Molecular Markers In Bladder Cancer Research Articles

JAM3: A prognostic biomarker for bladder cancer via epithelial-mesenchymal transition regulation.

Understanding the intricate relationship between prognosis, immune function, and molecular markers in bladder cancer (BC) demands sophisticated analytical methods. To identify novel biomarkers for predicting prognosis and immune function in BC patients, we combined weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression analysis. This was conducted using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Ultimately, we screened the junctional adhesion molecule 3 (JAM3) as an independent risk factor in BC. High levels of JAM3 were linked to adverse clinical parameters, such as higher T and N stages. Additionally, a JAM3-based nomogram model accurately predicted 1-, 3- and 5-year survival rates of BC patients, indicating potential clinical utility. Functional enrichment analysis revealed that high JAM3 expression activated the calcium signaling pathway, the extracellular matrix (ECM)-receptor interaction, and the PI3K-Akt signaling pathway, and was positively correlated with genes associated with epithelial-mesenchymal transition (EMT). Subsequently, we found that overexpression of JAM3 promoted the migration and invasion abilities in BC cells, regulating the expression levels of N-cadherin, matrix metallopeptidase 2 (MMP2), and Claudin-1 thereby promoting EMT levels. Additionally, we showed that JAM3 was negatively correlated with anti-tumor immune cells such as CD8+ T cells, while positively correlated with pro-tumor immune cells such as M2 macrophages, suggesting its involvement in immune cell infiltration. The immune checkpoint CD200 also showed a positive correlation with JAM3. Our findings revealed that elevated JAM3 levels are predictive of poor prognosis and immune cell infiltration in BC patients by regulating the EMT process.

CALD1, CNN1, and TAGLN identified as potential prognostic molecular markers of bladder cancer by bioinformatics analysis.

Bladder cancer (BC) is one of the most common malignant neoplasms in the genitourinary tract. We employed the GSE13507 data set from the Gene Expression Omnibus (GEO) database in order to identify key genes related to tumorigenesis, progression, and prognosis in BC patients. The data set used in this study included 10 normal bladder mucosae tissue samples and 165 primary BC tissue samples. Differentially expressed genes (DEGs) in the 2 types of samples were identified by GEO2R. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the online website DAVID. The online website STRING was used to construct a protein-protein interaction network. Moreover, the plugins in MCODE and cytoHubba in Cytoscape were employed to find the hub genes and modules in these DEGs. We identified 154 DEGs comprising 135 downregulated genes and 19 upregulated genes. The GO enrichment results were mainly related to the contractile fiber part, extracellular region part, actin cytoskeleton, and extracellular region. The KEGG pathway enrichment results mainly comprised type I diabetes mellitus, asthma, systemic lupus erythematosus, and allograft rejection. A module was identified from the protein-protein interaction network. In total, 15 hub genes were selected and 3 of them comprising CALD1, CNN1, and TAGLN were associated with both overall survival and disease-free survival. CALD1, CNN1, and TAGLN may be potential biomarkers for diagnosis as well as therapeutic targets in BC patients.

Molecular markers in bladder cancer

PurposeUse of molecular markers in urine, tissue or blood offers potential opportunities to improve understanding of bladder cancer biology which may help identify disease earlier, risk stratify patients, improve prediction of outcomes or help target therapy.MethodsA review of the published literature was performed, without restriction of time.ResultsDespite the fast-growing literature about the topic and the approval of several urinary biomarkers for use in clinical practice, they have not reached the level of evidence for widespread utilization. Biomarkers could be used in different clinical scenarios, mainly to overcome the limitations of current diagnostic, predictive, and prognostic tools. They have been evaluated to detect bladder cancer in asymptomatic populations or those with hematuria and in surveillance of disease as adjuncts to cystoscopy. There is also a potential role as prognosticators of disease recurrence, progression and survival both in patients with non-invasive cancers and in those with advanced disease. Finally, they promise to be helpful in predicting the response to local and/or systemic chemotherapy and/or immunotherapy.ConclusionsTo date, due to the lack of high-quality prospective trials, the level of evidence provided by the current literature remains low and, therefore, the potential of biomarkers exceeds utilization in clinical practice.

Corrélation des altérations génétiques à l’agressivité anatomo-pathologique des carcinomes urothéliaux de la vessie : performance du test BCA-1

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. 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. 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). 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.

The promise of novel molecular markers in bladder cancer.

Bladder cancer is the fourth most common malignancy in the US and is associated with the highest cost per patient. A high likelihood of recurrence, mandating stringent surveillance protocols, has made the development of urinary markers a focus of intense pursuit with the hope of decreasing the burden this disease places on patients and the healthcare system. To date, routine use of markers is not recommended for screening or diagnosis. Interests include the development of a single urinary marker that can be used in place of or as an adjunct to current screening and surveillance techniques, as well identifying a molecular signature for an individual’s disease that can help predict progression, prognosis, and potential therapeutic response. Markers have shown potential value in improving diagnostic accuracy when used as an adjunct to current modalities, risk-stratification of patients that could aid the clinician in determining aggressiveness of surveillance, and allowing for a decrease in invasive surveillance procedures. This review discusses the current understanding of emerging biomarkers, including miRNAs, gene signatures and detection of circulating tumor cells in the blood, and their potential clinical value in bladder cancer diagnosis, as prognostic indicators, and surveillance tools, as well as limitations to their incorporation into medical practice.

What are the currently available and in development molecular markers for bladder cancer? Will they prove to be useful in the future?

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.

A review of molecular biomarkers for bladder cancer

Background : Numerous molecular markers for bladder cancer have been identified and investigated with various laboratory techniques. Molecular markers are isolated from tissue, serum and urine. They fall into proteomic, genetic and epigenetic categories. Some of molecular markers show promising results in terms of facilitating early diagnosis and guiding treatment. Molecular markers or the so- called biomarkers can provide additional information alongside staging, grading and lymphovascular invasion, for better prognostication. Aim :This studyprovides an up-to-date review of the frequently studied and most important biomarkers that have shown consistent relevance in relation to bladder cancer. Methods : The key words were searched on the PubMed, Google scholar and NHS library search engines. Results : More than twenty biomarkers as per our methodology were identified but only half of them have shown consistence relevance in bladder cancer. Conclusion : It is envisaged that a combination of a few biomarkers, which are investigated frequently and have shown clinical relevance, could possibly provide useful information in predicting recurrence and provide useful prognostic information. So far none of the biomarkers for bladder cancer are adopted in the UK standard practice. Despite that the Food and Drug Administration (FDA) had approved some of these biomarkers, none of the urology associations incorporated them in to their guidelines as yet. However, it won’t be long before a final consensus is reached to integrate molecular staging in to the current TNM staging system. Key words : Molecular markers, biomarkers, proteomics, tumour markers, bladder cancer, oncology

Who needs numbers more: patients or doctors?

Who needs numbers more: patients or doctors?

Individual risk assessment in bladder cancer patients based on a multi-marker panel

To investigate whether a combined application of urine cytology (CYT) and molecular markers for bladder cancer (BC) can predict tumor aggressiveness. The study comprised 2,113 patients who underwent urethrocystoscopy and transurethral resection of the bladder. CYT, fluorescence in situ hybridization (FISH), immunocytology (uCyt+) and nuclear matrix protein 22 test (NMP22-ELISA) were performed. Results of the individual tests and of a multi-marker panel were correlated with pT-stages and tumor grades. Five hundred and two of 2,113 (23.8 %) patients had BC. False-negative test rates of CYT (p < 0.001), FISH (p = 0.01) and NMP22-ELISA (p = 0.05) were lower in patients with muscle-invasive BC compared with patients with non-muscle-invasive BC. Furthermore, false-negative rates of CYT (p < 0.001), FISH (p = 0.0002) and NMP22-ELISA (p < 0.001) were lower in patients with G3/CIS compared with patients with G1-G2 BC. In patients with evidence of tumor in urethrocystoscopy, the presence of simultaneously positive CYT and NMP22 was associated with a 20-fold risk for G3/CIS (p < 0.0001). This is the first study investigating the combined use of four urine markers in addition to cystoscopy to predict tumor aggressiveness. Our results indicate that combined application of urine markers as an adjunct to cystoscopy may facilitate identification of patients harboring high-grade tumors.

Annual Endoscopy and Urine Cytology for the Surveillance of Bladder Tumors After Enterocystoplasty for Congenital Bladder Anomalies

It is currently recommended that patients with congenital bladder anomalies managed by enterocystoplasty undergo annual surveillance with urine cytology and endoscopy. We reviewed our experience with this protocol and suggest modifications based on this experience. A total of 65 patients 10 years or more after enterocystoplasty were placed on an annual surveillance protocol consisting of interval medical history, renal-bladder ultrasound, serum B12, electrolytes, creatinine, urinalysis, urine cytology and endoscopy. Of the 65 patients 50 (77%) with enterocystoplasty (ileal in 40 and colonic in 10) remain on the protocol. Median age at the initiation of surveillance was 28 years (range 24 to 40) with a median time from augmentation of 15 years (range 12 to 29). During the first 5 years of surveillance 26 of 250 cytology results (10.5%) were suspicious for cancer. Further evaluation revealed no evidence of malignancy. Specificity for cytology was 90% with unknown sensitivity. Of 250 surveillance endoscopic evaluations 4 lesions (1.6%) were identified and biopsied/removed. Pathological evaluation revealed 1 adenomatous polyp, 1 squamous metaplasia and 2 nephrogenic adenomas. Due to the low event rate and high cost routine cytology and endoscopy were discontinued after each patient completed 5 years of followup and annual evaluations were maintained. No tumors developed during the median surveillance interval of 15 years (range 12 to 20). Currently median patient age is 42 years (range 36 to 59) and median time since augmentation is 27 years (range 23 to 40). Due to the low incidence of malignancy, lack of proven benefit and enhanced cost containment we recommend that annual surveillance endoscopy and cytology be discontinued.

Genetic Polymorphisms of p53 Codon 72 and Bladder Cancer Susceptibility: A Hospital-Based Case–Control Study

p53 is one of the most widely investigated molecular markers in bladder cancer and its polymorphisms have been related to individual cancer risks. The objective of this study was to explore the association of p53 codon 72 polymorphism with susceptibility and clinicopathologic characteristics of bladder cancer in a Chinese population. We investigated the impact of p53 codon 72 polymorphism in a hospital-based case-control study of bladder cancer. We tested peripheral blood samples from 120 patients with bladder cancer and 120 healthy individuals of similar age and from the same geographical region. The polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism assay. There was an association between smoking status and bladder cancer (odds ratio [OR] = 2.25; 95% confidence interval [95% CI] = 1.31, 3.87; p = 0.003). Patients with bladder cancer had a significantly lower frequency of Arg/Arg (OR = 0.53; 95% CI = 0.31, 0.89; p = 0.02) and Arg allele (OR = 0.66; 95% CI = 0.45, 0.95; p = 0.03) than controls. Patients with invasive bladder cancer had a significantly lower frequency of Arg/Arg (OR = 0.29; 95% CI = 0.10, 0.88; p = 0.03) than those with superficial bladder cancer. When stratifying by the grade and histological type of bladder cancer, we found no statistical association. These data suggest that the p53 codon 72 Arg/Arg genotype and Arg allele are associated with a lower risk of bladder cancer in Chinese population.

Expression of HYAL1 and Survivin RNA as Diagnostic Molecular Markers for Bladder Cancer

Urinary tumor markers that help in the early detection of bladder cancer promise a significant improvement in sensitivity, specificity and convenience over conventional, invasive diagnostic tests. We assessed the diagnostic efficacy of hyaluronidase (HYAL1) and survivin for early bladder cancer detection. The study included 166 patients diagnosed with bladder carcinoma, 112 with benign bladder lesions and 100 healthy volunteers who served as controls. All underwent serological assessment of schistosomiasis antibody, urine cytology, and hyaluronidase (HYAL1) and survivin RNA estimation by qualitative and semiquantitative reverse transcriptase-polymerase chain reaction in urothelial cells from voided urine. Positivity rates of HYAL1 RNA and survivin RNA on qualitative reverse transcriptase-polymerase chain reaction were significantly different among the 3 groups. Mean rank using semiquantitative method was increased in the malignant vs the other groups. The best cutoff for HYAL1 and survivin RNA was 0.25 each. Using these cutoffs HYAL1 and survivin RNA sensitivity was 91% and 75%, respectively, with absolute specificity. HYAL1 RNA detected all patients with stages 0 and I bladder cancer (p <0.037). Urine cytology sensitivity improved when combined with hyaluronidase or survivin RNA on semiquantitative reverse transcriptase-polymerase chain reaction. The detection of urinary HYAL1 and survivin RNA is a promising noninvasive test for bladder cancer early detection. HYAL1 RNA was more sensitive and specific than urine cytology. Semiquantitative reverse transcriptase-polymerase chain reaction is favored for its high sensitivity and specificity.

Differential Proteomic Analysis of Nuclear Matrix in Muscle-Invasive Bladder Cancer: Potential to Improve Diagnosis and Prognosis

Introduction: Although several molecular markers for bladder cancer have been identified, at present little information on prognostic biomarkers is available in the literature. Prognostication of this tumor is largely based on clinicopathological characteristics. Our aim was to identify nuclear matrix (NM) proteins that might serve to better characterize the phenotype of the invasive bladder cancer and to investigate their diagnostic and prognostic roles. Methods: NM proteins expressed in normal (n=3) or non-tumoral (n=9) tissue specimens and muscle-invasive bladder cancer (n=21) specimens were analyzed by two dimensional (2D) gel electrophoresis. PDQuest image analysis software was used to generate a comparative NM proteome analysis. Selected spots were characterized by liquid chromatography coupled to tandem mass spectrometry and Western blot. Results: We detected over 800 protein spots in each 2D map and 43 spots were identified. 30 proteins were differentially expressed by bladder tumor cells; among these, 19 proteins were detected in bladder tumoral tissues but not in normal and non-tumoral tissues and seven proteins correlated with tumor stage. One protein (p54nrb) was strongly correlated with vascular invasions and appeared to be also significantly (P <0.0001) associated with a decreased probability of survival. Conclusion: Important alterations in NM proteins occur in muscle-invasive bladder cancer. The differentially expressed proteins include biomarkers potentially useful for disease diagnosis, progression and prognosis. Our findings beyond improving the understanding of the biology of bladder cancer, could help to stratify patients into different prognostic subgroups and to select those who might be better candidate to multimodal therapeutic approaches.

Molecular markers in bladder cancer

Bladder cancer is a diverse disease whose molecular phenotypes are being elucidated. In this review, we summarize currently known molecular pathways and associated markers in bladder cancer. Genetic and epigenetic aberrations have been closely associated with tumor pathogenesis and prognosis. Cell cycle markers have been most extensively studied. More recently, apoptotic and angiogenic pathways are being investigated. Studying the role of multiple concurrent molecular alterations improves the prognostic ability of these markers. The use of tissue microarrays and high-throughput molecular profiling is accelerating the discovery of new markers. Molecular biology is paramount to our understanding of bladder cancer pathogenesis. The search for new markers, and elucidating cross-talk between markers in different pathways, is warranted. Molecular markers have the potential benefit of improving detection, prognosis and treatment of bladder cancer. In addition, understanding the molecular profile of the individual patient could usher us into a new era of improving prediction of the natural history of the disease and providing a more personalized and tailored treatment. Prospective trials are still needed, however, to objectively establish the true benefit of these markers in prognostic and therapeutic arenas.

Molecular markers for bladder cancer: the road to a multimarker approach

Bladder cancer is the seventh most common malignancy worldwide, with almost 14,000 patients dying from this disease in the USA alone. Because of the need for long-term and frequent follow-up, as well as the paucity of sensitive and specific noninvasive tests, bladder cancer management has the highest cost per patient among all cancer types. Several molecular markers, especially members of the cell cycle regulation and apoptosis pathways, have been investigated. However, no individual marker has been prognostically powerful enough to change clinical management. The combined analysis of a panel of markers spanning different pathways is the most promising approach. We give an overview of the most important molecular markers functioning in crucial pathways and focus on their role in multimarker analysis.

False-positive lesions detected by fluorescence cystoscopy: any association with p53 and p16 expression?

To determine p53 and p16 status as molecular markers of bladder cancer, in histologically proven benign bladder biopsies, obtained from lesions suspect for malignancy as judged by fluorescence cystoscopy. Immunohistochemical (IHC) staining was performed for p53 and p16, using the antibodies DO-7 and AB-4, respectively. The tissue sections were scored in percentages of nuclear staining for p53 and p16. Of 247 biopsies, 41/49 lesions appeared suspicious on fluorescence cystoscopy, but were histopathologically benign. 2/40 (5%) were > or =20% p53 positive as compared to 7/128 (5.5%) of all histopathologically benign biopsies. 24/37 (64.9%) were p16 negative (<5% positive cells) as compared to 84/125 (67.2%) of all benign biopsies. Most biopsies had a moderate to high degree of chronic cystitis. False positive lesions of fluorescence cystoscopy did not differ from benign lesions detected by standard white light cystoscopy with regard to p53 and p16 immunoreactivity. Little evidence remains for these lesions to be pre-malignant.

Molecular markers in bladder cancer

Bladder cancer is one of the malignancies for which extensive information regarding molecular pathogenesis and genetic predictors of natural history as well as response to various modalities of treatment based on molecular profile is available. As more prognostic markers are being investigated in clinical trial settings, in the not very distant future we will be able to use these predictive markers in clinical decision-making. Bladder cancer is the second most common genitourinary tumor and is a significant cause of morbidity and mortality. A need for tumor markers that can be incorporated into clinical practice to add prognostic information and to refine the conventional TNM and grading systems in terms of treatment response and prognosis is crucial. Intravesical and systemic chemotherapy in bladder cancer are limited in their efficacy in the treatment of bladder cancer patients primarily when they are unable to induce apoptosis in bladder tumor cells. Understanding the apoptotic signals and the cascade of reactions that give pro-survival signals will go a long way in refining the treatments and will help in the future to individualize cancer therapies. It is imperative to study the role of these mechanisms in prospective clinical trials in a quest to find predictive markers that can help to tailor treatments, keeping in view the molecular heterogeneity.

The Clinical Significance of Molecular Markers to Bladder Cancer

Stage and grade of transitional cell carcinoma are currently the most useful tools for taking therapeutic decisions and evaluating the prognosis of bladder cancer patients. However, as there are remarkable differences in biological behavior and "biological potential" of tumors classified in the same stage, it is very difficult to predict which superficial tumors will recur and which tumors will give distant metastases. During the last two decades, the better understanding of the molecular mechanisms involved in carcinogenesis and tumor progression has provided a large number of molecular markers of bladder cancer, with a potential diagnostic and prognostic value. This article reviews comprehensively the molecular role and evaluates the clinical significance and the perspectives of these molecular markers. We concluded that, although at the moment there is not a single marker able to predict with accuracy the biological potential of bladder cancer, the most promising markers, at this point, are deletions of chromosome 9, and the tumor suppressor gene p53. Clinical studies are in progress for the assessment of other biological molecules with prognostic potential, such as the E-cadherin, the protein p120, and the telomerase.

Indications and outcome of radiotherapy for invasive bladder cancer: review of developments during 2002.

To highlight recent developments in the selection of patients for bladder preservation and in the optimization of outcome after radiation. Techniques in the delivery of radiation continue to improve. Increasing phase II evidence indicates that bladder preservation with multimodality approaches is safe and effective in selected patients. The list of molecular markers of bladder cancer with potential clinical relevance continues to extend. Three studies on target delineation, set-up errors and organ motion during radiation show that radiation techniques can be improved considerably thereby reducing the risk of geographical miss. Two large studies with long follow-ups report excellent outcome after bladder preserving treatment strategies using concurrent chemotherapy and radiation. Results seem comparable with those reported for contemporary radical cystectomy. Molecular characterization of bladder cancer is rapidly expanding, but has up to now no established role in the selection or tailoring of treatment options for individual bladder cancer patients.

Genetic studies and molecular markers of bladder cancer

Genetic studies and molecular markers of bladder cancer