Biomarker Commons

Promoter methylation of H-cadherin is a potential biomarker in patients with bladder transitional cell carcinoma.

Int Urol Nephrol. 2012 Feb;44(1):111-7

Authors: Lin YL, Liu XQ, Li WP, Sun G, Zhang CT

Abstract
OBJECTIVES: H-cadherin, functions as a tumor suppressor, is frequently silenced by promoter methylation in human cancers. The aim of this study was to evaluate the feasibility of using H-cadherin methylation in tumor tissues as a potential biomarker in patients with bladder transitional cell carcinoma (TCC).
MATERIALS AND METHODS: We examined the methylation status of H-cadherin in 133 primary bladder TCC samples and 43 normal bladder epithelial tissues using methylation-specific polymerase chain reaction (MSP) and then analyzed the associations between H-cadherin methylation and clinicopathologic features as well as patients' outcome.
RESULTS: H-cadherin methylation was detected in 47 (35.3%) bladder TCC samples, but not found in controls (P = 0.0000). Moreover, H-cadherin methylation was significantly associated with advanced stage (P = 0.0006), high grade (P = 0.0165), larger tumor size (P = 0.0225), tumor recurrence (P = 0.0106), and poor prognosis (P = 0.0000). In addition, multivariate analysis indicated that H-cadherin methylation is independently associated with poor outcome and had a relative risk of death of 3.832 (P = 0.0071, 95% confidence interval: 1.443-10.176).
CONCLUSIONS: The results suggest that H-cadherin methylation may be used as a potential biomarker for the malignancy of bladder TCC and as an independent prognostic biomarker in patients with bladder TCC.

PMID: 21516472 [PubMed - indexed for MEDLINE]

The role of microRNA-binding site polymorphisms in DNA repair genes as risk factors for bladder cancer and breast cancer and their impact on radiotherapy outcomes.

Carcinogenesis. 2012 Mar;33(3):581-6

Authors: Teo MT, Landi D, Taylor CF, Elliott F, Vaslin L, Cox DG, Hall J, Landi S, Bishop DT, Kiltie AE

Abstract
MicroRNAs (miRNAs) are involved in post-transcriptional regulation of gene expression through binding to messenger RNAs (mRNA) thereby promoting mRNA degradation or altered translation. A single-nucleotide polymorphism (SNP) located within a miRNA-binding site could thus alter mRNA translation and influence cancer risk and treatment response. The common SNPs located within the 3'-untranslated regions of 20 DNA repair genes were analysed for putative miRNA-binding sites using bioinformatics algorithms, calculating the difference in Gibbs free binding energy (ΔΔG) for each wild-type versus variant allele. Seven SNPs were selected to be genotyped in germ line DNAs both from a bladder cancer case-control series (752 cases and 704 controls) and 202 muscle-invasive bladder cancer radiotherapy cases. The PARP-1 SNP rs8679 was also genotyped in a breast cancer case-control series (257 cases and 512 controls). Without adjustment for multiple testing, multivariate analysis demonstrated an association with increased bladder cancer risk with PARP1 rs8679 (P(trend) = 0.05) while variant homozygotes of PARP1 rs8679 were also noted to have an increased breast cancer risk (P = 0.03). In the radiotherapy cases, carriers of the RAD51 rs7180135 minor allele had improved cancer-specific survival (hazard ratio 0.52, 95% confidence interval 0.31-0.87, P = 0.01). This is the first report of associations between DNA repair gene miRNA-binding site SNPs with bladder and breast cancer risk and radiotherapy outcomes. If validated, these findings may give further insight into the biology of bladder carcinogenesis, allow testing of the RAD51 SNP as a potential predictive biomarker and also reveal potential targets for new cancer treatments.

PMID: 22166496 [PubMed - indexed for MEDLINE]

Proteomic analysis of urinary biomarker candidates for nonmuscle invasive bladder cancer.

Proteomics. 2012 Jan;12(1):135-44

Authors: Lindén M, Lind SB, Mayrhofer C, Segersten U, Wester K, Lyutvinskiy Y, Zubarev R, Malmström PU, Pettersson U

Abstract
Nonmuscle invasive tumors of the bladder often recur and thereby bladder cancer patients need regular re-examinations which are invasive, unpleasant, and expensive. A noninvasive and less expensive method, e.g. a urine dipstick test, for monitoring recurrence would thus be advantageous. In this study, the complementary techniques mass spectrometry (MS) and Western blotting (WB)/dot blot (DB) were used to screen the urine samples from bladder cancer patients. High resolving MS was used to analyze and quantify the urinary proteome and 29 proteins had a significantly higher abundance (p<0.05) in bladder cancer samples compared with control urine samples. The increased abundance found in urine from bladder cancer patients compared with controls was confirmed with Western blot for four selected proteins; fibrinogen β chain precursor, apolipoprotein E, α-1-antitrypsin, and leucine-rich α-2-glycoprotein 1. Dot blot analysis of an independent urine sample set pointed out fibrinogen β chain and α-1-antitrypsin as most interesting biomarkers having sensitivity and specificity values in the range of 66-85%. Exploring the Human Protein Atlas (HPA) also revealed that bladder cancer tumors are the likely source of these proteins. They have the potential of being useful in diagnosis, monitoring of recurrence and thus may improve the treatment of bladder tumors, especially nonmuscle invasive tumors.

PMID: 22065568 [PubMed - indexed for MEDLINE]

External validation of a biomarker based pre-cystectomy algorithm to predict nonorgan confined urothelial cancers.

J Urol. 2012 Mar;187(3):840-4

Authors: Margel D, Bostrom P, Baniel J, Yossepowitch O, Zlotta A, Fleshner N

Abstract
PURPOSE: The role of neoadjuvant chemotherapy before surgery in patients with muscle invasive bladder cancer remains debated and the need for tools to identify patients who would benefit from chemotherapy is pertinent. We previously published a preoperative algorithm to predict nonorgan confined disease. This algorithm included tumor markers (CEA, CA 125 and CA 19-9) as well as clinical parameters. In this study we validated the accuracy of this algorithm in an independent, external cohort.
MATERIALS AND METHODS: We used the Toronto Biobank to measure preoperative serum levels of CEA, CA 125 and CA 19-9 in 76 consecutive patients with clinically organ confined bladder cancer (cT2 or less) who underwent radical cystectomy. Clinical parameters were retrieved from our prospective bladder information system database and incorporated into our marker based algorithm. A numerical score was generated for each patient and a previously published cutoff was used to predict the presence of nonorgan confined disease. The accuracy of the model was quantified with the area under the curve, and the positive and negative predictive values were calculated.
RESULTS: On pathological evaluation 38 patients (50%) had nonorgan confined tumors. The AUC of the algorithm was 0.79 (95% CI 0.69-0.89). The positive and negative predictive values were 79% (95% CI 71-87) and 74% (95% CI 66-82), respectively.
CONCLUSIONS: We externally validated a pre-cystectomy model to predict pathological stage. The algorithm may possibly aid in selecting patients who would benefit from neoadjuvant chemotherapy before cystectomy.

PMID: 22245328 [PubMed - indexed for MEDLINE]

[Expression and significance of macrophage migration inhibitory factor in bladder urothelial cell carcinoma].

Zhonghua Zhong Liu Za Zhi. 2011 Jan;33(1):28-31

Authors: Guo YS, Dai YP, Li W, Liu LD

Abstract
OBJECTIVE: To evaluate the expression and clinical significance of macrophage migration inhibitory factor (MIF) in patients with bladder urothelial cell carcinoma.
METHODS: Immunohistochemical staining for MIF was performed on tissue sections of 110 patients with bladder urothelial cell carcinoma and 10 normal controls, and the correlations between MIF and clinicopathological characteristics and prognosis were also analyzed.
RESULTS: Normal bladder urothelium from control subjects showed negative or weak staining of MIF. Of the cancer specimens, 72/110 (65.5%) showed a moderate to strong staining of MIF. The expression of MIF protein was found predominantly in the tumor cell cytoplasm and inversely correlated with tumor stage. 27 cases also showed a positive intranuclear staining of MIF, which was inversely correlated with tumor grade, stage and tumor size. Kaplan-Meier analysis showed that the expression of MIF in the cell nuclei was associated with disease-free survival for the cancer patients, but multivariate analysis showed that MIF was not an independent prognostic factors.
CONCLUSIONS: The expression of MIF in non-muscle invasive bladder cancer tissues was more frequently than that in muscle-invasive disease, the positive staining of MIF in cell nuclei might be a favorable biomarker for patients with bladder urothelial cell carcinoma.

PMID: 21575460 [PubMed - indexed for MEDLINE]

[Biomarker for bladder cancer].

Gan To Kagaku Ryoho. 2012 Jan;39(1):48-53

Authors: Miyazaki J, Nishiyama H

PMID: 22454984 [PubMed - indexed for MEDLINE]

Osteopontin overexpression predicts poor prognosis of upper urinary tract urothelial carcinoma.

Urol Oncol. 2011 Nov;29(6):703-9

Authors: Ke HL, Chang LL, Yang SF, Lin HH, Li CC, Wu DC, Wu WJ

Abstract
OBJECTIVES: Studies indicate overexpression of osteopontin (OPN) promotes carcinogenesis, progression and metastasis of multiple human malignancies. However, the function of OPN in urothelial carcinoma (UC) of the upper urinary tract has not been investigated. This study evaluates the clinical significance of OPN expression in upper urinary tract UC.
MATERIALS AND METHODS: One hundred and ten cases (median age = 64, range = 24-84 years) of renal pelvic or ureter UC were retrospectively reviewed in this study. OPN expression were evaluated by immunohistochemistry staining on paraffin-embedded section of the tumor and scored by two qualified pathologists.
RESULTS: High OPN expression was found in 54 (49.1%) of the cancer specimens. OPN expression was not significantly correlated with tumor T stage (P = 0.761), N stage (P = 0.339) or grade (P = 0.349). However, OPN expression was differently expressed by gender (P = 0.012) and cancer location (P = 0.026). OPN expression did not correlate with bladder recurrence-free (P = 0.661) or extra-bladder recurrence-free (P = 0.787) survival, but high OPN expression was a significant predictor for cancer-specific survival (P = 0.014).
CONCLUSION: Our findings indicated that higher OPN expression is a potential biomarker to predict patient survival. Further study is necessary to investigate the role of OPN in the carcinogenesis of upper urinary tract UC.

PMID: 20022267 [PubMed - indexed for MEDLINE]

Metabolomic profiling reveals potential markers and bioprocesses altered in bladder cancer progression.

Cancer Res. 2011 Dec 15;71(24):7376-86

Authors: Putluri N, Shojaie A, Vasu VT, Vareed SK, Nalluri S, Putluri V, Thangjam GS, Panzitt K, Tallman CT, Butler C, Sana TR, Fischer SM, Sica G, Brat DJ, Shi H, Palapattu GS, Lotan Y, Weizer AZ, Terris MK, Shariat SF, Michailidis G, Sreekumar A

Abstract
Although alterations in xenobiotic metabolism are considered causal in the development of bladder cancer, the precise mechanisms involved are poorly understood. In this study, we used high-throughput mass spectrometry to measure over 2,000 compounds in 58 clinical specimens, identifying 35 metabolites which exhibited significant changes in bladder cancer. This metabolic signature distinguished both normal and benign bladder from bladder cancer. Exploratory analyses of this metabolomic signature in urine showed promise in distinguishing bladder cancer from controls and also nonmuscle from muscle-invasive bladder cancer. Subsequent enrichment-based bioprocess mapping revealed alterations in phase I/II metabolism and suggested a possible role for DNA methylation in perturbing xenobiotic metabolism in bladder cancer. In particular, we validated tumor-associated hypermethylation in the cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) promoters of bladder cancer tissues by bisulfite sequence analysis and methylation-specific PCR and also by in vitro treatment of T-24 bladder cancer cell line with the DNA demethylating agent 5-aza-2'-deoxycytidine. Furthermore, we showed that expression of CYP1A1 and CYP1B1 was reduced significantly in an independent cohort of bladder cancer specimens compared with matched benign adjacent tissues. In summary, our findings identified candidate diagnostic and prognostic markers and highlighted mechanisms associated with the silencing of xenobiotic metabolism. The metabolomic signature we describe offers potential as a urinary biomarker for early detection and staging of bladder cancer, highlighting the utility of evaluating metabolomic profiles of cancer to gain insights into bioprocesses perturbed during tumor development and progression.

PMID: 21990318 [PubMed - indexed for MEDLINE]

High CD10 expression predicts favorable outcome in surgically treated lymph node-positive bladder cancer patients.

Hum Pathol. 2012 Feb;43(2):269-75

Authors: Seiler R, von Gunten M, Thalmann GN, Fleischmann A

Abstract
CD10 predicts survival in different cancers. The prognostic significance in bladder cancer still has to be documented. One hundred fifty lymph node-positive bladder cancer patients were treated by cystectomy and standardized pelvic lymphadenectomy in curative intent. CD10 expression was evaluated in tissue microarrays (TMAs) constructed from histopathological normal urothelium, primary tumor (tumor center and invasion front), and corresponding lymph node metastases and correlated with tumor characteristics (stage, extracapsular extension, number, and total diameter of metastases) and survival. CD10 expression was successively lost from normal urothelium to primary tumor to metastases (P < .05) and decreased from the tumor center to the invasion front (P < .002). High CD10 expression in tumor center or invasion front (P < .05) but not in the metastases predicted favorable outcome; the prognostic information in the tumor center was independent from tumor stage and lymph node parameters. High CD10 expression level was not associated with specific tumor characteristics. A well-defined sampling strategy for TMAs allows detection of specific biomarker expression patterns and may generate prognostic information inherent in particular tumor areas. The favorable outcome in bladder cancer patients with high CD10 expression might suggest a tumor suppressive function of CD10.

PMID: 21835428 [PubMed - indexed for MEDLINE]

Statistical evaluation of CZE-UV and CZE-ESI-MS data of intact α-1-acid glycoprotein isoforms for their use as potential biomarkers in bladder cancer.

Electrophoresis. 2010 Oct;31(19):3314-25

Authors: Ongay S, Martín-Álvarez PJ, Neusüss C, de Frutos M

Abstract
α-1-acid glycoprotein (AGP) is a highly heterogeneous protein that presents a vast number of isoforms (molecules of the protein differing in its peptidic and/or glycosidic moieties). In the last years, several authors have studied the potential use of AGP as a cancer biomarker. These studies focus on the correlation of different features of AGP structure (i.e. fucosylation, antennarity) with cancer or on the total protein blood concentration. In this study, the potential of CZE-UV and CZE-ESI-MS analysis of intact AGP isoforms to study the correlation of this protein with bladder cancer is shown. Samples from 16 individuals (eight healthy, eight bladder cancer) were analyzed and characterized in great detail including data on intact protein isoforms and on released glycans. The analytical data were evaluated employing different statistical techniques (ANOVA; principal component analysis, PCA; linear discriminant analysis; and partial least squares-discriminant analysis). Statistical differences between the two groups of study were observed. The best results were obtained by linear discriminant analysis of the CZE-ESI-MS data for intact AGP isoforms (93.75% of correct classification). Due to MS characterization, it can be observed that differences between the samples are mainly due to higher abundance of AGP isoforms containing tri- and tetra-antennary fucosylated oligosaccharides in cancer patients. The results show the great potential of CE-MS in combination with advanced data processing for the use of intact protein isoforms as disease biomarkers.

PMID: 22216449 [PubMed - indexed for MEDLINE]

Bladder cancer determination via two urinary metabolites: a biomarker pattern approach.

Mol Cell Proteomics. 2011 Oct;10(10):M111.007922

Authors: Huang Z, Lin L, Gao Y, Chen Y, Yan X, Xing J, Hang W

Abstract
The purpose of this study was to use metabonomic profiling to identify a potential specific biomarker pattern in urine as a noninvasive bladder cancer (BC) detection strategy. A liquid chromatography-mass spectrometry based method, which utilized both reversed phase liquid chromatography and hydrophilic interaction chromatography separations, was performed, followed by multivariate data analysis to discriminate the global urine profiles of 27 BC patients and 32 healthy controls. Data from both columns were combined, and this combination proved to be effective and reliable for partial least squares-discriminant analysis. Following a critical selection criterion, several metabolites showing significant differences in expression levels were detected. Receiver operating characteristic analysis was used for the evaluation of potential biomarkers. Carnitine C9:1 and component I, were combined as a biomarker pattern, with a sensitivity and specificity up to 92.6% and 96.9%, respectively, for all patients and 90.5% and 96.9%, respectively for low-grade BC patients. Metabolic pathways of component I and carnitine C9:1 are discussed. These results indicate that metabonomics is a practicable tool for BC diagnosis given its high efficacy and economization. The combined biomarker pattern showed better performance than single metabolite in discriminating bladder cancer patients, especially low-grade BC patients, from healthy controls.

PMID: 21799048 [PubMed - indexed for MEDLINE]

Discrimination of agonist and antagonist forms of CXCL10 in biological samples.

Clin Exp Immunol. 2012 Jan;167(1):137-48

Authors: Casrouge A, Bisiaux A, Stephen L, Schmolz M, Mapes J, Pfister C, Pol S, Mallet V, Albert ML

Abstract
The ready access to commercially available multiplex assays and the importance of inflammation in disease pathogenesis has resulted in an abundance of studies aimed at identifying surrogate biomarkers for different clinically important questions. Establishing a link between a biomarker and disease pathogenesis, however, is quite complex, and in some instances this complexity is compounded by post-translational modifications and the use of immunoassays that do not always discriminate between the different forms of the same protein. Herein, we provide a detailed description of an assay system that has been established to discriminate the agonist form of CXCL10 from the NH(2) -terminal truncated form of the molecule generated by dipeptidylpeptidase IV (DPP4) cleavage. We demonstrate the utility of this assay system for monitoring agonist and antagonist forms of CXCL10 in culture supernatant, patient plasma and urine samples. Given the important role of CXCL10 in chronic inflammatory diseases and its suggested role as a predictive marker in managing patients with chronic hepatitis C, asthma, atopic dermatitis, transplantation, tuberculosis, kidney injury, cancer and other diseases, we believe that our method will be of general interest to the research and medical community.

PMID: 22132893 [PubMed - indexed for MEDLINE]

VEGF-C as a decision-making biomarker for selected patients with invasive bladder cancer who underwent bladder-preserving radical surgery.

Arch Med Res. 2011 Jul;42(5):405-11

Authors: Li Z, Qi F, Qi L, Zhang H, Chen M, Wang L, Zu X

Abstract
BACKGROUND AND AIMS: We proved the feasibility of radical transurethral resection in selected patients with muscle-invasive bladder cancer with a minimum follow-up of >5 years. A follow-up schedule was developed based on progression and recurrence during this period.
METHODS: The study included 93 patients with invasive bladder cancer treated by radical transurethral resection. Student t test was used for continuous variables to establish clinical progression predictive factors. VEGF-C protein expressions were tested by immunohistochemistry postsurgery.
RESULTS: The overall survival and disease-specific survival rates for all 93 patients were 59.1% and 65.2%, respectively. The clinical stage of the tumor influenced overall survival (p = 0.024) and disease-specific survival (p = 0.047). A significantly higher overall survival and disease-specific survival rate for patients with low levels of VEGF-C was 69.6% and 75.0%, respectively, than for those with high levels of VEGF-C (45.9 and 54.1%, respectively, p <0.05).The presence of bladder Tis reduced the survival rate (41.2 vs. 65.3%) and disease-specific survival (45.4 vs. 72.1%). Sensitivity, specificity and accuracy of VEGF-C in the evaluation of disease progression were 76.7, 77.8, 77.4%, respectively.
CONCLUSIONS: Patients with T2 stage, low level of VEGF-C and absence of bladder Tis were associated with high overall survival and disease-specific survival rate. VEGF-C level can evaluate disease progression and assist in choosing the appropriate treatment.

PMID: 21821075 [PubMed - indexed for MEDLINE]

Diagnostic performance of diffusion-weighted magnetic resonance imaging in bladder cancer: potential utility of apparent diffusion coefficient values as a biomarker to predict clinical aggressiveness.

Eur Radiol. 2011 Oct;21(10):2178-86

Authors: Kobayashi S, Koga F, Yoshida S, Masuda H, Ishii C, Tanaka H, Komai Y, Yokoyama M, Saito K, Fujii Y, Kawakami S, Kihara K

Abstract
OBJECTIVES: The diagnostic performance of diffusion-weighted magnetic resonance imaging (DW-MRI) in bladder cancer and the potential role of apparent diffusion coefficient (ADC) values in predicting pathological bladder cancer phenotypes associated with clinical aggressiveness were investigated.
METHODS: One hundred and four bladder cancer patients underwent DW-MRI and T2-weighted magnetic resonance imaging (T2W-MRI) before transurethral resection. The image sets were reviewed by two independent radiologists. ADC values were measured in 121 eligible tumours.
RESULTS: In detecting patients with bladder cancer, DW-MRI exhibited high sensitivity equivalent to that of T2W-MRI (>90%). Interobserver agreement was excellent for DW-MRI (κ score, 0.88) though moderate for T2W-MRI (0.67). ADC values were significantly lower in high-grade (vs. low-grade, P < 0.0001) and high-stage (T2 vs. T1 vs. Ta, P < 0.0001) tumours. At a cut-off ADC value determined by partition analysis, clinically aggressive phenotypes including muscle-invasive bladder cancer (MIBC) and high-grade T1 disease were differentiated from less aggressive phenotypes with a sensitivity of 88%, a specificity of 85% and an accuracy of 87%.
CONCLUSION: DW-MRI exhibits high diagnostic performance in bladder cancer with excellent objectivity. The ADC value could potentially serve as a biomarker to predict clinical aggressiveness in bladder cancer.

PMID: 21688007 [PubMed - indexed for MEDLINE]