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Wan X, Wang D, Zhang X, Xu M, Huang Y, Qin W, Chen S. Unleashing the power of urine‑based biomarkers in diagnosis, prognosis and monitoring of bladder cancer (Review). Int J Oncol 2025; 66:18. [PMID: 39917986 PMCID: PMC11837902 DOI: 10.3892/ijo.2025.5724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 01/13/2025] [Indexed: 02/21/2025] Open
Abstract
Bladder cancer (BCa) is a prevalent malignant neoplasm of the urinary tract with high incidence rate, frequent recurrence and rapid disease progression. Conventional approaches for diagnosing, prognosticating and monitoring BCa often rely on invasive procedures such as cystoscopy and tissue biopsy, which are associated with high costs and low patient compliance for follow‑up. Liquid biopsies have advantages, such as being non‑invasive, real‑time, and reproducible, in obtaining diverse biomarkers derived from cellular, molecular, proteomic and genetic signatures in urine or plasma samples. Although plasma‑based biomarkers have been clinically validated, urine provides greater specificity for directly assessing biological materials from urological sources. The present review summarizes advancements and current limitations in urinary protein, genetic and epigenetic biomarkers for disease progression and treatment response of BC, compares performance and application scenarios of urine and blood biomarkers and explores how urinary biomarkers may serve as an alternative or complementary tool to traditional diagnostic methods. The integration of urine‑based or plasma‑based biomarkers into existing diagnostic workflows offers promising avenues for improving accuracy and efficiency of diagnosis in the management of BCa. Notably, the emergence of synthetic biomarkers and urine metabolites, combined with artificial intelligence or bioinformatic technologies, has promise in the screening of potential targets. Continued research and validation efforts are needed to translate these findings into routine clinical practice, ultimately improving patient outcomes and decreasing the burden of BCa.
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Affiliation(s)
- Xuebin Wan
- Department of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, P.R. China
- Department of Research and Development, HaploX Biotechnology, Co., Ltd., Shenzhen, Guangdong 518057, P.R. China
| | - Dan Wang
- Department of Molecular Microbiology and Genetics, Institute for Microbiology and Genetics, University of Goettingen, Göttingen D-37077, Germany
| | - Xiaoni Zhang
- Department of Research and Development, HaploX Biotechnology, Co., Ltd., Shenzhen, Guangdong 518057, P.R. China
| | - Mingyan Xu
- Department of Research and Development, HaploX Biotechnology, Co., Ltd., Shenzhen, Guangdong 518057, P.R. China
| | - Yuying Huang
- Department of Pediatrics, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China
| | - Wenjian Qin
- Department of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, P.R. China
| | - Shifu Chen
- Department of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, P.R. China
- Department of Research and Development, HaploX Biotechnology, Co., Ltd., Shenzhen, Guangdong 518057, P.R. China
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Reynolds T, Riddick G, Meyers G, Gordon M, Flores Monar GV, Moon D, Moon C. Results Obtained from a Pivotal Validation Trial of a Microsatellite Analysis (MSA) Assay for Bladder Cancer Detection through a Statistical Approach Using a Four-Stage Pipeline of Modern Machine Learning Techniques. Int J Mol Sci 2023; 25:472. [PMID: 38203643 PMCID: PMC10778918 DOI: 10.3390/ijms25010472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 12/10/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
Several studies have shown that microsatellite changes can be profiled in urine for the detection of bladder cancer. The use of microsatellite analysis (MSA) for bladder cancer detection requires a comprehensive analysis of as many as 15 to 20 markers, based on the amplification and interpretations of many individual MSA markers, and it can be technically challenging. Here, to develop fast, more efficient, standardized, and less costly MSA for the detection of bladder cancer, we developed three multiplex-polymerase-chain-reaction-(PCR)-based MSA assays, all of which were analyzed via a genetic analyzer. First, we selected 16 MSA markers based on 9 selected publications. Based on samples from Johns Hopkins University (the JHU sample, the first set sample), we developed an MSA based on triplet, three-tube-based multiplex PCR (a Triplet MSA assay). The discovery, validation, and translation of biomarkers for the early detection of cancer are the primary focuses of the Early Detection Research Network (EDRN), an initiative of the National Cancer Institute (NCI). A prospective study sponsored by the EDRN was undertaken to determine the efficacy of a novel set of MSA markers for the early detection of bladder cancer. This work and data analysis were performed through a collaboration between academics and industry partners. In the current study, we undertook a re-analysis of the primary data from the Compass study to enhance the predictive power of the dataset in bladder cancer diagnosis. Using a four-stage pipeline of modern machine learning techniques, including outlier removal with a nonlinear model, correcting for majority/minority class imbalance, feature engineering, and the use of a model-derived variable importance measure to select predictors, we were able to increase the utility of the original dataset to predict the occurrence of bladder cancer. The results of this analysis showed an increase in accuracy (85%), sensitivity (82%), and specificity (83%) compared to the original analysis. The re-analysis of the EDRN study results using machine learning statistical analysis proved to achieve an appropriate level of accuracy, sensitivity, and specificity to support the use of the MSA for bladder cancer detection and monitoring. This assay can be a significant addition to the tools urologists use to both detect primary bladder cancers and monitor recurrent bladder cancer.
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Affiliation(s)
- Thomas Reynolds
- NEXT Bio-Research Services, LLC, 11601 Ironbridge Road, Suite 101, Chester, VA 23831, USA; (T.R.); (G.M.)
| | - Gregory Riddick
- NEXT Bio-Research Services, LLC, 11601 Ironbridge Road, Suite 101, Chester, VA 23831, USA; (T.R.); (G.M.)
| | - Gregory Meyers
- NEXT Bio-Research Services, LLC, 11601 Ironbridge Road, Suite 101, Chester, VA 23831, USA; (T.R.); (G.M.)
| | - Maxie Gordon
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 21093, USA; (M.G.)
- BCD Innovations USA, 10606 Candlewick Road, Lutherville, MD 21093, USA
| | | | - David Moon
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 21093, USA; (M.G.)
| | - Chulso Moon
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 21093, USA; (M.G.)
- BCD Innovations USA, 10606 Candlewick Road, Lutherville, MD 21093, USA
- Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institution, Cancer Research Building II, 5M3, 1550 Orleans Street, Baltimore, MD 21205, USA
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Reynolds T, Bertsche K, Moon D, Moon C. Qualification of the Microsatellite Instability Analysis (MSA) for Bladder Cancer Detection: The Technical Challenges of Concordance Analysis. Int J Mol Sci 2023; 25:209. [PMID: 38203379 PMCID: PMC10779061 DOI: 10.3390/ijms25010209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 11/27/2023] [Accepted: 12/07/2023] [Indexed: 01/12/2024] Open
Abstract
Bladder cancer (here we refer to transitional carcinoma of bladder) is a major cause of morbidity and mortality in the Western world, and recent understanding of its etiology, the molecular characteristics associated with its progression, renders bladder cancer an ideal candidate for screening. Cystoscopy is invasive and sometimes carries unwanted complications, but it is the gold standard for the detection of bladder cancer. Urine cytology, while the most commonly used test as an initial screening tool, is of limited value due to its low sensitivity, particularly for low-grade tumors. Several new "molecular assays" for the diagnosis of urothelial cancer have been developed over the last two decades. Here, we have established our new bladder cancer test based on an assay established for the Early Detection Research Network (EDRN) study. As a part of the study, a quality control CLIA/College of American Pathology (CAP) accredited laboratory, (QA Lab), University of Maryland Baltimore Biomarker Reference Laboratory (UMB-BRL), performed quality assurance analysis. Quality assurance measures included a concordance study between the testing laboratory (AIBioTech), also CLIA/CAP accredited, and the QA lab to ensure that the assay was performed and the results were analyzed in a consistent manner. Therefore, following the technical transfer and training of the microsatellite analysis assay to the UMB-BRL and prior to the initiation of analysis of the clinical samples by the testing lab, a series of qualification studies were performed. This report details the steps taken to ensure qualification of the assay and illustrates the technical challenges facing biomarker validation of this kind.
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Affiliation(s)
- Thomas Reynolds
- NEXT Bio-Research Services, LLC, 11601 Ironbridge Road, Suite 101, Chester, VI 23831, USA
| | - Katie Bertsche
- NEXT Bio-Research Services, LLC, 11601 Ironbridge Road, Suite 101, Chester, VI 23831, USA
| | - David Moon
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 21093, USA
| | - Chulso Moon
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 21093, USA
- BCD Innovations USA, 10606 Candlewick Road, Lutherville, MD 21093, USA
- Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institution, Cancer Research Building II, 5M3, 1550 Orleans Street, Baltimore, MD 21205, USA
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Reynolds T, Gordon M, Monar GVF, Moon D, Moon C. Development of Multiplex Polymerase Chain Reaction (PCR)-Based MSA Assay for Bladder Cancer Detection. Int J Mol Sci 2023; 24:13651. [PMID: 37686456 PMCID: PMC10488090 DOI: 10.3390/ijms241713651] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 08/18/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
Several studies have shown that microsatellite changes can be profiled in the urine to detect bladder cancer. Microsatellite analysis (MSA) of bladder cancer detection requires a comprehensive analysis of up to 15-20 markers based on amplifying and interpreting many individual MSA markers, which can be technically challenging. To develop fast, efficient, standardized, and less costly MSA to detect bladder cancer, we developed three multiplex polymerase chain reaction (PCR) based MSA assays, all of which were analyzed by a genetic analyzer. First, we selected 16 MSA markers based on nine publications. We developed MSA assays based on triplet or three-tube-based multiplex PCR (Triplet MSA assay) using samples from Johns Hopkins University (JHU Sample, first set of samples). In the second set of samples (samples from six cancer patients and fourteen healthy individuals), our Triplet Assay with 15 MSA markers correctly predicted all 6/6 cancer samples to be cancerous and 14/14 healthy samples to be healthy. Although we could improve our report with more clinical information from patient samples and an increased number of cancer patients, our overall results suggest that our Triplet MSA Assay combined with a genetic analyzer is a potentially time- and cost-effective genetic assay for bladder cancer detection and has potential use as a dependable assay in patient care.
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Affiliation(s)
- Thomas Reynolds
- NEXT Bio-Research Services, LLC, 11601 Ironbridge Road, Suite 101, Chester, VA 23831, USA
| | - Maxie Gordon
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 21093, USA
- BCD Innovations USA, 10606 Candlewick Road, Lutherville, MD 21093, USA
| | | | - David Moon
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 21093, USA
| | - Chulso Moon
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 21093, USA
- BCD Innovations USA, 10606 Candlewick Road, Lutherville, MD 21093, USA
- Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institution, Cancer Research Building II, 5M3, 1550 Orleans Street, Baltimore, MD 21205, USA
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Wang F, Sun N, Li Q, Yang J, Yang X, Liu D. Self-Referenced Synthetic Urinary Biomarker for Quantitative Monitoring of Cancer Development. J Am Chem Soc 2023; 145:919-928. [PMID: 36524698 DOI: 10.1021/jacs.2c09538] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Urinary monitoring of diseases has gained considerable attention due to its simple and non-invasive sampling. However, urinalysis remains limited by the dearth of reliable urinary biomarkers and the intrinsically enormous heterogeneity of urine samples. Herein, we report, to our knowledge, the first renal-clearable Raman probe encoded by an internal standard (IS)-conjugated reporter that acts as a quantifiable urinary biomarker for reliable monitoring of cancer development, simultaneously eliminating the impact of sample heterogeneity. Upon delivery of the probes into tumor microenvironments, the endogenously overexpressed β-glucuronidase (GUSB) can cleave the target-responsive residues of the probes to produce IS-retained gold nanoclusters, which were excreted into host urine and analyzed by Au growth-based surface-enhanced Raman spectroscopy. As a result, the in vivo GUSB activity was transformed into in vitro quantitative urinary signals. Based on this IS-encoded synthetic biomarker, both the cancer progression and therapy efficacy were quantitatively monitored, potentiating clinical implications.
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Affiliation(s)
- Fengchao Wang
- State Key Laboratory of Medicinal Chemical Biology, Research Center for Analytical Sciences, and Tianjin Key Laboratory of Molecular Recognition and Biosensing, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Ning Sun
- State Key Laboratory of Medicinal Chemical Biology, Research Center for Analytical Sciences, and Tianjin Key Laboratory of Molecular Recognition and Biosensing, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Qiang Li
- State Key Laboratory of Medicinal Chemical Biology, Research Center for Analytical Sciences, and Tianjin Key Laboratory of Molecular Recognition and Biosensing, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Jie Yang
- State Key Laboratory of Medicinal Chemical Biology, Research Center for Analytical Sciences, and Tianjin Key Laboratory of Molecular Recognition and Biosensing, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Xiaoqing Yang
- Tianjin Institute of Urology, the 2nd Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Dingbin Liu
- State Key Laboratory of Medicinal Chemical Biology, Research Center for Analytical Sciences, and Tianjin Key Laboratory of Molecular Recognition and Biosensing, College of Chemistry, Nankai University, Tianjin 300071, China
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Dang Q, Song M, Dang C, Zhan T, Zhang L. Experimental Study on Solidification Characteristics of Sessile Urine Droplets on a Horizontal Cold Plate Surface under Natural Convection. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2022; 38:7846-7857. [PMID: 35696680 DOI: 10.1021/acs.langmuir.2c01154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
As the human excreta, urine is often used as one of the test materials in medical research due to its composition and content directly reflecting the health status of the body. Considering that the substances in urine may show different effects on its freezing process, solidification characteristics of sessile urine droplets on a horizontal cold plate surface under natural convection were experimentally investigated by comparing with those of water droplets under same conditions. To make the conclusion analysis more reasonable, the urine of a human without any diseases, especially metabolic diseases, was treated and used. The characteristics include nucleation location, dynamic variation of droplet color, and temperatures at different heights inside the droplet, and so forth. It was found that, similar to that of a water droplet, the solidification process of a urine droplet also experiences the following four stages: supercooling, recalescence, freezing, and cooling, in chronological order. Differently, the urine droplet changes from transparent to blur white at the supercooling stage due to the precipitation of inorganic salts. For nucleation locations, 46.67% cases are at the bottom, while others are at the top and middle of urine droplets. For a 10 μL droplet on a surface of -30 °C, urine has a 0.95 s freezing duration shorter than water, and a 5.31 °C lower phase-transition temperature. Results of this study are expected to reflect the content of substances in urine and thus provide references for urinalysis of patients with metabolic diseases.
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Affiliation(s)
- Qun Dang
- Department of Energy and Power Engineering, School of Mechanical Engineering, Beijing Institute of Technology, Beijing 100081, China
| | - Mengjie Song
- Department of Energy and Power Engineering, School of Mechanical Engineering, Beijing Institute of Technology, Beijing 100081, China
| | - Chaobin Dang
- Graduate School of Engineering, University of Fukui, 3-9-1 Bunkyo, Fukui-shi, Fukui 910-8507, Japan
| | - Tianzhuo Zhan
- Graduate School of Interdisciplinary New Science, Toyo University, 2100 Kujirai, Kawagoe, Saitama 350-8585, Japan
| | - Long Zhang
- Department of Energy and Power Engineering, School of Mechanical Engineering, Beijing Institute of Technology, Beijing 100081, China
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Moon C, Gordon M, Moon D, Reynolds T. Microsatellite Instability Analysis (MSA) for Bladder Cancer: Past History and Future Directions. Int J Mol Sci 2021; 22:ijms222312864. [PMID: 34884669 PMCID: PMC8657622 DOI: 10.3390/ijms222312864] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 11/11/2021] [Accepted: 11/19/2021] [Indexed: 12/18/2022] Open
Abstract
Microsatellite instability (MSI), the spontaneous loss or gain of nucleotides from repetitive DNA tracts, is a diagnostic phenotype for gastrointestinal, endometrial, colorectal, and bladder cancers; yet a landscape of instability events across a wider variety of cancer types is beginning to be discovered. The epigenetic inactivation of the MLH1 gene is often associated with sporadic MSI cancers. Recent next-generation sequencing (NGS)-based analyses have comprehensively characterized MSI-positive (MSI+) cancers, and several approaches to the detection of the MSI phenotype of tumors using NGS have been developed. Bladder cancer (here we refer to transitional carcinoma of the bladder) is a major cause of morbidity and mortality in the Western world. Cystoscopy, a gold standard for the detection of bladder cancer, is invasive and sometimes carries unwanted complications, while its cost is relatively high. Urine cytology is of limited value due to its low sensitivity, particularly to low-grade tumors. Therefore, over the last two decades, several new "molecular assays" for the diagnosis of urothelial cancer have been developed. Here, we provide an update on the development of a microsatellite instability assay (MSA) and the development of MSA associated with bladder cancers, focusing on findings obtained from urine analysis from bladder cancer patients as compared with individuals without bladder cancer. In our review, based on over 18 publications with approximately 900 sample cohorts, we provide the sensitivity (87% to 90%) and specificity (94% to 98%) of MSA. We also provide a comparative analysis between MSA and other assays, as well as discussing the details of four different FDA-approved assays. We conclude that MSA is a potentially powerful test for bladder cancer detection and may improve the quality of life of bladder cancer patients.
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Affiliation(s)
- Chulso Moon
- Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institution, Cancer Research Building II, 5M3, 1550 Orleans Street, Baltimore, MD 21205, USA
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 21093, USA; (M.G.); (D.M.)
- BCD Innovations USA, 10606 Candlewick Road, Lutherville, MD 21093, USA
- Correspondence: ; Tel.: +1-(443)-370-5056
| | - Maxie Gordon
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 21093, USA; (M.G.); (D.M.)
- BCD Innovations USA, 10606 Candlewick Road, Lutherville, MD 21093, USA
| | - David Moon
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 21093, USA; (M.G.); (D.M.)
| | - Thomas Reynolds
- NEXT Bio-Research Services, LLC, 11601 Ironbridge Road, Suite 101, Chester, VA 23831, USA;
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Fan B, Huang Y, Wen S, Teng Q, Yang X, Sun M, Chen T, Huang Y, Wang Y, Liu Z. Predictive Value of Preoperative Positive Urine Cytology for Development of Bladder Cancer After Nephroureterectomy in Patients With Upper Urinary Tract Urothelial Carcinoma: A Prognostic Nomogram Based on a Retrospective Multicenter Cohort Study and Systematic Meta-Analysis. Front Oncol 2021; 11:731318. [PMID: 34660295 PMCID: PMC8519510 DOI: 10.3389/fonc.2021.731318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 09/08/2021] [Indexed: 11/13/2022] Open
Abstract
Background Upper urinary tract urothelial carcinoma (UUT-UC) is a rare and severe urinary malignancy. Several studies have explored the relationship between preoperative urine cytology and intravesical recurrence (IVR) in patients with UUT-UC. However, the results of these studies are controversial or even contradictory, and investigations with UUT-UC patients in northeast China are rare. Methods We first estimated the prognostic significance of preoperative urine cytology in the outcomes of intravesical recurrence in 231 UUT-UC patients (training cohort = 142, validation cohort = 89) after radical nephroureterectomy (RNU) by the nomogram model. Subsequently, we quantitatively combined our results with the published data after searching several databases to assess whether preoperative positive urine cytology was associated with poor intravesical recurrence-free survival and a high risk of tumor malignant biological behavior. Results Firstly, the multicenter retrospective cohort study demonstrated that preoperative positive urine cytology correlated with poor intravesical recurrence-free survival and can serve as significant independent predictors of IVR by Kaplan-Meier curves and Cox regression analysis. The construction of the nomogram demonstrated that predictive efficacy and accuracy were significantly improved when preoperative urine cytology was combined. Meanwhile, meta-analysis showed that preoperative positive urine cytology was associated with a 49% increased risk of IVR. In the subgroup analysis by region, study type, and sample size, the pooled hazard ratios (HRs) were statistically significant for the Japan subgroup (HR 1.32), China subgroup (HR 1.88), cohort study subgroup (HR 1.45), and the single-arm study subgroup (HR 1.63). Conclusions Preoperative urine cytology was validated as a potential predictor of intravesical recurrence in patients with UUT-UC after RNU, although these results need to be generalized with caution. Large, prospective trials are required to further confirm its significance in prognosis and tumor malignant biological behavior.
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Affiliation(s)
- Bo Fan
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yuanbin Huang
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China.,Department of Clinical Medicine, Dalian Medical University, Dalian, China
| | - Shuang Wen
- Department of Pathology, Dalian Friendship Hospital, Dalian, China
| | - Qiliang Teng
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xinrui Yang
- Department of Clinical Medicine, Dalian Medical University, Dalian, China
| | - Man Sun
- Department of Clinical Medicine, Dalian Medical University, Dalian, China
| | - Tingyu Chen
- Department of Clinical Medicine, Dalian Medical University, Dalian, China
| | - Yan Huang
- Department of Urology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Yumei Wang
- Department of Clinical Laboratory, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhiyu Liu
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
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Hayashi Y, Fujita K. Toward urinary cell-free DNA-based treatment of urothelial carcinoma: a narrative review. Transl Androl Urol 2021; 10:1865-1877. [PMID: 33968675 PMCID: PMC8100839 DOI: 10.21037/tau-20-1259] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Liquid biopsy technique targeting urinary cell-free DNA (cfDNA) is getting a lot of attention to overcome limitations of the present treatment strategy for urothelial carcinoma, including urothelial bladder carcinoma (UBC) and upper tract urothelial carcinoma (UTUC). Analysis of tumor-derived DNA in urine focusing either on genomic or epigenomic alterations, holds great potential as a noninvasive method for the detection of urothelial carcinoma with high accuracy. It is also predictive of prognosis and response to drugs, and reveals the underlying characteristics of different stages of urothelial carcinoma. Although cfDNA methylation analyses based on a combination of several methylation profiles have demonstrated high sensitivity for UBC diagnosis, there have been few reports involving epigenomic studies of urinary cfDNA. In mutational analyses, frequent gene mutations (TERT promoter, TP53, FGFR3, PIK3CA, RAS, etc.) have been detected in urine supernatant by using remarkable technological innovations such as next-generation sequencing and droplet digital PCR. These methods allow highly sensitive detection of rare mutation alleles while minimizing artifacts. In this review, we summarize the current insights into the clinical applications of urinary cfDNA from patients with urothelial carcinoma. Although it is necessary to conduct prospective multi-institutional clinical trials, noninvasive urine biopsy is expected to play an important role in the realization of precision medicine in patients with urothelial carcinoma in the near future.
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Affiliation(s)
- Yujiro Hayashi
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kazutoshi Fujita
- Department of Urology, Kindai University Faculty of Medicine, Osakasayama, Japan
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Białek Ł, Czerwińska K, Fus Ł, Krajewski W, Sadowska A, Radziszewski P, Dobruch J, Kryst P, Poletajew S. MCM5 urine expression (ADXBLADDER) is a reliable biomarker of high-risk non- muscle-invasive bladder cancer recurrence: A prospective matched case-control study. Cancer Biomark 2021; 30:139-143. [PMID: 32924986 DOI: 10.3233/cbm-200316] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Mini Chromosome Maintenance 5 (MCM5) is considered as a urinary biomarker of bladder cancer. ADXBLADDER is a commercially available test to detect MCM5 antibodies. OBJECTIVE External validation of ADXBLADDER test as a urinary biomarker of histopathologically confirmed non-muscle invasive bladder cancer (NMIBC) recurrence. METHODS The study enrolled 119 consecutive patients with a history of NMIBC and 37 healthy volunteers matched as controls. Single, full-void urine samples were collected from patients before cystoscopy ± TUR. To measure MCM5 expression, Arquer Diagnostics ADXBLADDER test was used. The study protocol was registered within the clinical trials database (NCT03796299). RESULTS Among patients with NMIBC history, recurrence was diagnosed in 83 patients (69.7%). ADXBLADDER demonstrated sensitivity of 73.5% (95% confidence interval (CI) 62.7%-82.6%), specificity of 33.3% (95% CI 18.6% to 51%), overall negative predictive value (NPV) of 35.3% (95% CI 23.3% to 49.5%) and overall positive predictive value of 71.8% (95% CI 66.1% to 76.8%) for detecting recurrence. In a control group, false positive ADXBLADDER results were noticed in 18 patients (48.6%). The sensitivity and NPV were the highest in invasive tumors (100% and 100%, respectively) and in high-grade recurrences (81.8% and 94.1%, respectively). CONCLUSIONS ADXBLADDER has a moderate sensitivity and poor specificity in detecting NMIBC recurrence. However, it properly diagnoses patients with T1+ stage recurrence or high-grade tumors.
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Affiliation(s)
- Łukasz Białek
- First Department of Urology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Katarzyna Czerwińska
- Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Łukasz Fus
- Department of Pathology, Medical University of Warsaw, Warsaw, Poland
| | - Wojciech Krajewski
- Department and Clinic of Urology, Medical University of Wroclaw, Wroclaw, Poland
| | - Anna Sadowska
- Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Radziszewski
- Department of General, Oncological and Functional Urology, Medical University of Warsaw, Warsaw, Poland
| | - Jakub Dobruch
- First Department of Urology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Piotr Kryst
- Second Department of Urology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Sławomir Poletajew
- Second Department of Urology, Centre of Postgraduate Medical Education, Warsaw, Poland
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Sun T, Hutchinson L, Tomaszewicz K, Caporelli ML, Meng X, McCauley K, Fischer AH, Cosar EF, Cornejo KM. Diagnostic value of a comprehensive, urothelial carcinoma-specific next-generation sequencing panel in urine cytology and bladder tumor specimens. Cancer Cytopathol 2021; 129:537-547. [PMID: 33539671 DOI: 10.1002/cncy.22410] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 11/06/2020] [Accepted: 01/04/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND Urine cytology can reliably diagnose high-grade urothelial carcinoma (HGUC) but not low-grade urothelial carcinoma (LGUC), and a more sensitive test is needed. Previously, a pilot study highlighted the possible diagnostic utility of next-generation sequencing (NGS) in identifying both LGUC and HGUC in urine cytology specimens. METHODS Twenty-eight urine ThinPrep cytology specimens and preceding or subsequent bladder tumor biopsy/resection specimens obtained within 3 months were included in the study (LGUC, n = 15; HGUC, n = 13). A customized, bladder-specific NGS panel was performed; it covered 69 frequently mutated or altered genes in urothelial carcinoma (UC) that were reported by The Cancer Genome Atlas and the Catalogue of Somatic Mutations in Cancer. RESULTS The sequencing results were compared between the urine cytology specimens and the corresponding bladder tumor biopsies/resections. TP53 was the most frequently identified mutation in HGUC cases (11 of 13 [85%]). PIK3CA and KDM6A were the most frequently identified mutations in LGUC: they occurred in 7 of 15 cases (47%) and in 6 of 15 cases (40%), respectively. Additional frequent mutations identified in the panel included ARID1A (n = 5), EP300 (n = 4), LRP1B (n = 3), ERBB2 (n = 2), STAG2 (n = 2), FGFR3 (n = 3), MLL (n = 2), MLL3 (n = 2), CREBBP1 (n = 1), RB1 (n = 1), and FAT4 (n = 1). Overall, the concordance between the cytology and surgical specimens was 75%. The sensitivity and specificity for identifying mutations in urine cytology specimens were 84% and 100%, respectively. CONCLUSIONS A bladder-specific NGS panel increases the sensitivity and specificity of urine cytology's diagnostic utility in both low- and high-grade tumors and may serve as a noninvasive surveillance method in the follow-up of patients with UC harboring known mutations.
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Affiliation(s)
- Tong Sun
- Department of Pathology, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Lloyd Hutchinson
- Department of Pathology, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Keith Tomaszewicz
- Department of Pathology, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Mandi-Lee Caporelli
- Department of Pathology, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Xiuling Meng
- Department of Pathology, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Kathleen McCauley
- Department of Pathology, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Andrew H Fischer
- Department of Pathology, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Ediz F Cosar
- Department of Pathology, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Kristine M Cornejo
- Department of Pathology, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts.,Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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12
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Chang H, Tsui K, Shen L, Huang H, Wang S, Chang P. Urinary Cell-Free DNA as a Potential Tumor Marker for Bladder Cancer. Int J Biol Markers 2018; 22:287-94. [DOI: 10.1177/172460080702200408] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The objective was to assess the possibility of measuring urine creatinine (UCr)-adjusted urinary cell-free (ucf) DNA concentration as a noninvasive screening tool for bladder cancer. Using PicoGreen-based detection, the ucf-DNA/UCr concentration was quantified in urine supernatant specimens from 46 bladder cancer patients and 98 controls and compared to 400-bp real-time PCR-based detection, which detected the amplification of 400-bp β-actin (named 400-bp ucf-DNA/UCr). The mean concentrations for both PicoGreen and 400-bp ucf-DNA (ng/mL)/UCr (mg/dL) were significantly higher in bladder cancer patients than in controls: 15.28 vs 6.68 (p<0.001, t-test) and 14.98 vs 1.07 (p<0.001), respectively. Among different stages and grades, no significant difference was found between these two methods. The areas under the ROC curves of PicoGreen and 400-bp ucf-DNA/UCr were 0.571 (95% confidence interval, 0.451–0.692) and 0.805 (95% confidence interval, 0.713–0.896), respectively. In 400-bp ucf-DNA/UCr, the best sensitivity and specificity were 86.1% and 72.0% at the cutoff value of 0.0645. These data indicated that 400-bp ucf-DNA/UCr is more reliable for bladder cancer detection than PicoGreen. In conclusion, our results suggest that ucf-DNA/UCr can be used as a potential tumor marker for bladder cancer, especially for detecting longer DNA fragments.
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Affiliation(s)
- H.W. Chang
- Faculty of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung
| | - K.H. Tsui
- Chang Gung Bioinformatics Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan
| | - L.C. Shen
- Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung
| | - H.W. Huang
- Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung
- National Sun Yat-Sen University-Kaohsiung Medical University Joint Center, Kaohsiung
| | - S.N. Wang
- Division of Hepato-biliary-pancreatico Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung - Taiwan
| | - P.L. Chang
- Chang Gung Bioinformatics Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan
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13
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Yousef PG, Gabril MY. An update on the molecular pathology of urinary bladder tumors. Pathol Res Pract 2017; 214:1-6. [PMID: 29254798 DOI: 10.1016/j.prp.2017.11.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 10/27/2017] [Accepted: 11/03/2017] [Indexed: 01/21/2023]
Abstract
Urothelial carcinoma is the fourth most common tumors after prostate cancer, lung, and colorectal carcinoma but the second most common urologic malignancy. Urothelial carcinoma composed more than 90% of bladder tumors while squamous cell carcinoma and adenocarcinomas composed 5% and 2% respectively. The intense research involving the different molecular aspects of bladder cancer has provided a great insight into identifying more about molecular profiling and pathways of bladder cancer. In this review, we will highlight the general concepts of the molecular features; profiling and classification as well as the molecular pathways for bladder carcinomas, especially urothelial carcinoma. Also, we will discuss the advances of molecular biomarkers for screening, early diagnosis, surveillance and potential prognosis of urothelial carcinoma of the bladder. Studies showed that accumulation of genetic alterations involving the clonal expansion of altered cells with growth advantages through sequential multi-step pathways results in progression of bladder tumors. The accumulated research data from literature has revealed that the genomic signatures of urothelial carcinoma are required to subclassify bladder cancer into genetically distinct subgroups. These findings could improve the understating of pathogenesis as well as will provide new therapeutic modules e.g. targeted therapy.
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Affiliation(s)
- Peter G Yousef
- Pathology and Laboratory Medicine, London Health Sciences Centre, Western University, London, Ontario, Canada
| | - Manal Y Gabril
- Pathology and Laboratory Medicine, London Health Sciences Centre, Western University, London, Ontario, Canada.
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14
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Léon P, Cancel Tassin G, Sighar K, Compérat E, Gaffory C, Ondet V, Hugonin S, Audouin M, Doizi S, Traxer O, Ciofu C, Rouprêt M, Lacave R, Cussenot O. [Correlation of genetic and cytogenetic alterations in pathological aggressiveness urothelial carcinoma of the bladder: Performance of BCA-1, a mini-array comparative genomic hybridisation-based test]. Prog Urol 2017; 27:451-457. [PMID: 28576425 DOI: 10.1016/j.purol.2017.05.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 05/05/2017] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Urothelial carcinomas are the fourth leading cause of cancer in humans. Their incidence is increasing by more than 50% in 25 years. The superficial forms (70% cases) require a close active surveillance to identify frequent recurrences and progression to invasive stage. Our main goal was to identify prognostic molecular markers for bladder cancer that could be used alone or in combination in routine clinical practice. In this aim, we evaluated the capability of the BCA-oligo test based on a CGH array to correctly classify tumoral grade/stage. METHOD Urinary DNA was extracted from 81 patients with superficial bladder cancer and has been hybridized on the BCA-oligo array. The results from the molecular analysis were correlated with the tumoral grade and stage. RESULTS Several chromosomal alterations were significantly more frequent in tumors of higher grade and more advanced stage. A significant association was observed between a high grade and the presence of one of these alterations: loss on 6p, gain on 8q or 13q, loss or gain on 9q or 11q, with an odds ratio of 6.91 (95% CI=2.20-21.64; P=0.0009). Moreover, a significant association was found between a more advanced stage (pT1) and the presence of one of these alterations: loss on 6p, gain on 8q, loss or gain on 5p, with an odds ratio of 15.2 (95% CI=3.71-62.58; P=0.0002). CONCLUSION Our results showed that molecular analyses of superficial bladder cancers based on urinary DNA and the BCA-oligo test could be used as prognostic factor for the tumor evolution, allowing then a more adapted clinical management.
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Affiliation(s)
- P Léon
- GRC n(o) 5, ONCOTYPE-URO, institut universitaire de cancérologie, UPMC université Paris 06, 75020 Paris, France; Département de chirurgie urologique, CHU de Reims, rue Cognacq-Jay, 51000 Reims, France.
| | - G Cancel Tassin
- GRC n(o) 5, ONCOTYPE-URO, institut universitaire de cancérologie, UPMC université Paris 06, 75020 Paris, France; CeRePP, 75020 Paris, France
| | - K Sighar
- Arraygenomics, 78960 Voisins-le-Bretonneux, France
| | - E Compérat
- GRC n(o) 5, ONCOTYPE-URO, institut universitaire de cancérologie, UPMC université Paris 06, 75020 Paris, France; CeRePP, 75020 Paris, France; Département d'anatomopathologie, hôpital de la Pitié-Salpétrière, UPMC université Paris 06, AP-HP, 75013 Paris, France
| | - C Gaffory
- GRC n(o) 5, ONCOTYPE-URO, institut universitaire de cancérologie, UPMC université Paris 06, 75020 Paris, France; CeRePP, 75020 Paris, France
| | - V Ondet
- GRC n(o) 5, ONCOTYPE-URO, institut universitaire de cancérologie, UPMC université Paris 06, 75020 Paris, France; CeRePP, 75020 Paris, France; Département de chirurgie urologique, hôpital Tenon, UPMC université Paris 06, AP-HP, 75020 Paris, France
| | - S Hugonin
- Département de biologie tumorale, hôpital Tenon, UPMC université Paris 06, AP-HP, 75020 Paris, France
| | - M Audouin
- GRC n(o) 5, ONCOTYPE-URO, institut universitaire de cancérologie, UPMC université Paris 06, 75020 Paris, France; Département de chirurgie urologique, hôpital Tenon, UPMC université Paris 06, AP-HP, 75020 Paris, France
| | - S Doizi
- Département de chirurgie urologique, hôpital Tenon, UPMC université Paris 06, AP-HP, 75020 Paris, France
| | - O Traxer
- Département de chirurgie urologique, hôpital Tenon, UPMC université Paris 06, AP-HP, 75020 Paris, France
| | - C Ciofu
- Département de chirurgie urologique, hôpital Tenon, UPMC université Paris 06, AP-HP, 75020 Paris, France
| | - M Rouprêt
- GRC n(o) 5, ONCOTYPE-URO, institut universitaire de cancérologie, UPMC université Paris 06, 75020 Paris, France; CeRePP, 75020 Paris, France; Département de chirurgie urologique, hôpital de la Pitié-Salpétrière, UPMC université Paris 06, AP-HP, 75013 Paris, France
| | - R Lacave
- Département de biologie tumorale, hôpital Tenon, UPMC université Paris 06, AP-HP, 75020 Paris, France
| | - O Cussenot
- GRC n(o) 5, ONCOTYPE-URO, institut universitaire de cancérologie, UPMC université Paris 06, 75020 Paris, France; CeRePP, 75020 Paris, France; Département de chirurgie urologique, hôpital Tenon, UPMC université Paris 06, AP-HP, 75020 Paris, France
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Cornou C, Bats AS, Ngo C, Rossi L, Capmas P, Laurent-Puig P, Bensaid C, Nos C, Lefrère-Belda MA, Lécuru F. Screening and diagnosis of endometrial cancer in Lynch syndrome. World J Obstet Gynecol 2016; 5:218-225. [DOI: 10.5317/wjog.v5.i4.218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 08/30/2016] [Accepted: 10/27/2016] [Indexed: 02/05/2023] Open
Abstract
Lynch syndrome (LS) is an autosomal dominant inherited cancer predisposition syndrome caused by a mismatch of DNA repair (MMR system). Lifetime risk of developing endometrial and ovarian cancer in LS is higher than in the general population and gynecologic screening appears interesting. Screening is based on several tests: pelvic ultrasound, endometrial biopsy and hysteroscopy for endometrial cancer, pelvic ultrasound and CA125 for ovarian cancer. Those tests appear efficient for the diagnosis of gynecologic cancers in LS. Nevertheless, screening tests have not proved clinical benefit until now, and potential problems of compliance, risk of false negative cases, and interval cancer associated with screening do justify offering prophylactic surgery to patients. Women with LS should be informed of the potential benefits and risks of screening and the importance of evaluation in case of gynecologic symptoms or abnormal bleeding. Chemoprevention by progestin-containing oral contraceptives and the treatment of premalignant lesion are available options for reducing the risk of endometrial cancer in LS population.
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Krabbe LM, Woldu SL, Shariat SF, Lotan Y. Improving diagnostic molecular tests to monitor urothelial carcinoma recurrence. Expert Rev Mol Diagn 2016; 16:1189-1199. [PMID: 27696932 DOI: 10.1080/14737159.2016.1244006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION The high recurrence rates associated with non-muscle invasive bladder cancer require close surveillance with cystoscopy, an invasive and expensive procedure with risk of missing cancer. Finding an accurate urinary biomarker that can detect recurrent disease would represent a significant advancement in management. Areas covered: This review summarizes the commercially-available urinary biomarkers including cytology, UroVysion, BTA, NMP22, uCyt+, and Cxbladder assays. Additionally, we review recent investigational urinary biomarkers that hold promise in bladder cancer surveillance. Expert commentary: The quest for a reliable urinary biomarker for bladder cancer is decades-old and seems intuitive given the direct contact of urine with malignant urothelium. Beyond urine cytology, there are many commercially-available products approved for surveillance. However, none of the assays are routinely used due to lack of sensitivity and/or specificity. As such, emerging technologies, in particular the '-omic' technologies have resulted in a proliferation of promising reports on novel biomarkers in recent literature.
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Affiliation(s)
- Laura-Maria Krabbe
- a Department of Urology , UT Southwestern Medical Center , Dallas , TX , USA.,b Department of Urology , University of Muenster Medical Center , Muenster , Germany
| | - Solomon L Woldu
- a Department of Urology , UT Southwestern Medical Center , Dallas , TX , USA
| | - Shahrokh F Shariat
- a Department of Urology , UT Southwestern Medical Center , Dallas , TX , USA.,c Department of Urology, Comprehensive Cancer Center , Medical University of Vienna , Vienna , Austria.,d Department of Urology and Medical Oncology , Weill Medical College of Cornell University , New York , NY , USA
| | - Yair Lotan
- a Department of Urology , UT Southwestern Medical Center , Dallas , TX , USA
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Abdulmajed MI, Sancak EB, Reşorlu B, Al-Chalaby GZ. What are the currently available and in development molecular markers for bladder cancer? Will they prove to be useful in the future? Turk J Urol 2015; 40:228-32. [PMID: 26328183 DOI: 10.5152/tud.2014.60973] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2013] [Accepted: 05/05/2014] [Indexed: 11/22/2022]
Abstract
Urothelial carcinoma is the 9(th) most common cancer worldwide. Most urothelial tumors are non-muscle invasive on presentation. However, two-thirds of non-invasive bladder cancers will eventually recur with a 25% risk of progression to muscle-invasive bladder cancer. Tumor stage, histological grade and pathological invasion of blood vessels and lymphatic tissue are the main indicators for urothelial cancer prognosis. The gold standard for diagnosing bladder cancer is conventional white-light cystoscopy and biopsy. Urine cytology is a highly specific, sensitive test for high-grade tumors or carcinoma in situ (CIS). Urinary NMP22 has an overall sensitivity and specificity for detecting bladder cancer of 49% and 87%, respectively. However, there are false-positive results in the presence of urinary tract infection or hematuria. The detection of specific gene mutations related to urothelial cancers has been studied and employed to reproduce markers helpful for diagnosis. According to current studies, molecular markers can be used to predict tumor recurrence. From a prognostic point of view, new molecular markers have yet to be established as reliable indicators of tumor aggressiveness. We aimed to review the molecular markers with possible prognostic significance that have been discussed in the literature. This review examined the literature for various molecular markers under development for bladder cancer in an attempt to optimize patient care and reduce the costs of treating these patients.
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Affiliation(s)
- Mohamed Ismat Abdulmajed
- Department of Urology, Wrexham Maelor Hospital, Betsi Cadwaladr University Health Board, Wrexham, Wales, United Kingdom
| | - Eyüp Burak Sancak
- Department of Urology, Çanakkale Onsekiz Mart University Faculty of Medicine, Çanakkale, Turkey
| | - Berkan Reşorlu
- Department of Urology, Çanakkale Onsekiz Mart University Faculty of Medicine, Çanakkale, Turkey
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Todenhöfer T, Hennenlotter J, Guttenberg P, Mohrhardt S, Kuehs U, Esser M, Aufderklamm S, Bier S, Harland N, Rausch S, Gakis G, Stenzl A, Schwentner C. Prognostic relevance of positive urine markers in patients with negative cystoscopy during surveillance of bladder cancer. BMC Cancer 2015; 15:155. [PMID: 25884545 PMCID: PMC4374530 DOI: 10.1186/s12885-015-1089-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Accepted: 02/19/2015] [Indexed: 12/14/2022] Open
Abstract
Background The role of urine markers in the surveillance of patients with non-muscle invasive bladder cancer (NMIBC) is discussed extensively. In case of negative cystoscopy the additional prognostic value of these markers has not been clearly defined yet. The present study is the first systematic approach to directly compare the ability of a urine marker panel to predict the risk of recurrence and progression in bladder cancer (BC) patients with no evidence of relapse during surveillance for NMIBC. Methods One hundred fourteen patients who underwent urine marker testing during surveillance for NMIBC and who had no evidence of BC recurrence were included. For all patients cytology, Fluorescence-in-situ-hybridization (FISH), immunocytology (uCyt+) and Nuclear matrix protein 22 enzyme-linked immunosorbent assay (NMP22) were performed. All patients completed at least 24 months of endoscopic and clinical follow-up of after inclusion. Results Within 24 months of follow-up, 38 (33.0%) patients experienced disease recurrence and 11 (9.8%) progression. Recurrence rates in patients with positive vs. negative cytology, FISH, uCyt+ and NMP22 were 52.6% vs. 21.9% (HR = 3.9; 95% CI 1.75-9.2; p < 0.001), 47.6% vs. 25.0% (HR 2.7; 1.2-6.2; p = 0.01), 43.8% vs. 22.4% (HR 3.3; 1.5-7.6; p = 0.003) and 43.8% vs. 16.7% (HR 4.2; 1.7-10.8; p = 0.001). In patients with negative cytology, a positive NMP22 test was associated with a shorter time to recurrence (p = 0.01), whereas FISH or uCyt+ were not predictive of recurrence in these patients. In the group of patients with negative cytology and negative NMP22, only 13.5% and 5.4% developed recurrence and progression after 24 months. Conclusions Patients with positive urine markers at time of negative cystoscopy are at increased risk of recurrence and progression. In patients with negative cytology, only NMP22 is predictive for recurrence. Patients with negative marker combinations including NMP22 harbour a low risk of recurrence. Therefore, the endoscopic follow-up regimen may be attenuated in this group of patients.
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Affiliation(s)
- Tilman Todenhöfer
- Department of Urology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany. .,Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC, V3Z6H, Canada.
| | - Jörg Hennenlotter
- Department of Urology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany.
| | - Philipp Guttenberg
- Department of Urology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany.
| | - Sarah Mohrhardt
- Department of Urology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany.
| | - Ursula Kuehs
- Department of Urology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany.
| | - Michael Esser
- Department of Urology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany.
| | - Stefan Aufderklamm
- Department of Urology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany.
| | - Simone Bier
- Department of Urology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany.
| | - Niklas Harland
- Department of Urology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany.
| | - Steffen Rausch
- Department of Urology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany.
| | - Georgios Gakis
- Department of Urology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany.
| | - Arnulf Stenzl
- Department of Urology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany.
| | - Christian Schwentner
- Department of Urology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany.
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Su SF, de Castro Abreu AL, Chihara Y, Tsai Y, Andreu-Vieyra C, Daneshmand S, Skinner EC, Jones PA, Siegmund KD, Liang G. A panel of three markers hyper- and hypomethylated in urine sediments accurately predicts bladder cancer recurrence. Clin Cancer Res 2014; 20:1978-89. [PMID: 24691641 DOI: 10.1158/1078-0432.ccr-13-2637] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE The high risk of recurrence after transurethral resection of bladder tumor of nonmuscle invasive disease requires lifelong treatment and surveillance. Changes in DNA methylation are chemically stable, occur early during tumorigenesis, and can be quantified in bladder tumors and in cells shed into the urine. Some urine markers have been used to help detect bladder tumors; however, their use in longitudinal tumor recurrence surveillance has yet to be established. EXPERIMENTAL DESIGN We analyzed the DNA methylation levels of six markers in 368 urine sediment samples serially collected from 90 patients with noninvasive urothelial carcinoma (Tis, Ta, T1; grade low-high). The optimum marker combination was identified using logistic regression with 5-fold cross-validation, and validated in separate samples. RESULTS A panel of three markers discriminated between patients with and without recurrence with the area under the curve of 0.90 [95% confidence interval (CI), 0.86-0.92] and 0.95 (95% CI, 0.90-1.00), sensitivity and specificity of 86%/89% (95% CI, 74%-99% and 81%-97%) and 80%/97% (95% CI, 60%-96% and 91%-100%) in the testing and validation sets, respectively. The three-marker DNA methylation test reliably predicted tumor recurrence in 80% of patients superior to cytology (35%) and cystoscopy (15%) while accurately forecasting no recurrence in 74% of patients that scored negative in the test. CONCLUSIONS Given their superior sensitivity and specificity in urine sediments, a combination of hyper- and hypomethylated markers may help avoid unnecessary invasive exams and reveal the importance of DNA methylation in bladder tumorigenesis.
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Affiliation(s)
- Sheng-Fang Su
- Authors' Affiliations: Departments of Urology and Preventive Medicine; Program in Genetic, Molecular, and Cellular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles; and Department of Urology, School of Medicine, University of Stanford, Stanford, California
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Sapre N, Anderson PD, Costello AJ, Hovens CM, Corcoran NM. Gene-based urinary biomarkers for bladder cancer: An unfulfilled promise? Urol Oncol 2014; 32:48.e9-17. [DOI: 10.1016/j.urolonc.2013.07.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Revised: 07/01/2013] [Accepted: 07/01/2013] [Indexed: 01/05/2023]
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Abstract
Urinary bladder cancer is a heterogeneous disease with diverse genetic and environmental risk factors that can influence disease risk or clinical course for recurrence, progression, and survival. Therefore, identification of these factors is paramount for disease prevention and optimal clinical management of bladder cancer patients. Of particular interest is the need to identify molecular biomarkers that can give accurate assessment of tumor biological potential and to predict treatment response. Recent advances in molecular biology, cytogenetic, and genomic research have spurred discovery efforts for novel genetic, epigenetic, and proteomic biomarkers that are prognostic for cancer. This review focuses on some of the important germ line polymorphisms found to be correlated with clinical outcomes in bladder cancer. So far, most of the identified candidate loci were based on prior knowledge of pathogenesis and had not been validated for clinical applications. The future challenges are to analyze the wealth of information from whole-genome studies, to understand the underlying biological mechanisms of these associations, the network of gene-gene and gene-environment interactions, and to apply these markers for the identification of high-risk population for targeted, personalized therapy.
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Abstract
Biomarkers are increasingly being applied to the clinical management of patients with bladder cancer. The biomarkers in current clinical use focus on bladder cancer detection. Biomarkers for prognosis and as intermediate endpoints for chemoprevention are being evaluated in clinical trials. This review provides an overview of the performance characteristics of current clinical markers and other markers that are currently under evaluation.
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Affiliation(s)
- H B Grossman
- The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 110, Houston, TX 77030-4095, USA
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van Tilborg AAG, Kompier LC, Lurkin I, Poort R, El Bouazzaoui S, van der Keur K, Zuiverloon T, Dyrskjot L, Orntoft TF, Roobol MJ, Zwarthoff EC. Selection of microsatellite markers for bladder cancer diagnosis without the need for corresponding blood. PLoS One 2012; 7:e43345. [PMID: 22927958 PMCID: PMC3425555 DOI: 10.1371/journal.pone.0043345] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Accepted: 07/19/2012] [Indexed: 01/02/2023] Open
Abstract
Microsatellite markers are used for loss-of-heterozygosity, allelic imbalance and clonality analyses in cancers. Usually, tumor DNA is compared to corresponding normal DNA. However, normal DNA is not always available and can display aberrant allele ratios due to copy number variations in the genome. Moreover, stutter peaks may complicate the analysis. To use microsatellite markers for diagnosis of recurrent bladder cancer, we aimed to select markers without stutter peaks and a constant ratio between alleles, thereby avoiding the need for a control DNA sample. We investigated 49 microsatellite markers with tri- and tetranucleotide repeats in regions commonly lost in bladder cancer. Based on analysis of 50 blood DNAs the 12 best performing markers were selected with few stutter peaks and a constant ratio between peaks heights. Per marker upper and lower cut off values for allele ratios were determined. LOH of the markers was observed in 59/104 tumor DNAs. We then determined the sensitivity of the marker panel for detection of recurrent bladder cancer by assaying 102 urine samples of these patients. Sensitivity was 63% when patients were stratified for LOH in their primary tumors. We demonstrate that up-front selection of microsatellite markers obliterates the need for a corresponding blood sample. For diagnosis of bladder cancer recurrences in urine this significantly reduces costs. Moreover, this approach facilitates retrospective analysis of archival tumor samples for allelic imbalance.
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Affiliation(s)
| | | | - Irene Lurkin
- Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | - Ricardo Poort
- Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | | | | | | | - Lars Dyrskjot
- Aarhus University Hospital, Department of Clinical Biochemistry, Skejby, Denmark
| | - Torben F. Orntoft
- Aarhus University Hospital, Department of Clinical Biochemistry, Skejby, Denmark
| | | | - Ellen C. Zwarthoff
- Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
- * E-mail:
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Abstract
The remarkable growth in our knowledge of the biology of cancer is leading to the identification of previously elusive pathways and networks involved in cancer causation. The development of technologies has played a pivotal role in furthering this understanding and appreciation of the complexity of tumorigenesis, and is advancing efforts to fully grasp the biology and exploit the knowledge for improvements in cancer detection, prevention, and therapy. The future of molecular screening, i.e. detection of risk or cancer via molecular determinants, has never been so close to a reality. Molecular assays employed in cancer detection and therapy are likely to revolutionize cancer treatment through individual-based diagnosis and treatment, i.e. personalized medicine. A number of detection techniques, such as the detection of aberrant DNA and RNA, the presence of auto-antibodies in serum or plasma, and protein profiling, are already in limited use for patient stratification for clinical trials and for predicting drug response.
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Affiliation(s)
- Sudhir Srivastava
- Cancer Biomarkers Research Group, National Cancer Institute, Rockville, Maryland 20852, USA.
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Microsatellite instability analysis in uterine cavity washings as a screening tool for endometrial cancer in Lynch syndrome. Fam Cancer 2012; 10:655-7. [PMID: 21822721 DOI: 10.1007/s10689-011-9470-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Although patients with Lynch syndrome (LS) are at high risk of endometrial cancer, gynecologic screening has been poorly investigated and diagnostic value of current screening tests remains unclear. Microsatellite instability (MSI) phenotype is found in more than 90% of endometrial cancers developed in LS patients. Here we report the first two cases of unstable endometrial tumors with detection of MSI in uterine cavity washings cells. This new technique may be a promising screening tool in LS.
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Iyer G, Milowsky MI. Fibroblast growth factor receptor-3 in urothelial tumorigenesis. Urol Oncol 2012; 31:303-11. [PMID: 22285006 DOI: 10.1016/j.urolonc.2011.12.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Revised: 12/02/2011] [Accepted: 12/03/2011] [Indexed: 12/18/2022]
Abstract
Fibroblast growth factor receptor-3 (FGFR3) is a receptor tyrosine kinase implicated in the tumorigenesis of multiple malignancies, including bladder and other urothelial cancers, multiple myeloma, and cervical cancer. In urothelial carcinoma (UC), constitutive receptor activation occurs most commonly through substitution of a wild-type residue with cysteine in the extracellular domain of FGFR3, thereby resulting in dimerization (through disulfide bridge formation) and subsequent stimulation of tyrosine kinase activity. Activating mutations of FGFR3 have been observed in up to 70% of non-muscle-invasive bladder tumors, while overexpression of a wild-type receptor, found in approximately 40% of tumors, has been correlated with more invasive disease. The identification of FGFR3 mutations in UC has sparked substantial interest in the therapeutic exploitation of these aberrations, and in vitro studies have provided evidence that such alterations may represent driver oncogenic lesions. In this review, we discuss the biologic and prognostic impact of FGFR3 mutations in UC as well as FGFR3 as a potential target for novel therapeutics.
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Affiliation(s)
- Gopa Iyer
- Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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Roobol MJ, Bangma CH, el Bouazzaoui S, Franken-Raab CG, Zwarthoff EC. Feasibility study of screening for bladder cancer with urinary molecular markers (the BLU-P project). Urol Oncol 2011; 28:686-90. [PMID: 21062653 DOI: 10.1016/j.urolonc.2009.12.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2009] [Revised: 11/26/2009] [Accepted: 12/01/2009] [Indexed: 11/15/2022]
Abstract
INTRODUCTION The prognosis of bladder cancer (BC) depends mainly on its histology, grade, and stage. Patients with superficial BC (70% of the urothelial carcinomas) have a relatively good prognosis, but patients diagnosed with invasive, high grade BC, and those who progress to invasive BC, have a poor prognosis and will not survive their disease in many cases due to their metastases, despite the currently available treatment options. Early detection can only be beneficial regarding mortality if the high risk cancers are recognized and treated at a localized stage. MATERIALS AND METHODS Previous pilot studies on early detection consisted of home-based repeated hematuria testing and, in case of hematuria, a urologic evaluation with cytology and cystoscopy was carried out. This design resulted in too many cystoscopies. The recently initiated [Bladder Cancer Urine Marker Project (BLU-P) study www.blu-project.org] assesses the feasibility of a population-based screening for BC and at the same time evaluates a screening algorithm using next to hematuria testing, sensitive specific urine markers for BC (NMP22, FGFR3, MA analyses and MLPa) in an attempt to circumvent the high number of cystoscopies. RESULTS So far 1,611 men are included and 23.5% tested positive for hematuria (11.6% had one or more true positive test results). The additional molecular-based screening tests before referring to cystoscopy resulted in a decrease of the number of cystoscopies from 378 to 66 (82.5%). In those men referred for cystoscopy, so far only 1 BC case was detected. CONCLUSIONS Further research is needed to evaluate whether this extremely low detection rate is caused by, e.g., a healthy screenee bias or that the additional selection step using the molecular urine tests is too strict and diagnoses are missed.
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Affiliation(s)
- M J Roobol
- Erasmus Medical Centre, Department of Urology and Pathology, Rotterdam, The Netherlands.
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29
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Larré S, Camparo P, Comperat E, Gil Diez De Medina S, Traxer O, Roupret M, Sebe P, Cancel-Tassin G, Sighar K, Lozach F, Cussenot O. Diagnostic, staging, and grading of urothelial carcinomas from urine: performance of BCA-1, a mini-array comparative genomic hybridisation-based test. Eur Urol 2010; 59:250-7. [PMID: 21056532 DOI: 10.1016/j.eururo.2010.10.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2010] [Accepted: 10/06/2010] [Indexed: 12/29/2022]
Abstract
BACKGROUND Cytogenetic abnormalities occur at an early stage of bladder urothelial carcinomas (BUC), and their frequency increases as the cancer becomes more advanced. OBJECTIVE To assess the diagnostic performance of a test based on cytogenetic abnormalities to diagnose, stage, and grade BUC from the urine. DESIGN, SETTING, AND PARTICIPANTS We used a 341 bacterial artificial chromosome (BAC) comparative genomic hybridisation (CGH)-array chip (BCA-1) designed to include loci affected in BUC. The chip was first used on 32 frozen BUC biopsies to design staging (BN0) and grading (BN1 and BN2) prediction models based on Bayesian networks analysis. The models were then validated on external data obtained from 98 tumour samples using a 2464 BAC CGH-array chip. The performance of the test was finally assessed on 44 urine pellets collected, including 22 patients who had BUC and 22 controls. MEASUREMENTS We measured sensitivity and specificity to diagnose BUC stage and grade from urine pellets. RESULTS AND LIMITATIONS In the urine, BCA-1 test sensitivity was 95%, specificity was 86%, and accuracy was 91%. The BN0 staging model identified T1-4 tumours in the urine with a sensitivity of 90%, a specificity of 83%, and an accuracy of 87%. The BN1 and BN2 grading models detected high-grade disease with a sensitivity, specificity, and accuracy of 86%, 88%, and 87%, respectively, using BN1 and 100%, 63%, and 82%, respectively, using BN2. BN models performed with similar sensitivity but reduced specificity using the external data. BCA-1 failed to produce results for eight additional samples (failure rate: 9%). The test needed high quantities and quality of DNA, and external validation in larger, prospective, and better-designed studies is necessary to confirm feasibility and performance. CONCLUSIONS The BCA-1 mini-CGH-array chip detected BUC in urine with a high diagnostic performance. It could also accurately discriminate low-grade from high-grade tumours and, to a lesser extent, lamina propria-invasive tumours from pTa tumours.
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Affiliation(s)
- Stéphane Larré
- Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom.
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Lintula S, Hotakainen K. Developing biomarkers for improved diagnosis and treatment outcome monitoring of bladder cancer. Expert Opin Biol Ther 2010; 10:1169-80. [PMID: 20446896 DOI: 10.1517/14712598.2010.489546] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
IMPORTANCE OF THE FIELD A non-invasive marker for the follow-up and diagnosis of bladder cancer is highly needed. Several markers have been studied with regard to sensitivity and specificity in detecting bladder cancer. Comparison of studies is complicated by limited data on tumor characteristics and treatment details. Many studies do not differentiate between primary and recurrent tumors, nor is the performance of the studied marker assessed separately in superficial and invasive or high- versus low-grade tumors. AREAS COVERED IN THIS REVIEW The field of bladder cancer biomarker research from the past 15 years. WHAT THE READER GAIN: A summary of the current field of bladder biomarker research with concluding remarks on some specific challenges in developing biomarkers for improved diagnosis and monitoring the disease. TAKE HOME MESSAGE In general, the best new markers give higher sensitivity than urinary cytology, but specificity is usually lower. By using new markers, the intervals between follow-up cystoscopies can be increased and the detection of relapse can be improved. But to date no non-invasive biomarker has proven to be sensitive and specific enough available to replace cystoscopy, neither in the diagnosis nor in the follow-up of bladder cancer. However, new marker combinations and algorithms for risk assessment hold promise for the future.
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Affiliation(s)
- Susanna Lintula
- University of Helsinki, Department of Clinical Chemistry, Helsinki, Finland.
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31
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Abstract
A common belief is that the earlier that cancer is detected, the better the chance exists for reduced mortality and morbidity. The advent of new and emerging molecular, genetic, and imaging technologies has broadened the possible strategies for early detection and prevention, but a beneficial impact on mortality needs to be supported by clinical evidence. Molecular markers are being identified that are enhancing our ability to predict and detect cancer before it develops and at the earliest signs of impending carcinogenic transformation. Of the innumerable molecular markers in development, a standalone early detection marker with acceptable sensitivity and specificity is available for bladder cancer, although for most cancer sites there are promising avenues of research that will likely produce results in the next decade. The perfect molecular marker would be one that is inherently related to the disease, specifically to the processes of malignant tumorigenesis or to the defense mechanisms of the individual. For example, mutations associated with increased cancer risk often produce gene products that interfere with tumor-suppressor pathways (eg, DNA repair or cell-cycle control) or support oncogenic pathways (eg, through genetic instability or silencing the apoptotic pathway). Finding molecular markers associated with these processes, and where in the process they produce their actions, can lead to interventions based on maintaining support for the normal process and interrupting the action of the products of the mutation. The search for molecular markers for cancer prevention and early detection presents a formidable challenge that requires a systematic and scientifically sound validation process. The search encompasses a broad range of scientific disciplines, including biochemistry, genetics, histology, immunology, informatic technologies, and epidemiology; strategies to identify and understand molecular markers are approached with multidisciplinary teams focused on understanding the mechanistic basis of cancer and the processes and pathways that underlie carcinogenesis.
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Affiliation(s)
- Barbara K Dunn
- National Cancer Institute, Division of Cancer Prevention, Bethesda, MD 20892-7340, USA.
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Pandith AA, Shah ZA, Siddiqi MA. Oncogenic role of fibroblast growth factor receptor 3 in tumorigenesis of urinary bladder cancer. Urol Oncol 2010; 31:398-406. [PMID: 20822928 DOI: 10.1016/j.urolonc.2010.07.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2010] [Revised: 07/19/2010] [Accepted: 07/20/2010] [Indexed: 12/18/2022]
Abstract
Bladder cancer is the second most common genitourinary tumor and constitutes a very heterogeneous disease. Molecular and pathologic studies suggest that low-grade noninvasive and high-grade invasive urothelial cell carcinoma (UCC) arise via distinct pathways. Low-grade noninvasive UCC represent the majority of tumors at presentation. A high proportion of patients with low-grade UCC develop recurrences but usually with no progression to invasive disease. At presentation, a majority of the bladder tumors (70%-80%) are low-grade noninvasive (pTa). Several genetic changes may occur in bladder cancer, but activating mutations in the fibroblast growth factor receptor 3 (FGFR3) genes are the most common and most specific genetic abnormality in bladder cancer. Interestingly, these mutations are associated with bladder tumors of low stage and grade, which makes the FGFR3 mutation the first marker that can be used for diagnosis of noninvasive bladder tumors. Since the first report of FGFR3 involvement in bladder tumors, numerous studies have been conducted to understand its function and thereby confirm the oncogenic role of this receptor particularly in noninvasive groups. Efforts are on to exploit this receptor as a therapeutic target, which holds much promise in the treatment of bladder cancer, particularly low-grade noninvasive tumors. Further studies need to explore the potential use of FGFR3 mutations in bladder cancer diagnosis, prognosis, and in surveillance of patients with bladder cancer. This review focuses on the role of FGFR3 in bladder tumors in the backdrop of various studies published.
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Affiliation(s)
- Arshad A Pandith
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India
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33
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Charakterisierung von DNA-Methylierungs-Biomarkern für das Harnblasenkarzinom. DER PATHOLOGE 2010; 31 Suppl 2:244-50. [DOI: 10.1007/s00292-010-1367-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Moncada V, Srivastava S. Biomarkers in oncology research and treatment: early detection research network: a collaborative approach. Biomark Med 2010; 2:181-95. [PMID: 20477439 DOI: 10.2217/17520363.2.2.181] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Several important criteria are essential for the development of biomarkers in clinical oncology. First, the biomarkers should be easily measured using standardized and cost-efficient methods. Second, biomarkers should be easily attainable from clinical materials such as body fluids and cells. Third, biomarkers should have clearly defined cutoff values with high sensitivity and specificity. Lastly, the predictive value of biomarkers should be possible in strata as large as possible. Single biomarkers may not be able to meet all of these criteria, which necessitates the development of biomarker panels. High-throughput technologies will be necessary for measuring these biomarker sets and translation of these methods into a clinical setting will be necessary in order to employ these biomarkers in a healthcare setting. One of the most important aspects of biomarker development will be standardization and statistical evaluation of biomarker studies. Guidelines for biomarker studies need to be developed that will enable standardization to take place. The Early Detection Research Network has been in the forefront of this objective. Early detection of cancer through appropriately validated biomarkers will provide for decreased morbidity and mortality and allow for the development of new therapeutic tools targeted specifically toward eradication of these early malignancies, hopefully increasing the survival rate of patients diagnosed with early-stage cancer.
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Affiliation(s)
- Victoria Moncada
- Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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35
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Sturgeon CM, Duffy MJ, Hofmann BR, Lamerz R, Fritsche HA, Gaarenstroom K, Bonfrer J, Ecke TH, Grossman HB, Hayes P, Hoffmann RT, Lerner SP, Löhe F, Louhimo J, Sawczuk I, Taketa K, Diamandis EP. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in liver, bladder, cervical, and gastric cancers. Clin Chem 2010; 56:e1-48. [PMID: 20207771 DOI: 10.1373/clinchem.2009.133124] [Citation(s) in RCA: 139] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Updated National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for the use of tumor markers in the clinic have been developed. METHODS Published reports relevant to use of tumor markers for 4 cancer sites--liver, bladder, cervical, and gastric--were critically reviewed. RESULTS Alpha-fetoprotein (AFP) may be used in conjunction with abdominal ultrasound for early detection of hepatocellular carcinoma (HCC) in patients with chronic hepatitis or cirrhosis associated with hepatitis B or C virus infection. AFP concentrations >200 microg/L in cirrhotic patients with typical hypervascular lesions >2 cm in size are consistent with HCC. After a diagnosis of HCC, posttreatment monitoring with AFP is recommended as an adjunct to imaging, especially in the absence of measurable disease. Although several urine markers have been proposed for bladder cancer, none at present can replace routine cystoscopy and cytology in the management of patients with this malignancy. Some may, however, be used as complementary adjuncts to direct more effective use of clinical procedures. Although carcinoembryonic antigen and CA 19-9 have been proposed for use gastric cancer and squamous cell carcinoma antigen for use in cervical cancer, none of these markers can currently be recommended for routine clinical use. CONCLUSIONS Implementation of these recommendations should encourage optimal use of tumor markers for patients with liver, bladder, cervical, or gastric cancers.
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Affiliation(s)
- Catharine M Sturgeon
- Department of Clinical Biochemistry, Royal Infirmary of Edinburgh, Edinburgh, UK.
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Quantitative loss of heterozygosity analysis for urothelial carcinoma detection and prognosis. Urology 2010; 76:515.e1-7. [PMID: 20206968 DOI: 10.1016/j.urology.2009.11.046] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2009] [Revised: 10/14/2009] [Accepted: 11/14/2009] [Indexed: 11/21/2022]
Abstract
OBJECTIVES To evaluate loss of heterozygosity (LOH) using microsatellite polymorphism analysis as a diagnostic and prognostic marker at the time of transurethral resection and as a follow-up marker preceding cystoscopic evidence of recurrence compared with cytology. METHODS A total of 127 urothelial carcinoma (UC) patients were included. Tumors were staged and graded according to the International Union Against Cancer-tumor, node, metastases system and to the 2004 World Health Organization classification. LOH urinalysis was performed using 8 markers and marker-specific LOH thresholds. Thirty control samples, obtained from healthy volunteers, were used to determine the positive cut-off for each marker. RESULTS LOH was significantly more sensitive than cytology in low-grade (64.8% vs 38.5%, P <.001) and low-stage UC (68.6% vs 45.5%, P <.001). The cumulative sensitivity of cytology and LOH reached 74.7% (P <.001) for low-grade and 80.2% (P <.001) for low-stage tumors. Both urinary LOH at TP53 and chromosome 9p markers were associated with an increased risk of recurrence (relative risk = 1.73 [1.30-2.31], P = .0002) and occurred more frequently in the initial urine samples of patients who later relapsed from primary tumors (36.4% vs 0.0%, P <.05 and 57.6% vs 15.8%, P = .0001). Among 32 relapse patients, LOH was positive alongside cystoscopy in 25 of 32 cases and tested positive before cystoscopy detected recurrence in a further 5 of 25 cases. CONCLUSIONS UC diagnosis and monitoring would greatly benefit from supplementing conventional cytology with LOH urinalysis, using a panel of 8 microsatellite markers with specific threshold levels. Given the limitations of both cystoscopy and cytology, novel molecular markers are needed for detection and follow-up of UC.
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van der Aa MN, Steyerberg EW, Bangma C, van Rhijn BW, Zwarthoff EC, van der Kwast TH. Cystoscopy Revisited as the Gold Standard for Detecting Bladder Cancer Recurrence: Diagnostic Review Bias in the Randomized, Prospective CEFUB Trial. J Urol 2010; 183:76-80. [DOI: 10.1016/j.juro.2009.08.150] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2009] [Indexed: 11/15/2022]
Affiliation(s)
- Madelon N.M. van der Aa
- Department of Pathology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Urology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Ewout W. Steyerberg
- Department of Public Health, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Chris Bangma
- Department of Urology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Bas W.G. van Rhijn
- Department of Urology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Ellen C. Zwarthoff
- Department of Pathology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Theo H. van der Kwast
- Department of Pathology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Pathology, University Health Network, Toronto, Ontario, Canada
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38
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Miyake M, Sugano K, Sugino H, Imai K, Matsumoto E, Maeda K, Fukuzono S, Ichikawa H, Kawashima K, Hirabayashi K, Kodama T, Fujimoto H, Kakizoe T, Kanai Y, Fujimoto K, Hirao Y. Fibroblast growth factor receptor 3 mutation in voided urine is a useful diagnostic marker and significant indicator of tumor recurrence in non-muscle invasive bladder cancer. Cancer Sci 2010; 101:250-8. [PMID: 19843069 PMCID: PMC11159328 DOI: 10.1111/j.1349-7006.2009.01334.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
The fibroblast growth factor receptor (FGFR)-3 gene encodes a receptor tyrosine kinase that is frequently mutated in non-muscle invasive bladder cancer (NMIBC). A sensitive and quantitative assay using peptide nucleic acid-mediated real-time PCR was developed for detecting FGFR3 mutations in the urine samples and evaluated as a molecular marker for detecting intravesical recurrence of NMIBC in patients undergoing transurethral resection of bladder tumor. FGFR3 mutation was examined in tumor tissues and serially taken pre- and postoperative urine sediments in 45 NMIBC patients with a median follow up of 32 months. FGFR3 mutations were detected in 53.3% (24/45) of primary tumor tissues, among which intravesical recurrence developed in 37.5% (9/24) of cases. FGFR3 mutation in the primary tumor was not a significant prognostic indicator for recurrence, while the proportion of FGFR3 mutation (i.e. tumor cellularity was >or=11%) in the preoperative urine sediments was a significant indicator for recurrence in patients with FGFR3 mutations in the primary tumors. FGFR3 mutations were detected in 78% (7/9) of postoperative urine samples from recurrent cases with FGFR3 mutations in the tumor, while no mutations were detected in the urine of 15 non-recurrent cases. Urine cytology was negative in all cases with FGFR3 mutations in the primary tumors, while the sensitivity of cytological examination was as high as 56% (5/9) in cases showing wild-type FGFR3 in the primary tumors. Urine FGFR3 mutation assay and cytological examination may be available in the future as complementary diagnostic modalities in postoperative management of NMIBC.
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Affiliation(s)
- Makito Miyake
- Oncogene Research Unit/Cancer Prevention Unit, Tochigi Cancer Center Research Institute, 4-9-13 Yonan, Utsunomiya, Japan
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Van Tilborg AAG, Bangma CH, Zwarthoff EC. Bladder cancer biomarkers and their role in surveillance and screening. Int J Urol 2009; 16:23-30. [PMID: 19120523 DOI: 10.1111/j.1442-2042.2008.02174.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Early detection of bladder cancer and its recurrences is essential for improved prognosis and long-term survival. The detection and follow-up of these patients is currently based on cystoscopy, which is expensive and invasive, and, in most cases, cytology, which is non-invasive but not very sensitive. During recent years, many urine-based tests have been developed and tested in different patient populations. In this review we discuss new developments for biomarkers in bladder cancer that have potential use in surveillance and screening. In almost all publications authors compare sensitivity of the test with a concomitantly executed cystoscopy, for example, determine cross-sectional sensitivity. However, it has also been shown that false positive test results may be followed by a positive cystoscopy in the near future, showing that cystoscopy itself does not provide 100% sensitivity. This suggests that for a proper evaluation of urine-based tests, longitudinal studies should be carried out and the results communicated to the urologist.
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Affiliation(s)
- Angela A G Van Tilborg
- Department of Pathology, Josephine Nefkens Institute, Erasmus MC, CA, Rotterdam, The Netherlands
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40
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Lin HH, Ke HL, Huang SP, Wu WJ, Chen YK, Chang LL. Increase sensitivity in detecting superficial, low grade bladder cancer by combination analysis of hypermethylation of E-cadherin, p16, p14, RASSF1A genes in urine. Urol Oncol 2009; 28:597-602. [PMID: 19181545 DOI: 10.1016/j.urolonc.2008.12.008] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2008] [Revised: 11/29/2008] [Accepted: 12/02/2008] [Indexed: 10/21/2022]
Abstract
OBJECTIVES To identify a better set of DNA methylation markers to detect superficial, low grade cancer cell in urine sediment for improving cancer treatment, morbidity, and mortality. MATERIALS AND METHODS Methylation-specific PCR (MSP) assay was used to detect promoter hypermethylation in 4 genes (E-cadherin, p16, p14, and RASSF1A) to identify reliable biomarkers for bladder cancer diagnosis in primary tumor DNA and urine sediment DNA from 57 bladder cancer patients. Urine DNA was compared with 20 healthy controls. RESULTS Fifty-one (90%) tumor DNA and 47 urine DNA (83%) samples from bladder cancer patients revealed hypermethylation in at least 1 of the 4 analyzed genes, whereas all urine samples from normal controls were negative. The sensitivity of MSP assay for detecting E-cadherin, p16, p14 and RASSF1A in tumor cells in voided urine was 35%, 35%, 33%, and 65%, respectively. Diagnostic sensitivity was 75% for combining RASSF1A and p14, and 83% for RASSF1A, p14 and E-cadherin. Urine cytology, however, detect only 13 (28%) cases of cancer or suspicious cancer. For detecting superficial and invasive bladder tumor, urine cytology revealed a sensitivity of 23% (6/26) and 35% (7/20), respectively. In contrast, MSP detected hypermethylation in the urine of 80% (37/46) bladder cancer patients. Moreover, hypermethylation analysis of E-cadherin, p14 or RASSF1A genes in urine sediment DNA detected in 85% (22/26) of superficial, 85% (11/13) of low grade, 75% (15/20) of invasive and 79% (26/33) of high grade bladder cancers. Importantly, hypermethylation was detected in the urine DNA of 90% (18/20) superficial tumors with negative or atypia cytology. CONCLUSIONS Hypermethylation of E-cadherin, p14 or RASSF1A in urine sediment DNA is a potential biomarker for detecting superficial, low grade cancer. Besides, hypermethylation of these 3 genes is a valuable adjunct diagnostic marker to urine cytology, which can enhance the diagnostic accuracy and follow-up treatment of bladder cancer patients.
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Affiliation(s)
- Hui-Hui Lin
- Department of Microbiology, Kaohsiung Medical University, Kaohsiung, Taiwan
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Shirodkar SP, Lokeshwar VB. Bladder tumor markers: from hematuria to molecular diagnostics--where do we stand? Expert Rev Anticancer Ther 2008; 8:1111-23. [PMID: 18588456 DOI: 10.1586/14737140.8.7.1111] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Bladder cancer is a common malignancy in the USA. Currently, the detection of initial tumors and recurrent disease is based on evaluation of voided urinary specimens, often followed by cystoscopy. With the high rate of recurrence, cystoscopies are regularly repeated with the aim of halting progression of the disease. For patients, this process is fraught with anxiety, pain and high cost. As a result, intense work is being done in the field of bladder tumor markers with the goal of identifying bladder cancer earlier, both in the initial diagnosis and in recurrences of known tumor. The possibility of identifying a marker that could noninvasively differentiate benign and malignant causes of hematuria, and identify recurrences prior to their pathologic progression is the objective of this area of research. Currently, a large number of tumor markers exist, each scrutinized in both the laboratory and in clinical trials. Here we present many of the most widely used and tested markers. Background details are provided as to the mechanism of detection of malignant cells, the results of recent trials and future directions of study. Some novel modalities for tumor detection are also presented. The next few years will no doubt bring newer markers and lead to the elimination of others. Studies continue to refine the role of these markers in clinical practice, but their ultimate efficacy will need to be borne out in large-scale clinical trials in a multitude of settings.
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Affiliation(s)
- Samir P Shirodkar
- Department of Urology (M-800), Miller School of Medicine University of Miami, P.O. Box 016960, Miami, Florida 33101, USA.
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van der Aa MNM, Zwarthoff EC, Steyerberg EW, Boogaard MW, Nijsen Y, van der Keur KA, van Exsel AJA, Kirkels WJ, Bangma C, van der Kwast TH. Microsatellite analysis of voided-urine samples for surveillance of low-grade non-muscle-invasive urothelial carcinoma: feasibility and clinical utility in a prospective multicenter study (Cost-Effectiveness of Follow-Up of Urinary Bladder Cancer trial [CEFUB]). Eur Urol 2008; 55:659-67. [PMID: 18501499 DOI: 10.1016/j.eururo.2008.05.001] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2008] [Accepted: 05/05/2008] [Indexed: 11/27/2022]
Abstract
BACKGROUND Microsatellite analysis (MA) of voided-urine samples has been promoted as an alternative for cystoscopy surveillance (UCS) of patients with low-grade non-muscle-invasive papillary urothelial carcinoma (UC). OBJECTIVE To assess the feasibility and clinical utility of MA on voided-urine samples in a routine setting to detect or predict bladder cancer recurrences. DESIGN, SETTING, AND PARTICIPANTS We evaluated 228 patients monitored by MA of voided-urine samples and synchronous UCS who participated in a longitudinal prospective study in 10 hospitals. Follow-up started after diagnosis of a primary or recurrent pTa, pT1, grade 1 or grade 2 papillary UC. MEASUREMENTS Clinico-pathological parameters and fibroblast growth factor receptor 3 (FGFR3) gene mutation status of the inclusion tumour were determined. MA outcome was analysed in 1012 urine samples during a mean follow-up of 41 mo. Poor DNA quality prevented MA in 19% (197/1012) of the samples, leaving 815 visits for a cross-sectional analysis of sensitivity and specificity. We determined the predictive value (PPV) in a longitudinal analysis for 458 series with persistent MA results. Factors influencing diagnostic quality of MA were investigated. Kaplan-Meier analysis was performed to relate MA results to recurrence. RESULTS AND LIMITATIONS Cross-sectional sensitivity and specificity of MA for detection of a recurrence were 58% (49/84) and 73% (531/731), respectively. One pT1 grade 3 UC was missed. In a longitudinal analysis, the 2-yr risk to develop a recurrence reached 83% if MA outcome was persistently positive and 22% when MA was persistently negative. PPV of MA was higher with wild-type FGFR3 gene status and smoking habits. All four upper urinary tract tumours detected were preceded by a positive MA test. CONCLUSIONS Consecutive positive MA results are a strong predictor for future recurrences, but sensitivity needs to be improved, for example, by patient selection and testing of additional genetic markers in urine samples.
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Lam T, Nabi G. Potential of urinary biomarkers in early bladder cancer diagnosis. Expert Rev Anticancer Ther 2008; 7:1105-15. [PMID: 18028019 DOI: 10.1586/14737140.7.8.1105] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Carcinoma of urinary bladder ranks among the top ten most common cancers worldwide. Approximately 80% of the disease is superficial (limited to mucosa and lamina propria) at the time of presentation. However, the majority of these tumors recur and 15-20% progress into muscle-invasive disease. Cystoscopic surveillance of the urinary bladder remains the standard of care to identify these recurrences on follow-up. Not only is this an invasive procedure, but the sensitivity of cystoscopy can be as low as 70%, so there can be up to 30% of tumors that are missed. Urinary cytology, with recognized limitations, has been used as an adjunct to this procedure, pending discovery of alternate urinary biomarkers. In the past decade there has been tremendous advancement in producing urinary biomarkers for urinary bladder cancer research, reflecting advancements in genomics and proteomics. An ideal biomarker should be able to replace cystoscopic examination and be cost effective. Unfortunately, most of the identified protein or molecular biomarkers have failed this test. This article critically appraises the status of these urinary biomarkers in urinary bladder cancer, in addition to highlighting some of the difficulties in this research area.
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Affiliation(s)
- Thomas Lam
- University of Aberdeen, Academic Urology Unit, First floor, Health Sciences Building, Aberdeen AB25 2ZD, UK.
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44
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Considerations on the use of diagnostic markers in management of patients with bladder cancer. World J Urol 2007; 26:39-44. [DOI: 10.1007/s00345-007-0232-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2007] [Accepted: 11/29/2007] [Indexed: 12/22/2022] Open
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Detection of bladder cancer from the urine using fluorescence in situ hybridization technique. Pathol Oncol Res 2007; 13:187-94. [PMID: 17922047 DOI: 10.1007/bf02893498] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2007] [Accepted: 09/05/2007] [Indexed: 10/21/2022]
Abstract
The authors report on their first experiences with the UroVysion fluorescence in situ hybridization (FISH) kit developed for the detection of bladder cancer. This new non-invasive diagnostic application of the FISH technique in the field of urology was elaborated to replace cystoscopy. The special urine examination method detects genetic alterations of the urothelial cells found in the urine, using fluorescent directlabeled DNA probes binding to the peri-centromeric regions of chromosomes 3, 7 and 17 as well as on the 9p21 locus. We aimed to evaluate the utility of UroVysion test in the light of the histological diagnosis. Urine samples from 43 bladder cancer patients and 12 patients with no or benign alterations were studied using a new application of FISH technique: the UroVysion reagent kit. The obtained FISH results were compared with the histological findings of the transurethral surgical resection specimens. The study rated the specificity and sensitivity of the technique 100% and 87%, respectively. Therefore, the technique could well fit into the diagnostic process of bladder carcinomas. Statistical analyses showed significant correlation between tumor progression and the severity of the genetic alterations detected by this FISH technique. Furthermore, positive correlation was found between tumor grade and the proportion of tumor cells showing genetic abnormality. The noninvasiveness, the robustness of evaluation and the high specificity/sensitivity are all in favor of this technique. The disadvantages are the higher costs of the technical background and the required future clinical studies to determine whether this technique can replace cystoscopy.
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Knowles MA. Role of FGFR3 in urothelial cell carcinoma: biomarker and potential therapeutic target. World J Urol 2007; 25:581-93. [PMID: 17912529 PMCID: PMC4876910 DOI: 10.1007/s00345-007-0213-4] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2007] [Accepted: 08/27/2007] [Indexed: 10/22/2022] Open
Abstract
Although non-invasive bladder tumours (pTa) are the most common group of bladder tumours at presentation, there has until recently been relatively little information on their molecular biology. Thus it was of great interest when mutations in the FGF receptor 3 (FGFR3) were identified in bladder tumours and it became apparent that these were most common in tumours of low grade and stage. Since the initial description of activating mutations of FGFR3, there have been numerous studies confirming the frequency and spectrum of these mutations in bladder cancers of all grades and stages. Mutation screening techniques have evolved and improved. FGFR3 mutation has been assessed as a predictive biomarker in tumour tissues and as a diagnostic biomarker in urine. Efforts have been made to understand the function of FGFR3 in urothelial and other cells. Although our understanding of FGFR3 function is incomplete, it is already apparent that this may represent an important therapeutic target not only in non-invasive bladder cancer but also in a significant number of invasive tumours. This review summarises the current state of knowledge of this interesting receptor in urothelial carcinoma (UC).
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Affiliation(s)
- Margaret A Knowles
- Cancer Research UK Clinical Centre, Section of Oncology, Leeds Institute of Molecular Medicine, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.
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Frigerio S, Padberg BC, Strebel RT, Lenggenhager DM, Messthaler A, Abdou MT, Moch H, Zimmermann DR. Improved detection of bladder carcinoma cells in voided urine by standardized microsatellite analysis. Int J Cancer 2007; 121:329-38. [PMID: 17373664 DOI: 10.1002/ijc.22690] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Successful treatment of bladder cancer depends largely on early diagnosis of primary and recurrent disease. Sensitive, specific and noninvasive procedures for detection are especially needed for grade 1 and 2 bladder tumors, because of the relatively low sensitivity of cytology. Here we introduce a novel strategy to improve the sensitivity and reliability of microsatellite analyses by employing marker-specific threshold values for loss-of-heterozygosity (LOH) at 10 loci. These individual cut-offs were experimentally determined with 35 normal control tissues and subsequently validated in a retrospective study with bladder cancer biopsies from 86 patients. In a prospective analysis of voided urines samples and matched blood probes from 91 patients, LOH-analysis, UroVysion FISH and conventional urine cytology were compared with histological findings of consecutive transurethral biopsies. Whereas all samples could be analyzed by our LOH assay, only 56 samples were suitable for all 3 analyses. The highest sensitivity was obtained with our LOH-assay/cytology approach (G1-2: 72%; G3: 96%) being only surpassed by a combination of all 3 techniques (G1-2: 83%; G3: 100%). Since over 93% of the patients with recurrent disease were identified by LOH/cytology-analyses of their voided urine samples, a monitoring scheme alternating cystoscopy with LOH/cytology-examination could now be envisioned to reduce invasive interventions and consequently improve follow-up compliance, especially in patients with low grade tumors.
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Affiliation(s)
- Simona Frigerio
- Institute of Surgical Pathology, University Hospital, Zurich, Switzerland
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Black PC, Brown GA, Dinney CP. Molecular Markers of Urothelial Cancer and Their Use in the Monitoring of Superficial Urothelial Cancer. J Clin Oncol 2006; 24:5528-35. [PMID: 17158538 DOI: 10.1200/jco.2006.08.0895] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Multiple molecular markers have been described for use in bladder cancer patients. Some of these have been studied more extensively than others, and it is difficult for the clinician to maintain a perspective over the myriad findings that have been made. We have reviewed a selection of markers used for surveillance with an emphasis on clinical utility. The best studied markers and those with the most promising preliminary results were selected. Only studies that included surveillance for recurrence in patients with a history of bladder cancer were considered. Each marker is briefly described and its performance in monitoring bladder cancer patients is summarized. Several promising markers are available, although only four have obtained US Food and Drug Administration approval. The clinical applications that have been studied include replacement or reduction in the number of cystoscopies performed in the surveillance of bladder cancer patients, substitution for or complementary use with urinary cytology in the same setting, predicting disease recurrence and progression, and predicting and monitoring treatment response. None of the markers have been proved sensitive and specific enough to replace cystoscopy. Others, such as nuclear matrix protein 22 (NMP22) and UroVysion, appear to have some utility when used to complement or replace cytology. The other applications have not been adequately studied for any given marker. While multiple molecular markers exist for bladder cancer, their full clinical utility will not be realized until more multicenter prospective trials are conducted to verify their efficacy and safety in the monitoring of patients with superficial bladder cancer.
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Affiliation(s)
- Peter C Black
- Department of Urology, the University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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Takata M, Kerman K, Nagatani N, Konaka H, Namiki M, Tamiya E. Label-free bioelectronic immunoassay for the detection of human telomerase reverse transcriptase in urine. J Electroanal Chem (Lausanne) 2006. [DOI: 10.1016/j.jelechem.2006.07.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Nielsen ME, Gonzalgo ML, Schoenberg MP, Getzenberg RH. Toward critical evaluation of the role(s) of molecular biomarkers in the management of bladder cancer. World J Urol 2006; 24:499-508. [PMID: 17102951 DOI: 10.1007/s00345-006-0116-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Abstract
Among genitourinary malignancies, bladder cancer is a common, potentially dangerous and exceedingly costly disease entity. Predicated on substantial gains in our understanding of the natural history and molecular biology of bladder cancer, recent years have seen an explosion of new applied technologies to aid clinicians in the management of bladder cancer. Herein we present a systematic overview of general conceptual issues and specific strategies of potential relevance to the clinical evaluation of patients with bladder cancer. A number of basic epidemiological issues provide the relevant background within which we should consider candidate biomarkers. Within this framework, we highlight a number of important recent research findings representative of the large number of candidate bladder cancer biomarkers that have emerged. With several markers already having obtained regulatory approval for clinical use, this topic is of clear relevance not only to researchers but also to the practicing physician. Bladder cancer is a common, costly, and potentially dangerous disease with the opportunity for significant technological inroads in the area of applied biomarkers. An appreciation of basic epidemiological considerations informs our consideration of the state of the art and identifies specific strategies amenable to further innovation.
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Affiliation(s)
- Matthew E Nielsen
- Department of Urology, Johns Hopkins University School of Medicine, Marburg 143, 600 N Wolfe St., Baltimore, MD 21287-2101, USA.
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