A Systematic Review of the Diagnostic and Prognostic Value of Urinary Protein Biomarkers in Urothelial Bladder Cancer

Abstract

For over 80 years, cystoscopy has remained the gold-standard for detecting tumours of the urinary bladder. Since bladder tumours have a tendency to recur and progress, many patients are subjected to repeated cystoscopies during long-term surveillance, with the procedure being both unpleasant for the patient and expensive for healthcare providers. The identification and validation of bladder tumour specific molecular markers in urine could enable tumour detection and reduce reliance on cystoscopy, and numerous classes of biomarkers have been studied. Proteins represent the most intensively studied class of biomolecule in this setting.As an aid to researchers searching for better urinary biomarkers, we report a comprehensive systematic review of the literature and a searchable database of proteins that have been investigated to date. Our objective was to classify these proteins as: 1) those with robustly characterised sensitivity and specificity for bladder cancer detection; 2) those that show potential but further investigation is required; 3) those unlikely to warrant further investigation; and 4) those investigated as prognostic markers. This work should help to prioritise certain biomarkers for rigorous validation, whilst preventing wasted effort on proteins that have shown no association whatsoever with the disease, or only modest biomarker performance despite large-scale efforts at validation.

Pathological significance and prognostic implications of heme oxygenase 1 expression in non-muscle-invasive bladder cancer: Correlation with cell proliferation, angiogenesis, lymphangiogenesis and expression of VEGFs and COX-2

“…In addition, various molecular and biological markers, such as survivin, interleukins, microRNAs, have also been reviewed (4,5). However, there are no clinically definitive markers for NMIBC, as tumor growth, invasion, metastasis and recurrence are regulated by complex underlying mechanisms.…”

Bladder Cancer Markers and Recent Innovations

“…The majority of the biomarker studies could not be classified as unequivocal. This conclusion may be due to a loss of information (stage/grade/sensitivity/specificity) or due to a non-representative patient population that overstates the sensitivity and specificity [130].…”

“…DJ-1 has been reported of bladder cancer patients [131]. In Kumar et al probably was overestimated the presence coronin-1A (a cytoskeletal protein) in urine of patient with bladder cancer [130,132]. OrenesPiñero et al realized an immunohistochemistry analysis, followed a proteomics analysis, that showed Reg-1 (lithostathine-1-alpha) overexpression in bladder tumors [133].…”

“…It should not be influenced by the presence concurrently of other diseases and by the presence of hematuria or irritative symptoms that often occur in patients with bladder cancer [20]. An ideal biomarker should be also able to identify, in a clear way, the disease before its clinical manifestation and, at the same time, to provide accurate prognostic information [17,23]. By developing non-invasive molecular assays which are able to analyze body fluids, it would be easier to perform a large-scale screening of individuals most at risk [20,22].…”

Detection of Urothelial Bladder Carcinoma via Microfluidic Immunoassay and Single-Cell DNA Copy-Number Alteration Analysis of Captured Urinary-Exfoliated Tumor Cells

“…UroVysion FISH assay detects aneuploidy in chromosomes 3, 7, and 17, as well as, the loss of 9p21 locus in urine specimens but its detection accuracy varies widely (10). Although promising, these markers are not commonly used because of the insufficient accuracy, high cost or ambiguous clinical readout (11) and to reduce their relatively high false-positive rates, they are often used in conjunction with cystoscopy (12).…”