficacy of novel molecular therapeutic agents for bladder cancer. The molecular targets for such therapies must be widely sampled in a tumor population to assess expression in separate clones.
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Affiliation(s)
- Brian J Duggan
- Department of Urology, Belfast City Hospital, Northern Ireland.
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Stoehr R, Wild P, Hartmann A. Lasermicrodissection--an important prerequisite for the molecular-genetic analysis of bladder cancer. Pathol Res Pract 2003; 199:355-62. [PMID: 12924435 DOI: 10.1078/0344-0338-00431] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The past 10 years have shown that a crucial point in the molecular-genetic analysis of malignant tumors is the exact histopathological definition and separation of the investigated lesions. Laser microdissection has become an important tool allowing for the study of specific histological entities and defined preneoplastic lesions. Reliable detection of tumor-specific alterations can be compromised by the presence of normal cells. This requires microdissection of pure tumor cell populations (>80%), necessary for detecting chromosomal alterations by loss of heterozygosity analysis (LOH) and fluorescence in situ hybridization (FISH). The combination of microdissection and molecular methods could also be useful for studying multifocal lesions of the urothelial tract. This article describes in detail the use of laser microdissection, whole genome amplification by Improved Primer Extension Preamplification (I-PEP)-PCR and subsequent LOH, FISH, and sequencing analyses for the investigation of urothelial tumors and their precursors, e.g. dysplasias and hyperplasias. The combination of the described methods allows for a wide spectrum of molecular investigations in lesions with a limited number of tumor cells, and might help to understand the fundamental alterations involved in urothelial carcinogenesis.
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Affiliation(s)
- Robert Stoehr
- Institute of Pathology, University of Regensburg, Germany
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24
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Peng XM, Chen XJ, Li JG, Gu L, Huang YS, Gao ZL. Novel assay of competitively differentiated polymerase chain reaction for screening point mutation of hepatitis B virus. World J Gastroenterol 2003; 9:1743-6. [PMID: 12918112 PMCID: PMC4611535 DOI: 10.3748/wjg.v9.i8.1743] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Point mutation, one of the commonest gene mutations, is the most important molecular pathogenesis of cancer and chronic infection. The commonest methods for detection of point mutation are based on polymerase chain reaction (PCR). These techniques, however, cannot be used in large scale screening since they are neither accurate nor simple. For this reason, this study established a novel method of competitively differentiated PCR (CD-PCR) for screening point mutation in clinical practice.
METHODS: Two competitively differentiated primers for mutant-type and wild-type templates respectively with an identically complemented region in 3’ end except for last 2 base pairs and a different non-complemented region in 5’ end were designed. Thus, competitive amplification might be carried out at a lower annealing temperature at first, and then differentiated amplification at a higher annealing temperature when primers could not combine with initial templates. The amplification was performed in one-tube. The products of CD-PCR were detected using microplate hybridization assay. CD-PCR was evaluated by detecting G1896A variant of hepatitis B virus (HBV) in form of recombinant plasmids and in sera from patients with hepatitis B, and compared with allele-specific PCR (AS-PCR) and competitive AS-PCR.
RESULTS: CD-PCR was successfully established. It could clearly distinguish wild-type and mutant-type plasmid DNA of G1896A variant when the amount of plasmid DNA was between 102-108copies/reaction, while for AS-PCR and competitive AS-PCR, the DNA amount was between 102-104copies/reaction. CD-PCR could detect one copy of G1896A variant among 10-100 copies of wild-type plasmid DNA. The specificity of CD-PCR was higher than those of AS-PCR and competitive AS-PCR in the detection of HBV G1896A variant in sera from patients with hepatitis B. CD-PCR was independent of the amount of HBV DNA in serum. HBV G1896A variant was more often found in HBeAg (-) patients with a lower level of detectable viremia than that with a higher level of detectable viremia (P = 0.0192).
CONCLUSION: CD-PCR is more specific since it is less influenced by the amount of initial templates and the cross amplification between mutant- and wild-type amplified products. It is also simple and time-saving. Thus, CD-PCR might be useful in routine gene typing and point mutation screening. HBV G1896A or other more important mutations have to be routinely detected in patients with a detectable level of viremia after HBeAg/antibody conversion in clinical practice.
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Affiliation(s)
- Xiao-Mou Peng
- Department of Infectious Diseases, the Third Affiliated Hospital, Zhongshan University, Guangzhou 510630, China.
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