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REVIEW ARTICLE
Year : 2019  |  Volume : 46  |  Issue : 2  |  Page : 37-40

Use of urinary biomarkers in cancer of the bladder: Current status


1 Department of Urology, JN Medical College, KLE Academy of Higher Education and Research, (Deemed-to-be University); Kidney Foundation KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Belagavi, Karnataka, India
2 Department of Urology, Kidney Foundation KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Belagavi, Karnataka, India
3 Kidney Foundation KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Belagavi, Karnataka, India

Date of Web Publication28-Jan-2020

Correspondence Address:
Dr. Rajendra B Nerli
Department of Urology, JN Medical College, KLE Academy of Higher Education and Research, (Deemed-to-be University), JNMC Campus, Nehru Nagar, Belagavi, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jss.JSS_19_19

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  Abstract 


Bladder cancer (BCa) is a common genitourinary cancer worldwide. It has been further classified into muscle invasive bladder cancer and nonmuscle invasive bladder cancer. Currently, the detection of BCa requires an unpleasant and expensive cystoscopy and biopsy, which is often accompanied by several adverse effects. Thus, a need is felt to develop novel diagnostic methods for initial detection and surveillance of the disease. Several urine-based tests have been approved by the Food and Drug Administration, USA, for the detection and surveillance of BCa, which are also commercially available. However, as of today, the sensitivity, specificity, and diagnostic accuracy of these urine-based assays are still suboptimal. To improve these, a number of novel molecular markers as well as multiple assays need to be introduced in clinical practice. At present, there is a growing need and evidence toward the use of minimally invasive “liquid biopsy” to identify biomarkers in BCa. DNA- and RNA-based markers in body fluids such as urine appear as promising potential markers in diagnostic, prognostic, predictive, and monitoring BCa. We report a nonsystematic review of the literature in regard to urinary biomarkers for BCa.

Keywords: Bladder cancer, exosomes, guidelines, liquid biopsy, microRNA, urinary biomarkers


How to cite this article:
Nerli RB, Ghagane SC, Pujar SV, Rangrez SS. Use of urinary biomarkers in cancer of the bladder: Current status. J Sci Soc 2019;46:37-40

How to cite this URL:
Nerli RB, Ghagane SC, Pujar SV, Rangrez SS. Use of urinary biomarkers in cancer of the bladder: Current status. J Sci Soc [serial online] 2019 [cited 2021 Jul 29];46:37-40. Available from: https://www.jscisociety.com/text.asp?2019/46/2/37/276976




  Introduction Top


The worldwide incidence of bladder cancer (BCa) has been on the rise over the past 60–70 years;[1],[2] however, smoking cessation programs have slowed down the rate over the last decade.[2] Males are 3–4 times more likely to develop BCa than females, probably because of an increased prevalence of smoking and exposure to environmental toxins.[1],[2] BCa is the 9th most common cancer worldwide and [2] the 13th most common cause of death.

BCa is a heterogeneous disease and presents with several diagnostic, therapeutic, and prognostic challenges.[3] Currently, BCa is diagnosed using invasive cystoscopy and biopsy with additional imaging using computerized tomography and magnetic resonance imaging. Quite often, the disease is understaged by these investigations as they lack sensitivity to detect all cancers (false negatives), specifically micrometastatic disease. These inadequacies in assessing the clinical and biologic potentials of a tumor result in over- and undertreatment with side effects of therapies.[4] Urinary cytology of urine specimens is a widely used noninvasive test for the detection and surveillance of BCa.[5],[6] Cytology is very specific (about 86%) but has low sensitivity (48%) limiting its use in low-grade BCa.[7],[8] Moreover, the diagnostic accuracy of urinary cytology is subjective, depending on the expertise of the cytopathologist.[9] This obviously raises the need for new molecular-based urinary tests so as to reduce or substitute the need for repeat endoscopy in BCa patients.[10],[11]

Several molecular markers have been identified in urine, tissue, and blood, which seem to offer promising opportunities to improve our understanding of BCa. These markers could help us identify the disease earlier, risk stratify the patients, improve prognostication and prediction of outcomes, and help in target therapy.[12] Correspondingly, a study conducted on cancer biomarkers suggested the use of combination of multiple urine biomarkers in early detection and a history of negative biopsies.[13] Urine-based markers have been extensively studied; however, the current guidelines have yet to embrace these markers in routine management of BCa.[14] In this review, we have looked at the use of urinary markers in clinical care and their use in different stages of the disease and different clinical scenarios. The evidence for this review was collected through a nonsystematic review of the literature.


  Urinary Markers Top


Proteomics and peptidomic analysis

Proteomic analyses of the urine sample have opened a new horizon for cancer biomarker discovery (21).[15] At present, seven tests are available for clinical use and six of them are Food and Drug Administration (FDA) approved. They include NMP22, NMP22 BladderChek, and UroVysion for BCa diagnosis and surveillance (FDA approved) and immunocytology (uCyt+), BTA-TRAK, and BTA-STAT approved for surveillance. Several novel protein markers are awaiting to be approved and are currently used experimentally. BCLA-1 and BCLA-4 are nuclear matrix proteins specifically targeting BCa tissues, with no interference with infection, smoking, catheterization, or cystitis.[16]

Circulating tumor and cell-free DNA

Bladder tumors are known to release DNA fragments into circulation, called circulating tumor DNA (ctDNA) containing tumor-specific mutations, variations of copy number, and alterations in DNA methylation status. The heterogeneity of tumor subclones gets reflected in this ctDNA. This ctDNA is detectable in over 70% of urine samples in patients with BCa [17] and allows to discriminate between BCa patients and controls.[18] CtDNA is easily accessible and measures about 180 and 200 base pairs but rapidly gets cleared from circulation following systemic therapy.[19] Digital polymerase chain reaction (PCR) and genome sequencing represent the methods of choice for cell-free DNA (cfDNA) analysis.

DNA methylation

In premalignant lesions, hyper- and hypomethylated regions are identified in the DNA. These alterations in DNA methylation status are chemically stable, develop early during tumorigenesis, and can be assessed in circulating cfDNA fragments and in cells shed into the urine.[20]

Cell-free DNA, mutation, and microsatellite alterations

As tumor-derived DNA can get released into circulation and mutations in cfDNA can be detected in various biological fluids, it has proposed to use these as noninvasive cancer biomarkers. For the diagnosis of low-grade BCa, loss of heterozygosity analysis is more sensitive than urine cytology (97% vs. 79%).[12] This helps improve the detection of low-grade and low-stage BCa, with 95% sensitivity for G1–G2 grades and 100% for pTis and pTa tumors.[21]


  Urinary Tumor RNA Top


Several classes of RNA such as messenger RNAs, microRNAs (miRs), and long noncoding RNAs have been recognized as potential noninvasive cancer biomarkers.[22] Elevated levels of circulating RNAs in cancer are known to return to normal levels following surgery,[23] suggesting that these RNA molecules have been released from tumors.

Extracellular vesicles and exosomes

In patients with BCa, urine analysis has demonstrated specific protein and miRNA pattern as well as extracellular vesicle enrichment.[24] Using a microarray platform and reverse transcription PCR analysis, miR-375 and miR146a have been found to specifically identify high-grade and low-grade BC, respectively.[25]

Exosomes are membrane vesicles secreted in nearly all body fluids at elevated levels in cancer patients relative to healthy participants.[26],[27] Exosomes in urine are known to contain miRNAs, in particular miR-1224-3p, miR-135b, and miR15b; in particular, miR-126/miR-152 ratio correlated with positive BCa diagnosis.[28]

Urinary microbiome

Wu et al. analyzed DNA extracted by urine pellets and observed specific enrichment of Acinetobacter, Anaerococcus, and Sphingobacterium in BCa cohort with respect to controls (122).[29] The increase of Herbaspirillum, Porphyrobacter, and Bacteroides in high-risk BCa patients suggests that these genera may represent new potential biomarkers.[30] Change or abnormal urinary microbiome has been suggested to be involved in bladder tumorigenesis.[12],[31]


  Use of Markers in Clinical Practice Top


BCa is a heterogeneous disease; hence, it is unlikely that one single marker can adequately characterize the potential and behavior of cancer so as to allow reliable treatment conclusions. Therefore, many investigators have evaluated comprehensive pathways rather than single markers.[31],[32] A panel of tumor markers including drivers from key pathways in combination with clinical and pathological variables might be the most promising approach for accurate risk stratification and clinical decision-making for BCa.

Urinary biomarkers for screening and hematuria workup

In patients with no previous history of BCa, urinary biomarkers could play a role for screening purposes. As the prevalence of the disease in the general population is low, it has been a challenge for developing effective screening strategies.[33] There is a limited role for screening for BCa in the general population, and to date, there have been no randomized controlled trials. These limitations could be overcome by identifying high-risk populations such as workers exposed to occupational hazards with carcinogenic potential or heavy smokers.[34] Lotan et al.[35] assessed the value of NMP22 in a high-risk population, including 1175 men and 327 women based on a history of at least 10 years of smoking or an occupational exposure of at least 15 years. Eighty-five (5.7%) participants had a positive NMP22. Three of the 69 patients undergoing further evaluation had abnormal findings (one pTa low-grade tumor, one pTa high-grade tumor, and one atypia). During long-term follow-up, only nine additional patients were diagnosed with BCa.[36] Moreover, what is interesting is that no patient had muscle invasive bladder cancer (MIBC) and a positive NMP22 was not associated with worse overall survival.

Urinary biomarkers may add value in risk-stratifying patients with asymptomatic microhematuria (AMH). Only 2% of the referred patients for AMH harbor BCa, and this has led to a nonchalant general approach to AMH with limited workups and delayed referrals resulting in late diagnosis, especially in women.[37] Urinary biomarkers in the setting of AMH may help early identification of patients at risk triaging and fastening referral for a urologic workup.[35],[38] Beukers et al.[39] used methylation analysis of OSR1, SIM2, OTX1, MEIS1, and ONECUT2 for developing a model for prediction of BCa. The model also included clinicopathologic characteristics such as type of hematuria, age, gender, and cytology results. The model yielded a sensitivity and specificity of 85% and 87%, respectively, with an area under the curve of 89%.

Several studies have suggested a potential role of urinary biomarkers in patients with AMH; however, prospective controlled trials are lacking and urgently needed. So far, there has been no evidence to suggest that the use of urinary biomarkers in a screening/early detection setting has an effect on cancer-specific mortality.[14] Due to low levels of evidence provided, urinary biomarkers are currently not recommended for the screening of BCa or in prioritization of patients with AMH.

Urinary biomarkers in surveillance setting

In a setting of surveillance, urinary biomarkers have been used to overcome the limitations of cystoscopy and urine cytology. Cystoscopy is invasive and may miss significant proportion of cancer recurrences, especially carcinoma in situ (CIS), whereas the latter has low sensitivity in low-/intermediate-risk non-MIBC (NMIBC) and suffers from considerable inter- and intraobserver variabilities, especially in patients after Bacillus Calmette-Guérin (BCG) immunotherapy.[40],[41],[42] The use of urinary biomarkers could be in two situations: (1) as an adjunct to cystoscopy and (2) its substitute. The role of a biomarker in clinical decision-making would be different in low-/intermediate-risk NMIBC and in high-risk NMIBC. In patients with low-grade disease, it is possible that a marker could reduce the number of cystoscopies needed. For high-grade cancers, the marker would be an adjunct to cystoscopy, and an abnormal result would increase awareness of patients and physicians, identify those at risk of progression, facilitate the interpretation of indeterminate results of cytology, and assess response to BCG.

The performances of most single biomarkers have been unsatisfactory; therefore, a panel of markers has been used to improve sensitivity or alternatively combining markers. One study found that combining the two tests among cytology, immunocytology, fluorescence in situ hybridization (FISH), and NMP22 resulted in sensitivity and negative predictive value of no >89.8% (immunocyt + NMP22) and 92.1% (FISH + immunocyt), respectively.[43] Based on these findings, the European Association of Urology, the American Urological Association, and the Society of Urologic Oncology do not recommend urinary biomarkers yet for the routine surveillance of patients with NMIBC.[14],[44]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Use of Markers i...
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