Current standard methods used to detect and monitor bladder urothelial cell carcinoma (UCC) are invasive or have low sensitivity. The incorporation into clinical practice of a non‐invasive tool for ...UCC assessment would enormously improve patients' quality of life and outcome. This study aimed to examine the microRNA (miRNA) expression profiles in urines of UCC patients in order to develop a non‐invasive accurate and reliable tool to diagnose and provide information on the aggressiveness of the tumor. We performed a global miRNA expression profiling analysis of the urinary cells from 40 UCC patients and controls using TaqMan® Human MicroRNA Array followed by validation of 22 selected potentially diagnostic and prognostic miRNAs in a separate cohort of 277 samples using a miRCURY LNA™ qPCR system. miRNA‐based signatures were developed by multivariate logistic regression analysis and internally cross‐validated. In the initial cohort of patients, we identified 40 and 30 aberrantly expressed miRNA in UCC compared with control urines and in high compared with low grade tumors, respectively. Quantification of 22 key miRNAs in an independent cohort resulted in the identification of a six miRNA diagnostic signature with a sensitivity of 84.8% and specificity of 86.5% (AUC = 0.92) and a two miRNA prognostic model with a sensitivity of 84.95% and a specificity of 74.14% (AUC = 0.83). Internal cross‐validation analysis confirmed the accuracy rates of both models, reinforcing the strength of our findings. Although the data needs to be externally validated, miRNA analysis in urine appears to be a valuable tool for the non‐invasive assessment of UCC.
What's new?
Accurate urinary tests to detect urothelial cell carcinoma (UCC) would improve patients' quality of life and outcome. Here, in the first global urine miRNA profiling study of UCC patients, the authors provide a list of dysregulated miRNAs that are candidate clinical biomarkers for the non‐invasive assessment of UCC. Furthermore, they describe miRNA panels consisting of a modest number of miRNAs that provide high UCC diagnostic and prognostic accuracy. Although clinical trials are needed to validate the data, the findings open the door to the possibility of implementing an accurate and reliable system for the non‐invasive assessment of UCC in clinical routine.
Abstract Context MicroRNAs (miRNA) are noncoding RNAs that post-transcriptionally regulate gene expression. Their altered expression and function have been observed in most urologic cancers. MiRNAs ...represent potential disease biomarkers and novel therapeutic targets. Objective To review and evaluate the evidence implicating miRNAs in the pathogenesis of prostate cancer (PCa), bladder cancer (BCa), and renal cancer. Evidence acquisition A systematic review was performed using PubMed and Embase to search for reports using strings for microRNA, non-coding RNA, cancer, prostate, bladder, and renal cancer. Identified manuscripts were retrieved and references searched. Selected studies were required to concentrate on the role of miRNA in these urologic cancers. Evidence synthesis We reviewed articles that focus on this topic. More than 40 miRNAs have been implicated in urologic cancer and many target common carcinogenic pathways. In particular, apoptosis avoidance, cell proliferation, epithelial-to-mesenchymal transition, angiogenic signalling, and the generation of androgen independence are targeted or facilitated by more than one miRNA. Little work has been done to evaluate the translational applications for this knowledge to date. Novel therapeutic strategies have been developed and are under investigation to selectively modulate miRNAs; such work would potentially enable personalised tumour therapy. Conclusions MiRNAs appear to be important modulators of urologic cancer. Their expression is frequently altered in these tumours, and many are functionally implicated in their pathogenesis. They require evaluation to determine the translational role and therapeutic potential for this knowledge.
To assess HER-2 and p-AKT expression in upper urinary tract urothelial carcinoma (UTUC) in order to determine their value as prognostic factors of tumour progression and cancer-specific survival.
One ...hundred consecutive UTUC patients were retrospectively included, between 1990-2004, in 4 tissue microarrays for immunostaining. Median follow-up: 33.03 months.
Positive HER-2 expression was found in 10 cases and cytoplasmic p-AKT expression in 84 cases; the expression intensity was strong: 30 cases, moderate: 28 and weak: 26. Nuclear p-AKT expression was found in 6 patients: 1 with strong, and 5 with moderate intensity. Nuclear p-AKT expression was an independent factor for tumour progression (HR=4.145, p=0.013), together with grade (HR=4.557, p=0.009) and stage (HR=2.085, p=0.003). In cancer-specific survival analysis, nuclear p-AKT expression (HR=4.268, p=0.017), together with grade (HR=5.214, p=0.035) and stage (HR=2.666, p=0.002) were identified as independent prognostic factors.
Nuclear p-AKT expression together with stage and grade constitute independent prognostic factors for tumour progression and cancer-specific survival.
Non-invasive urine-based biomarkers can potentially improve current diagnostic and monitoring protocols for bladder cancer (BC). Here we assess the performance of earlier published biomarker panels ...for BC detection (BC-116) and monitoring of recurrence (BC-106) in combination with cytology, in two prospectively collected patient cohorts.
Of the 602 patients screened for BC, 551 were found eligible. For the primary setting, 73 patients diagnosed with primary BC (n = 27) and benign urological disorders, including patients with macroscopic haematuria, cystitis and/or nephrolithiasis (n = 46) were included. In total, 478 patients under surveillance were additionally considered (83 BC recurrences; 395 negative for recurrence). Urine samples were analysed with capillary electrophoresis-mass spectrometry. The biomarker score was estimated via support vector machine-based software.
Validation of BC-116 biomarker panel resulted in 89% sensitivity and 67% specificity (AUC
= 0.82). A diagnostic score based on cytology and BC-116 resulted in good (AUC
= 0.85) but not significantly better performance (P = 0.5672). A diagnostic score including BC-106 and cytology was evaluated (AUC
= 0.82), significantly outperforming both cytology (AUC
= 0.72; P = 0.0022) and BC-106 (AUC
= 0.67; P = 0.0012).
BC-116 biomarker panel is a useful test for detecting primary BC. BC-106 classifier integrated with cytology showing >95% negative predictive value, might be useful for decreasing the number of cystoscopies during surveillance.
We assessed mutations in ERCC2, ERBB2, and ATM/RB1/FANCC as predictors of pathological response to neoadjuvant chemotherapy in bladder cancer. We confirmed an association of ERCC2 mutations with ...pathological response, but not with complete response, overall survival, or recurrence-free survival. Alterations in ERBB2 or ATM/RB1/FANCC were not predictive.
Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is recommended for patients with muscle-invasive bladder cancer (MIBC). It has been shown that somatic deleterious mutations in ERCC2, gain-of-function mutations in ERBB2, and alterations in ATM, RB1, and FANCC are correlated with pathological response to NAC in MIBC. The objective of this study was to validate these genomic biomarkers in pretreatment transurethral resection material from an independent retrospective cohort of 165 patients with MIBC who subsequently underwent NAC and radical surgery. Patients with ypT0/Tis/Ta/T1N0 disease after surgery were defined as responders. Somatic deleterious mutations in ERCC2 were found in nine of 68 (13%) evaluable responders and two of 95 (2%) evaluable nonresponders (p = 0.009; FDR = 0.03). No correlation was observed between response and alterations in ERBB2 or in ATM, RB1, or FANCC alone or in combination. In an exploratory analysis, no additional genomic alterations discriminated between responders and nonresponders to NAC. No further associations were identified between the aforementioned biomarkers and pathological complete response (ypT0N0) after surgery. In conclusion, we observed a positive association between deleterious mutations in ERCC2 and pathological response to NAC, but not overall survival or recurrence-free survival. Other previously reported genomic biomarkers were not validated.
It is currently unknown which patients will respond to chemotherapy before definitive surgery for bladder cancer. Previous studies described several gene mutations in bladder cancer that correlated with chemotherapy response. This study confirmed that patients with bladder cancer with a mutation in the ERCC2 gene often respond to chemotherapy.
Up to 70% of patients with non-muscle-invasive bladder cancer (NMIBC) experience disease recurrence, making it one of the most prevalent cancers in the United States. The purpose of this study was to ...test the performance of a multiplex urinary biomarker assay for the monitoring of voided urine for recurrent bladder cancer.
This retrospective, multicenter study included a total of 125 subjects with a history of bladder cancer. Voided urine specimens were collected before procedure from these subjects (53 with confirmed tumor recurrence and 72 with confirmed non-tumor recurrence) for analysis. A prediction rule generated from the performance characteristics of 10 single biomarkers (IL8, MMP9, MMP10, SERPINA1, VEGFA, ANG, CA9, APOE, SERPINE1, and SDC1) was measured using ELISA. The diagnostic performance of the biomarker panel was assessed using receiver operator curves (ROC) and descriptive statistical values (e.g., sensitivity and specificity).
The combination of all 10 biomarkers outperformed any single biomarker with a calculated AUROC for the diagnostic panel of 0.904 95% confidence interval (CI), 0.853-0.956. The multiplex assay achieved an overall sensitivity of 79% and specificity of 88% for recurrent bladder cancer and significantly outperformed the Urovysion cytogenetic assay (sensitivity 42%, specificity 94%) and voided urinary cytology (sensitivity 33%, specificity 90%).
A diagnostic panel of 10 urinary biomarkers that accurately detects primary bladder cancer also performs well for the detection of recurrent bladder cancer.
The identification of a reliable urine-based surveillance and detection assay would be of benefit to both patients and the healthcare system.
Abstract Objective The aim of this study was to analyze tumour gene expression profiles of progressive and non-progressive T1G3 bladder cancer (BC) patients to develop a gene expression signature to ...predict tumour progression. Methods Retrospective, multicenter study of 96 T1G3 BC patients without carcinoma in situ (CIS) who underwent a transurethral resection. Formalin-fixed paraffin-embedded tissue samples were collected. Global gene expression patterns were analyzed in 21 selected samples from progressive and non-progressive T1G3 BC patients using Illumina microarrays. Expression levels of 94 genes selected based on microarray data and based on literature were studied by quantitative polymerase chain reaction (qPCR) in an independent series of 75 progressive and non-progressive T1G3 BC patients. Univariate logistic regression was used to identify individual predictors. A variable selection method was used to develop a multiplex biomarker model. Discrimination of the model was measured by area under the receiver-operating characteristic curve. Interaction networks between the genes of the model were built by GeneMANIA Cytoscape plugin. Results A total of 1294 genes were found differentially expressed between progressive and non-progressive patients. Differential expression of 15 genes was validated by qPCR in an additional set of samples. A five-gene expression signature ( ANXA10 , DAB2 , HYAL2 , SPOCD1 , and MAP4K1 ) discriminated progressive from non-progressive T1G3 BC patients with a sensitivity of 79% and a specificity of 86% (AUC = 0.83). Direct interactions between the five genes of the model were not found. Conclusions Progressive and non-progressive T1G3 bladder tumours have shown different gene expression patterns. To identify T1G3 BC patients with a high risk of progression, a five-gene expression signature has been developed.
This chapter intends to introduce the new concepts that have been established in molecular biology over the last years and are being applied in translational research. The chapter is divided in four ...big blocks, which treat the molecular biology concepts and techniques in relation to DNA, RNA, proteins and metabolites, respectively. Moreover, we give examples of translational application of these new methodologies described.
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