Urinary Bladder Cancer Biomarkers
NCBI: db=pubmed; Term=biomarker[Title/Abstract] AND "Urinary Bladder Neoplasms"[Mesh]
Updated: 2 hours 5 min ago
Comparative and targeted proteomic analyses of urinary microparticles from bladder cancer and hernia patients.
J Proteome Res. 2012 Dec 7;11(12):5611-29
Authors: Chen CL, Lai YF, Tang P, Chien KY, Yu JS, Tsai CH, Chen HW, Wu CC, Chung T, Hsu CW, Chen CD, Chang YS, Chang PL, Chen YT
Bladder cancer is a common urologic cancer whose incidence continues to rise annually. Urinary microparticles are an attractive material for noninvasive bladder cancer biomarker discovery. In this study, we applied isotopic dimethylation labeling coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to discover bladder cancer biomarkers in urinary microparticles isolated from hernia (control) and bladder cancer patients. This approach identified 2964 proteins based on more than two distinct peptides, of which 2058 had not previously been reported as constituents of human urine exosomes/microparticles. A total of 107 differentially expressed proteins were identified as candidate biomarkers. Differences in the concentrations of 29 proteins (41 signature peptides) were precisely quantified by LC-MRM/MS in 48 urine samples of bladder cancer, hernia, and urinary tract infection/hematuria. Concentrations of 24 proteins changed significantly (p<0.05) between bladder cancer (n=28) and hernia (n=12), with area-under-the-curve values ranging from 0.702 to 0.896. Finally, we quantified tumor-associated calcium-signal transducer 2 (TACSTD2) in raw urine specimens (n=221) using a commercial ELISA and confirmed its potential value for diagnosis of bladder cancer. Our study reveals a strong association of TACSTD2 with bladder cancer and highlights the potential of human urinary microparticles in the noninvasive diagnosis of bladder cancer.
PMID: 23082778 [PubMed - in process]
Identification of urinary Gc-globulin as a novel biomarker for bladder cancer by two-dimensional fluorescent differential gel electrophoresis (2D-DIGE).
J Proteomics. 2012 Dec 21;77:225-36
Authors: Li F, Chen DN, He CW, Zhou Y, Olkkonen VM, He N, Chen W, Wan P, Chen SS, Zhu YT, Lan KJ, Tan WL
Improving the early detection rate and surveillance of bladder cancer remains a great challenge in medicine. Here, we identified sixteen proteins including Gc-globulin (GC) in urine from bladder cancer patients and normal controls by two-dimensional fluorescent differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF/TOF MS). Bioinformatics analyses indicated GC played important roles in the regulation of growth, apoptosis, death and epidermal growth factor receptor activity. The GC expression patterns in urine or tissue from cases and controls were further quantified by western blotting, immunohistochemical staining and enzyme-linked immunosorbent assay (ELISA). ELISA quantification by correcting for creatinine expression showed GC-Cr was significantly increased in bladder cancer patients than in benign bladder damages cases and normal controls (1013.70±851.25 versus 99.34±55.87, 105.32±47.81 ng/mg, respectively). Receiver operating characteristic (ROC) analysis suggested that at 161.086 ng/mg urinary GC, bladder cancer could be detected with 92.31% sensitivity and 83.02% specificity, and 1407.481 ng/mg with 82.61% sensitivity and 88.24% specificity could be used for the detection of infiltrating urothelial carcinoma of bladder cancer. Taken together, we identified GC as a potential novel urinary biomarker for the early detection and surveillance of bladder cancer.
PMID: 22986152 [PubMed - in process]
Prognostic value of p53 protein overexpression in upper tract urothelial carcinomas in Taiwan.
Anticancer Res. 2013 Mar;33(3):1091-8
Authors: Lee YC, Wu WJ, Li WM, Lin HH, Huang CN, Chai CY, Chang LL, Lin HL, Ke HL
BACKGROUND: p53 plays an important role in maintaining genomic stability and regulating the cell cycle. However, the accumulation of p53 protein has been reported to be involved in the carcinogenesis, progression, and metastasis of many types of human cancer. This study evaluates the clinical significance of p53 expression in upper tract urothelial carcinoma.
PATIENTS AND METHODS: One-hundred and twelve cases of upper tract urothelial carcinoma were included in this study. p53 expression was evaluated by immunohistochemistry and the association of p53 expression with clinicopathological variables was analyzed.
RESULTS: p53 expression was significantly correlated with patients who were undergoing hemodialysis (p=0.005) and had increased serum creatinine levels (p=0.001). High p53 expression was associated with poor progression-free (p=0.025) and cancer-specific survival (p=0.021), Cox regression analysis also revealed that p53 was an independent predictor of poor progression-free (hazard ratio=3.74, p=0.025) and cancer-specific (hazard ratio=5.87, p=0.030) survival.
CONCLUSION: Our findings indicate that p53 expression is a potential biomarker for predicting patient survival. Further study is necessary to investigate the role of p53 in the carcinogenesis of upper tract urothelial carcinoma.
PMID: 23482786 [PubMed - indexed for MEDLINE]
Serum DNA hypermethylation in patients with bladder cancer: results of a prospective multicenter study.
Anticancer Res. 2013 Mar;33(3):779-84
Authors: Hauser S, Kogej M, Fechner G, VON Pezold J, Vorreuther R, Lümmen G, Müller SC, Ellinger J
BACKGROUND: Cell-free serum DNA levels are increased in patients with cancer, and at least partially, these DNA fragments are derived from cancer cells. A few reports indicated that methylated serum DNA in patients with bladder cancer (BCA) is a useful non-invasive biomarker. The purpose of this prospective multicenter study was to validate earlier studies.
MATERIALS AND METHODS: In total, 227 consecutive participants (non-muscle invasive BCA, n=75; muscle-invasive BCA, n=20; transurethral bladder resection (TURB) without BCA, n=48; benign disease, n=31; healthy individuals, n=53), were recruited for this study. Cell-free serum DNA was isolated and digested with methylation-sensitive restriction-enzymes (Bsh1236I, HpaII and HinP1I) to quantify the amount of methylated (TIMP3, APC, RARB, TIG1, GSTP1, p14, p16, PTGS2 and RASSF1A) DNA fragments.
RESULTS: The amount of methylated DNA was usually small (<10%), and the methylation frequencies varied for different genes (e.g. frequent: TIMP3; moderate: APC, RARB, TIG1; infrequent: p16, PTGS2, p14, RASSF1A, GSTP1). Methylation levels at each gene site and the number of methylated genes were increased in BCA compared to healthy individuals, but were similar in BCA and patients with non-malignant disease. The number of methylated genes allowed for discrimination (62% sensitivity, 89% specificity) of BCA patients from healthy individuals. DNA hypermethylation was not correlated with advanced stage or grade in patients with BCA.
CONCLUSION: The detection of hypermethylated DNA in serum allows for discrimination of patients with BCA and healthy individuals, but there is no difference between patients with BCA and those with non-malignant disease, thereby limiting its value as a non-invasive biomarker.
PMID: 23482744 [PubMed - indexed for MEDLINE]
Role of the angiogenic components, VEGFA, FGF2, OPN and RHOC, in urothelial cell carcinoma of the urinary bladder.
Oncol Rep. 2012 Oct;28(4):1159-66
Authors: Zaravinos A, Volanis D, Lambrou GI, Delakas D, Spandidos DA
The objective of this study was to analyze the expression profile of the angiogenic components, vascular endothelial growth factor-A (VEGFA), basic fibroblast growth factor-2 (FGF2), osteopontin (OPN) and ras homolog gene family, member C (RHOC), in urothelial cell carcinoma (UCC) of the urinary bladder and to examine their role as candidate diagnostic biomarkers. Using qPCR, 77 samples of UCC of the urinary bladder and 77 matched tumor-associated normal samples were investigated to determine the expression of the four angiogenic components. The correlation between gene expression, patient survival and pathological features of the tumors was also examined. The VEGFA and OPN transcript levels were greater in the bladder cancer tissue than in the normal urothelium (P<0.001). Patients with higher VEGFA mRNA levels showed a tendency towards shorter cancer-specific survival. OPN levels showed a gradual increase, the lowest levels being found in non-invasive carcinoma and the highest in muscle invasive tumors. Elevated OPN levels indicated poor prognosis in connection with advanced disease stage (P<0.001). Both superficially invasive and muscle invasive tumors had significantly higher FGF2 levels compared to the control tissues (P=0.018 and P=0.050, respectively). Moreover, FGF2 was significantly higher in the metastatic vs. the non-metastatic tumors (P=0.0097). FGF2 levels exhibited a trend towards a correlation with worse patient survival. RHOC mRNA levels were higher in muscle invasive compared to superficially invasive tumors, as well as in grade III vs. grade I/II tumors. Furthermore, we detected worse overall survival for patients with high RHOC expression levels. VEGFA and FGF2 exhibited the best linear combination in the ROC curves for specificity and sensitivity. Thus, VEGFA and FGF2 may serve as candidate biomarkers for diagnostic purposes. Higher OPN expression may be used as a potential biomarker to predict patient survival relative to advanced tumor stage. However, further studies are required to investigate its role in urinary bladder carcinogenesis.
PMID: 22895562 [PubMed - indexed for MEDLINE]
Combination of molecular alterations and smoking intensity predicts bladder cancer outcome: a report from the Los Angeles Cancer Surveillance Program.
Cancer. 2013 Feb 15;119(4):756-65
Authors: Mitra AP, Castelao JE, Hawes D, Tsao-Wei DD, Jiang X, Shi SR, Datar RH, Skinner EC, Stein JP, Groshen S, Yu MC, Ross RK, Skinner DG, Cortessis VK, Cote RJ
BACKGROUND: Traditional single-marker and multimarker molecular profiling approaches in bladder cancer do not account for major risk factors and their influence on clinical outcome. This study examined the prognostic value of molecular alterations across all disease stages after accounting for clinicopathological factors and smoking, the most common risk factor for bladder cancer in the developed world, in a population-based cohort.
METHODS: Primary bladder tumors from 212 cancer registry patients (median follow-up, 13.2 years) were immunohistochemically profiled for Bax, caspase-3, apoptotic protease-activating factor 1 (Apaf-1), Bcl-2, p53, p21, cyclooxygenase-2, vascular endothelial growth factor, and E-cadherin alterations. "Smoking intensity" quantified the impact of duration and daily frequency of smoking.
RESULTS: Age, pathological stage, surgical modality, and adjuvant therapy administration were significantly associated with survival. Increasing smoking intensity was independently associated with worse outcome (P < .001). Apaf-1, E-cadherin, and p53 were prognostic for outcome (P = .005, .014, and .032, respectively); E-cadherin remained prognostic following multivariable analysis (P = .040). Combined alterations in all 9 biomarkers were prognostic by univariable (P < .001) and multivariable (P = .006) analysis. A multivariable model that included all 9 biomarkers and smoking intensity had greater accuracy in predicting prognosis than models composed of standard clinicopathological covariates without or with smoking intensity (P < .001 and P = .018, respectively).
CONCLUSIONS: Apaf-1, E-cadherin, and p53 alterations individually predicted survival in bladder cancer patients. Increasing number of biomarker alterations was significantly associated with worsening survival, although markers comprising the panel were not necessarily prognostic individually. Predictive value of the 9-biomarker panel with smoking intensity was significantly higher than that of routine clinicopathological parameters alone.
PMID: 23319010 [PubMed - indexed for MEDLINE]
Evaluation of reference genes for the analysis of serum miRNA in patients with prostate cancer, bladder cancer and renal cell carcinoma.
Int J Urol. 2012 Nov;19(11):1017-25
Authors: Sanders I, Holdenrieder S, Walgenbach-Brünagel G, von Ruecker A, Kristiansen G, Müller SC, Ellinger J
OBJECTIVES: To identify an appropriate reference gene for the analysis of circulating micro-ribonucleic acid in patients with urological malignancies.
METHODS: Serum from patients with prostate cancer (n = 24), bladder cancer (n = 24), renal cell carcinoma (n = 24) and control subjects (n = 48) was spiked with cel-miR-39, and then ribonucleic acid was isolated. Quantitative real-time polymerase chain reaction was used to determine the levels of candidate reference genes (RNU1-4, RNU6-2, SNORD43, SNORD44, SNORD48, SNORA74A, miR-let-7a-1, miR-106a). Reference gene stability was determined using the NormFinder, geNorm and comparative delta-Ct algorithm. The effect of normalization was tested with miR-21 as the target gene, as this was previously suggested to be upregulated in cancer patients' serum.
RESULTS: Recovery of cel-miR-39 (mean 11.6%, range 1-56%) was similar in control subjects and cancer patients. SNORD44 and SNORD74A levels were around the detection limit of the assay and were thus omitted. All remaining candidates showed satisfying stability; SNORD43 was the most stable reference gene using all three algorithms. A combination of two genes (SNORD43, RNU1-4) increases the stability somewhat. The level of miR-21 was similar in cancer patients and healthy controls, irrespective of the normalization strategy.
CONCLUSIONS: SNORD43 is a suitable reference gene for the analysis of circulating micro-ribonucleic acid in patients with urological malignancies. Our study questions the suitability of miR-21 as a biomarker for uro-oncological patients.
PMID: 22788411 [PubMed - indexed for MEDLINE]
Detecting DNA methylation of the BCL2, CDKN2A and NID2 genes in urine using a nested methylation specific polymerase chain reaction assay to predict bladder cancer.
J Urol. 2012 Dec;188(6):2101-7
Authors: Scher MB, Elbaum MB, Mogilevkin Y, Hilbert DW, Mydlo JH, Sidi AA, Adelson ME, Mordechai E, Trama JP
PURPOSE: Detection of methylated DNA has been shown to be a good biomarker for bladder cancer. Bladder cancer has the highest recurrence rate of any cancer and, as such, patients are regularly monitored using invasive diagnostic techniques. As urine is easily attainable, bladder cancer is an optimal cancer to detect using DNA methylation. DNA methylation is highly specific in cancer detection. However, it is difficult to detect because of the limited amount of DNA present in the urine of patients with bladder cancer. Therefore, an improved, sensitive and noninvasive diagnostic test is needed.
MATERIALS AND METHODS: We developed a highly specific and sensitive nested methylation specific polymerase chain reaction assay to detect the presence of bladder cancer in small volumes of patient urine. The genes assayed for DNA methylation are BCL2, CDKN2A and NID2. The regions surrounding the DNA methylation sites were amplified in a methylation independent first round polymerase chain reaction and the amplification product from the first polymerase chain reaction was used in a real-time methylation specific polymerase chain reaction. Urine samples were collected from patients receiving treatment at Wolfson Medical Center in Holon, Israel.
RESULTS: In a pilot clinical study using patient urine samples we were able to differentiate bladder cancer from other urogenital malignancies and nonmalignant conditions with a sensitivity of 80.9% and a specificity of 86.4%.
CONCLUSIONS: We developed a novel methylation specific polymerase chain reaction assay for the detection and monitoring of bladder cancer using DNA extracted from patient urine. The assay may also be combined with other diagnostic tests to improve accuracy.
PMID: 23083854 [PubMed - indexed for MEDLINE]
Genetic variants in miRNAs predict bladder cancer risk and recurrence.
Cancer Res. 2012 Dec 1;72(23):6173-82
Authors: Wang M, Chu H, Li P, Yuan L, Fu G, Ma L, Shi D, Zhong D, Tong N, Qin C, Yin C, Zhang Z
miRNAs play important roles in numerous cellular processes, including development, proliferation, apoptosis, and carcinogenesis. Because altered expression and function of miRNAs has been observed in bladder cancer, we investigated whether genetic variations in miRNAs are associated with bladder cancer risk and prognosis. Using bioinformatics tools, we selected five single-nucleotide polymorphisms located in miRNAs and used these to evaluate miRNA-disease associations in a two-stage model, consisting of 1,019 bladder cancer cases and 1,182 controls (683 cases and 728 controls in the training set and 336 cases and 454 controls in the test set). We found that miR-146a rs2910164 C allele was associated with significantly decreased risk of bladder cancer in both the training and test sets, as well as the combined set [OR = 0.80, 95% confidence interval (CI) = 0.71-0.90, P = 2.92 × 10(-4)]. Furthermore, the rs2910164 GC/CC genotypes conferred a significantly reduced risk of recurrence, compared with the GG genotype (P = 0.016). Functional analysis revealed that miR-146a rs2910164 C allele inhibited cell proliferation and significantly downregulated expression of IRAK1 and TRAF6 in bladder cancer cells. Additional examination of 64 bladder cancer tissues showed that individuals carrying the C allele had increased expression levels of miR-146a compared with those carrying the G allele (P = 0.010). Taken together, our findings show that miR-146a rs2910164 plays an important role in the risk and recurrence of bladder cancer, suggesting it may represent a biomarker for risk prevention and therapeutic intervention. Further larger and prospective cohorts are needed to validate our findings.
PMID: 22846912 [PubMed - indexed for MEDLINE]
Centrosome amplification in bladder washing cytology specimens is a useful prognostic biomarker for non-muscle invasive bladder cancer.
Cancer Genet. 2013 Jan-Feb;206(1-2):12-8
Authors: Miyachika Y, Yamamoto Y, Matsumoto H, Nishijima J, Kawai Y, Nagao K, Hara T, Sakano S, Matsuyama H
We investigated whether centrosome amplification (CA) obtained from bladder washing cytology (BWC) specimens may be a useful prognostic biomarker for patients with non-muscle invasive bladder cancer (NMIBC). The study cohort included 78 patients with pathologically confirmed NMIBC. BWC specimens were obtained from all patients during transurethral resection of bladder tumor (TURBT), and CA was evaluated by immunofluorescence staining using a pericentrin polyclonal antibody. A positive case of CA was defined as a specimen in which >5% of cells contained ≥3 centrosomes per cell. CA was detected in 26.9% (21 of 78) of BWC specimens obtained from NMIBC patients. Disease progression was observed in 11.5% (9 of 78) of patients, with a median follow-up of 32 months. In univariate analyses, CA obtained from BWC specimens, initial or recurrent, and washing cytology were significantly associated with progression-free survival (P = 0.009, 0.02, and 0.03, respectively). Multivariate Cox model analyses revealed that CA was the most significant prognostic factor for disease progression (hazard ratio: 2.22, 95% confidence interval: 1.13-4.90, P = 0.022). These data suggest that analysis of CA using bladder washing cytological specimens may provide crucial predictive information regarding disease progression in NMIBC.
PMID: 23290748 [PubMed - indexed for MEDLINE]
Bladder cancer diagnosis and identification of clinically significant disease by combined urinary detection of Mcm5 and nuclear matrix protein 22.
PLoS One. 2012;7(7):e40305
Authors: Kelly JD, Dudderidge TJ, Wollenschlaeger A, Okoturo O, Burling K, Tulloch F, Halsall I, Prevost T, Prevost AT, Vasconcelos JC, Robson W, Leung HY, Vasdev N, Pickard RS, Williams GH, Stoeber K
BACKGROUND: Urinary biomarkers for bladder cancer detection are constrained by inadequate sensitivity or specificity. Here we evaluate the diagnostic accuracy of Mcm5, a novel cell cycle biomarker of aberrant growth, alone and in combination with NMP22.
METHODS: 1677 consecutive patients under investigation for urinary tract malignancy were recruited to a prospective blinded observational study. All patients underwent ultrasound, intravenous urography, cystoscopy, urine culture and cytologic analysis. An immunofluorometric assay was used to measure Mcm5 levels in urine cell sediments. NMP22 urinary levels were determined with the FDA-approved NMP22® Test Kit.
RESULTS: Genito-urinary tract cancers were identified in 210/1564 (13%) patients with an Mcm5 result and in 195/1396 (14%) patients with an NMP22 result. At the assay cut-point where sensitivity and specificity were equal, the Mcm5 test detected primary and recurrent bladder cancers with 69% sensitivity (95% confidence interval = 62-75%) and 93% negative predictive value (95% CI = 92-95%). The area under the receiver operating characteristic curve for Mcm5 was 0.75 (95% CI = 0.71-0.79) and 0.72 (95% CI = 0.67-0.77) for NMP22. Importantly, Mcm5 combined with NMP22 identified 95% (79/83; 95% CI = 88-99%) of potentially life threatening diagnoses (i.e. grade 3 or carcinoma in situ or stage ≥pT1) with high specificity (72%, 95% CI = 69-74%).
CONCLUSIONS: The Mcm5 immunoassay is a non-invasive test for identifying patients with urothelial cancers with similar accuracy to the FDA-approved NMP22 ELISA Test Kit. The combination of Mcm5 plus NMP22 improves the detection of UCC and identifies 95% of clinically significant disease. Trials of a commercially developed Mcm5 assay suitable for an end-user laboratory alongside NMP22 are required to assess their potential clinical utility in improving diagnostic and surveillance care pathways.
PMID: 22792272 [PubMed - indexed for MEDLINE]
Endocan is upregulated on tumor vessels in invasive bladder cancer where it mediates VEGF-A-induced angiogenesis.
Cancer Res. 2013 Feb 1;73(3):1097-106
Authors: Roudnicky F, Poyet C, Wild P, Krampitz S, Negrini F, Huggenberger R, Rogler A, Stöhr R, Hartmann A, Provenzano M, Otto VI, Detmar M
Tumor-associated blood vessels differ from normal vessels and proteins present only on tumor vessels may serve as biomarkers or targets for antiangiogenic therapy in cancer. Comparing the transcriptional profiles of blood vascular endothelium from human invasive bladder cancer with normal bladder tissue, we found that the endothelial cell-specific molecule endocan (ESM1) was highly elevated on tumor vessels. Endocan was associated with filopodia of angiogenic endothelial tip cells in invasive bladder cancer. Notably, endocan expression on tumor vessels correlated strongly with staging and invasiveness, predicting a shorter recurrence-free survival time in noninvasive bladder cancers. Both endocan and VEGF-A levels were higher in plasma of patients with invasive bladder cancer than healthy individuals. Mechanistic investigations in cultured blood vascular endothelial cells or transgenic mice revealed that endocan expression was stimulated by VEGF-A through the phosphorylation and activation of VEGFR-2, which was required to promote cell migration and tube formation by VEGF-A. Taken together, our findings suggest that disrupting endocan interaction with VEGFR-2 or VEGF-A could offer a novel rational strategy to inhibit tumor angiogenesis. Furthermore, they suggest that endocan might serve as a useful biomarker to monitor disease progression and the efficacy of VEGF-A-targeting therapies in patients with bladder cancer.
PMID: 23243026 [PubMed - indexed for MEDLINE]
A multi-analyte assay for the non-invasive detection of bladder cancer.
PLoS One. 2012;7(10):e47469
Authors: Goodison S, Chang M, Dai Y, Urquidi V, Rosser CJ
Accurate urinary assays for bladder cancer (BCa) detection would benefit both patients and healthcare systems. Through genomic and proteomic profiling of urine components, we have previously identified a panel of biomarkers that can outperform current urine-based biomarkers for the non-invasive detection of BCa. Herein, we report the diagnostic utility of various multivariate combinations of these biomarkers. We performed a case-controlled validation study in which voided urines from 127 patients (64 tumor bearing subjects) were analyzed. The urinary concentrations of 14 biomarkers (IL-8, MMP-9, MMP-10, SDC1, CCL18, PAI-1, CD44, VEGF, ANG, CA9, A1AT, OPN, PTX3, and APOE) were assessed by enzyme-linked immunosorbent assay (ELISA). Diagnostic performance of each biomarker and multivariate models were compared using receiver operating characteristic curves and the chi-square test. An 8-biomarker model achieved the most accurate BCa diagnosis (sensitivity 92%, specificity 97%), but a combination of 3 of the 8 biomarkers (IL-8, VEGF, and APOE) was also highly accurate (sensitivity 90%, specificity 97%). For comparison, the commercial BTA-Trak ELISA test achieved a sensitivity of 79% and a specificity of 83%, and voided urine cytology detected only 33% of BCa cases in the same cohort. These data show that a multivariate urine-based assay can markedly improve the accuracy of non-invasive BCa detection. Further validation studies are under way to investigate the clinical utility of this panel of biomarkers for BCa diagnosis and disease monitoring.
PMID: 23094052 [PubMed - indexed for MEDLINE]
Significance of plasma osteopontin levels in patients with bladder urothelial carcinomas.
Mol Diagn Ther. 2012 Oct;16(5):311-6
Authors: Zhao L, Wang Y, Qu N, Huang C, Chen L
BACKGROUND AND OBJECTIVE: Previous studies have suggested that the plasma level of osteopontin may be a biomarker for cancer metastases and clinical prognosis; however, its role in bladder urothelial carcinoma (BUC) remains unknown. The purpose of this study was to explore the significance of plasma osteopontin levels in evaluating the pathologic features of BUC and its potential as a prognostic marker in BUC patients.
METHODS: A total of 225 patients with BUC were enrolled in this study, and 230 age-matched and sex-matched healthy volunteers were enrolled as control subjects. The histologic classification of BUC, clinical stage of the disease, and plasma osteopontin levels were determined at admission. Patients with non-muscle-invasive BUC underwent transurethral resection, while those with muscle-invasive BUC underwent radical cystectomy. Patients receiving transurethral resection and radical cystectomy were followed up to determine their tumor-free interval and overall survival, respectively.
RESULTS: The mean plasma osteopontin levels were significantly higher in BUC patients than in controls, significantly higher in patients with high-grade BUC than in those with low-grade BUC, and significantly higher in patients with muscle-invasive BUC than in those with non-muscle-invasive BUC. Patients with bladder-confined disease had the lowest osteopontin levels, while those with lymph node-positive disease had higher osteopontin levels, and those with metastatic BUC had the highest osteopontin expression. Kaplan-Meier analyses showed that a higher plasma osteopontin level was associated with a lower overall survival rate in muscle-invasive BUC patients receiving radical cystectomy.
CONCLUSION: Our results show that the plasma osteopontin level is associated with the clinical features of BUC and predicts the prognosis of muscle-invasive BUC in patients receiving radical cystectomy.
PMID: 23055388 [PubMed - indexed for MEDLINE]
Cell-free microRNAs in urine as diagnostic and prognostic biomarkers of bladder cancer.
Int J Oncol. 2012 Nov;41(5):1871-8
Authors: Yun SJ, Jeong P, Kim WT, Kim TH, Lee YS, Song PH, Choi YH, Kim IY, Moon SK, Kim WJ
miRNAs are small, non-coding RNAs that play important roles in various biological processes. The aims of our study were to investigate whether cell-free miRNAs can be measured in urine samples and might be an accurate biomarker of bladder cancer. Datasets of GSE20418 and GSE19717 were used for analysis, and two miRNAs, miR-145 and miR-200a, were selected for study. A total of 207 patients with primary transitional cell carcinoma of the urinary bladder and 144 healthy normal controls were enrolled. Using quantitative PCR, the levels of miR-145 and miR-200a in urine were measured and compared with the clinicopathological features of bladder cancer. According to our experiments, cell-free miRNAs were present in urine and were stable. Assessment of miR-145 levels was able to distinguish bladder cancer patients from non-cancer controls (77.8% sensitivity and 61.1% specificity for NMIBC, AUC 0.729; 84.1 and 61.1% for MIBC, respectively, AUC 0.790) and showed good correlation with grade (p=0.048). In addition, miR-200a was shown to be an independent predictor of NMIBC recurrence by multivariate analysis (OR 0.449, 95% CI 0.239‑0.842, p=0.013). A higher risk of recurrence was observed among patients with a lower miR-200a level compared to patients with higher miR-200a levels (log-rank test, p=0.040). Urinary cell-free miRNAs show promise as noninvasive biomarkers for diagnosis and recurrence of bladder cancer.
PMID: 22961325 [PubMed - indexed for MEDLINE]
Metadherin is a novel prognostic marker for bladder cancer progression and overall patient survival.
Asia Pac J Clin Oncol. 2012 Sep;8(3):e42-8
Authors: Zhou J, Li J, Wang Z, Yin C, Zhang W
AIM: Metadherin (MTDH) is a potential oncogene in tumor development and is highly expressed in various types of human cancers. However, there has been no report on the role of MTDH in bladder cancer. Our aim was to investigate the expression pattern of MTDH in bladder tissue at different clinic pathological stages and evaluate the potential of MTDH as a biomarker of bladder cancer.
METHODS: The expression of MTDH in bladder tumors at different stages and normal bladder tissue was examined using immunohistochemical staining and quantitative real-time polymerase chain reaction. A statistical analysis was used to test for the association of MTDH and bladder cancer classification, staging and prognosis. The expression of proliferation marker Ki67 was examined and the relation between MTDH and Ki67 was studied.
RESULTS: The expression of MTDH was not detected in normal bladder tissue; however, up to 65% (39/60) of bladder tumors were found to have positive MTDH expression. A significant correlation was found between MTDH expression and the Union for International Cancer Control stage (P < 0.001), World Health Organization classification (P = 0.001), tumor recurrence (P = 0.015) and tumor multiplicity (P = 0.026). Patients with higher MTDH expression had shorter overall survival time, suggesting the potential of MTDH to be an independent prognostic indicator of bladder cancer. The positive correlation between MTDH and of Ki67 suggests the ability to promote tumor growth of MTDH.
CONCLUSIONS: Our results suggest that MTDH protein may be a valuable marker of bladder cancer progression. MTDH expression is associated with poor overall survival in patients with bladder cancer.
PMID: 22898150 [PubMed - indexed for MEDLINE]
LC-MS-based serum metabolic profiling for genitourinary cancer classification and cancer type-specific biomarker discovery.
Proteomics. 2012 Aug;12(14):2238-46
Authors: Lin L, Huang Z, Gao Y, Chen Y, Hang W, Xing J, Yan X
Bladder cancer (BC) and kidney cancer (KC) are the first two commonly occurring genitourinary cancers in China. In this study, a comprehensive LC-MS-based method, which utilizes both reversed phase liquid chromatography (RPLC) and hydrophilic interaction chromatography (HILIC) separations, has been carried out in conjunction with multivariate data analysis to discriminate the global serum profiles of BC, KC, and noncancer controls. An independent test set consisting of different patients has been used to objectively evaluate the predictive ability of the analysis platform. Excellent sensitivity and specificity have been achieved in detection of KC and BC. The results suggest that serum metabolic profiling could be used for different types of genitourinary cancer diagnosis. Furthermore, cancer type-specific biomarkers were found through a critical selection criterion. As a result, eicosatrienol, azaprostanoic acid, docosatrienol, retinol, and 14'-apo-beta-carotenal were found as specific biomarkers for BC; and PE(P-16:0e/0:0), glycerophosphorylcholine, ganglioside GM3 (d18:1/22:1), C17 sphinganine, and SM(d18:0/16:1(9Z)) were found as specific biomarkers for KC. Receiver operating characteristic (ROC) analysis was used for the preliminary evaluation of the biomarkers. These biomarkers have great potential to be used in the clinical diagnosis after further rigorous assessment.
PMID: 22685041 [PubMed - indexed for MEDLINE]
Diagnostic potential of urinary α1-antitrypsin and apolipoprotein E in the detection of bladder cancer.
J Urol. 2012 Dec;188(6):2377-83
Authors: Urquidi V, Goodison S, Ross S, Chang M, Dai Y, Rosser CJ
PURPOSE: The ability to reliably diagnose bladder cancer in voided urine samples would be a major advance. Using high throughput technologies, we identified a panel of bladder cancer associated biomarkers with potential clinical usefulness. In this study we tested 4 potential biomarkers for the noninvasive detection of bladder cancer.
MATERIALS AND METHODS: We examined voided urine specimens from 124 patients, including 63 newly diagnosed with bladder cancer and 61 controls. Concentrations of proteins were assessed by enzyme-linked immunosorbent assay, including α1-antitrypsin, apolipoprotein E, osteopontin and pentraxin 3. Data were compared to the results of urinary cytology and the BTA Trak® enzyme-linked immunosorbent assay based bladder cancer detection assay. We used the AUC of ROC curves to compare the usefulness of each biomarker to detect bladder cancer.
RESULTS: Urinary levels of α1-antitrypsin, apolipoprotein E and bladder tumor antigen were significantly increased in subjects with bladder cancer. α1-Antitrypsin (AUC 0.9087, 95% CI 0.8555-0.9619) and apolipoprotein E (AUC 0.8987, 95% CI 0.8449-0.9525) were the most accurate biomarkers. The combination of α1-antitrypsin and apolipoprotein E (AUC 0.9399) achieved 91% sensitivity, 89% specificity, and a positive and negative predictive value of 89% and 90%, respectively. Multivariate regression analysis highlighted only apolipoprotein E as an independent predictor of bladder cancer (OR 24.9, 95% CI 4.22-146.7, p = 0.0004).
CONCLUSIONS: Alone or in combination, α1-antitrypsin and apolipoprotein E show promise for the noninvasive detection of bladder cancer (OR 24.9, 95% CI 4.22-146.7, p = 0.0004). Larger, prospective studies including more low grade, low stage tumors are needed to confirm these results.
PMID: 23088986 [PubMed - indexed for MEDLINE]
[Evaluation of novel gene UCA1 as a tumor biomarker for the detection of bladder cancer].
Zhonghua Yi Xue Za Zhi. 2012 Feb 14;92(6):384-7
Authors: Zhang Z, Hao H, Zhang CJ, Yang XY, He Q, Lin J
OBJECTIVE: To evaluate the clinical utility of novel gene urothelial carcinoma antigen 1 (UCA1) as a urinary tumor marker for the diagnosis of bladder urothelial carcinoma.
METHODS: A cohort of 180 cases of bladder cancer (including 94 cases in previous study), 144 cases of non-bladder-cancer individuals as control group (including 85 cases in previous study) from 2005 to 2009 were recruited. Reverse transcription PCR (RT-PCR) of urinary sediments was performed to detect the expression of UCA1. RNasin was added to the urinary sediments collected after 2007 from 86 cases of bladder cancer and 59 cases in control group to improve the quantity and quality of RNA isolation. The parameters of sensitivity, specificity, area under curve (AUC) of ROC and its 95%CI were calculated.χ(2) test was used to compare the sensitivity of UCA1 with NMP22 and cytology in 116 cases of bladder cancer with the parallel data of UCA1 and NMP22 and in 108 cases with the parallel data of UCA1 and cytology.
RESULTS: 95.4% of RNA was isolated successfully from urinary sediments after the addition of RNasin UCA1 was highly specific (92.4%, 133/144) and quite sensitive (84.4%, 152/180) in the diagnosis of bladder cancer with a favorable AUC-ROC of 0.898 (95%CI: 0.851 - 0.945). It was especially valuable for superficial G(2)-G(3) patients (sensitivity: 86.4%, 92.3%) at a high risk for muscular invasion.
CONCLUSION: With a high level of sensitivity and specificity, UCA1 is a promising urinary marker for the diagnosis of bladder cancer.
PMID: 22490897 [PubMed - indexed for MEDLINE]