Novel urinary biomarkers for the detection of bladder cancer: A systematic review

Tan, Wei Shen; Tan, Wei; Tan, Mae-Yen; Khetrapal, Pramit; Liang, Dong; deWinter, Patricia; Feber, Andrew; Kelly, John D.

doi:10.1016/j.ctrv.2018.05.012

Cited by 80 publications

(65 citation statements)

References 96 publications

(147 reference statements)

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“…A direct comparison of the performance of our markers to those previously reported is difficult due to the vast heterogeneity of the different studies regarding molecular levels, tumor subtypes, tumor history, different statistical approaches, sample size, type of controls and the way the results are reported. At a specificity of ≥95%, only few studies have reported biomarker sensitivities higher than ours . However, several of these markers identify high grade or muscle‐invasive UCa only, whereas our markers identify UCa across all stages and grades.…”

Section: Discussioncontrasting

confidence: 53%

“…At a specificity of ≥95%, only few studies have reported biomarker sensitivities higher than ours. 41,42 However, several of these markers identify high grade or muscle-invasive UCa only, whereas our markers identify UCa across all stages and grades. In addition, several of these markers and their diagnostic performances were tested in smaller collectives of UCa patients only.…”

Section: Discussionmentioning

confidence: 80%

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Noninvasive diagnosis of urothelial cancer in urine using DNA hypermethylation signatures—Gender matters

Köhler

Bonberg

Ahrens

et al. 2019

Intl Journal of Cancer

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Urothelial cancer (UCa) is the most predominant cancer of the urinary tract and noninvasive diagnosis using hypermethylation signatures in urinary cells is promising. Here, we assess gender differences in a newly identified set of methylation biomarkers. UCa‐associated hypermethylated sites were identified in urine of a male screening cohort (n = 24) applying Infinium‐450K‐methylation arrays and verified in two separate mixed‐gender study groups (n = 617 in total) using mass spectrometry as an independent technique. Additionally, tissue samples (n = 56) of mixed‐gender UCa and urological controls (UCt) were analyzed. The hypermethylation signature of UCa in urine was specific and sensitive across all stages and grades of UCa and independent on hematuria. Individual CpG sensitivities reached up to 81.3% at 95% specificity. Albeit similar methylation differences in tissue of both genders, differences were less pronounced in urine from women, most likely due to the frequent presence of squamous epithelial cells and leukocytes. Increased repression of methylation levels was observed at leukocyte counts ≥500/μl urine which was apparent in 30% of female and 7% of male UCa cases, further confirming the significance of the relative amounts of cancerous and noncancerous cells in urine. Our study shows that gender difference is a most relevant issue when evaluating the performance of urinary biomarkers in cancer diagnostics. In case of UCa, the clinical benefits of methylation signatures to male patients may outweigh those in females due to the general composition of women's urine. Accordingly, these markers offer a diagnostic option specifically in males to decrease the number of invasive cystoscopies.

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Section: Discussioncontrasting

confidence: 53%

Section: Discussionmentioning

confidence: 80%

Noninvasive diagnosis of urothelial cancer in urine using DNA hypermethylation signatures—Gender matters

Köhler

Bonberg

Ahrens

et al. 2019

Intl Journal of Cancer

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“…It is less biologically complex than plasma; however, urinary proteins still exhibit a large dynamic range, with high‐abundant proteins such as uromodulin often masking those with a lower concentration . To combat this, researchers have turned to urinary EVs for the enrichment of disease biomarkers, particularly for diseases of the urogenital system such as bladder cancer, which is hampered by low sensitivity for minimal residual disease testing . One novel study by Smalley and co‐workers investigated the impact of hematuria (blood in the urine, a common symptom of bladder cancer) on EV proteomic profiles by spiking blood from healthy control subjects into urine before HPLC–MS/MS analysis .…”

Section: Urinementioning

confidence: 99%

Tumor‐Derived Extracellular Vesicles as a Novel Source of Protein Biomarkers for Cancer Diagnosis and Monitoring

Ruhen

Meehan

2019

Proteomics

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“Liquid biopsies” have received attention as a complementary tool for traditional tissue biopsies that may enhance the spectrum of analysis for tumor‐derived factors. One such factor gaining prominence in the liquid biopsy field is extracellular vesicles (EVs), membrane‐bound nanovesicles which are secreted by cells into biofluids such as blood, urine, and saliva. EVs are released in both physiological and pathological conditions and can transport a variety of molecules, including proteins, metabolites, RNA, microRNAs, and DNA, to distant sites throughout the body. As such, they are emerging as a promising source of tumor biomarkers for the noninvasive diagnosis, prognosis, and monitoring of cancer patients. In particular, the wealth of tumor‐related information that can be gleaned from the EV proteomic cargo has become apparent through mass spectrometric analysis, which has provided new benchmarks for clinically focused biomarker research. In this review, the current achievements in the use of MS for identifying potential EV‐derived protein biomarkers of cancer are explored, and the techniques and challenges involved in this pursuit are summarized.

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“…Commercially available tests are licensed only as companion tests as they do not have the required diagnostic performance to replace cystoscopy (sensitivities of 57–82%) . Novel urinary biomarkers have reported high sensitivities but often lack robust prospective validation . Regardless of the performance of current or future urinary‐based biomarkers, it is essential to understand patient perception and willingness to forgo cystoscopy for non‐invasive testing.…”

Section: Introductionmentioning

confidence: 99%

Mixed‐methods approach to exploring patients’ perspectives on the acceptability of a urinary biomarker test in replacing cystoscopy for bladder cancer surveillance

et al. 2019

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Objectives To determine the minimal accepted sensitivity (MAS) of a urine biomarker that patients are willing to accept to replace cystoscopy and to assess qualitatively their views and reasons. Patients and Methods Patients were part of a prospective multicentre observational study recruiting people with bladder cancer for a urine biomarker study (DETECT II; ClinicalTrials.gov: NCT02781428). A mixed‐methods approach comprising (1) a questionnaire to assess patients’ experience with cystoscopy and patients’ preference for cystoscopy vs urinary biomarker, and (2) semi‐structured interviews to understand patient views, choice and reasons for their preference. Results A urine biomarker with an MAS of 90% would be accepted by 75.8% of patients. This was despite a high self‐reported prevalence of haematuria (51.0%), dysuria/lower urinary tract symptoms (69.1%) and urinary tract infection requiring antibiotics (25.8%). There was no association between MAS with patient demographics, adverse events experienced, cancer characteristics or distance of patients’ home to hospital. The qualitative analysis suggested that patients acknowledge that cystoscopy is invasive, embarrassing and associated with adverse events but are willing to tolerate the procedure because of its high sensitivity. Patients have confidence in cystoscopy and appreciate the visual diagnosis of cancer. Both low‐ and high‐risk patients would consider a biomarker with a reported sensitivity similar to that of cystoscopy. Conclusion Patients value the high sensitivity of cystoscopy despite the reported discomfort and adverse events experienced after it. The sensitivity of a urinary biomarker must be close to cystoscopy to gain patients’ acceptance.

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Novel urinary biomarkers for the detection of bladder cancer: A systematic review

Cited by 80 publications

References 96 publications

Noninvasive diagnosis of urothelial cancer in urine using DNA hypermethylation signatures—Gender matters

Noninvasive diagnosis of urothelial cancer in urine using DNA hypermethylation signatures—Gender matters

Tumor‐Derived Extracellular Vesicles as a Novel Source of Protein Biomarkers for Cancer Diagnosis and Monitoring

Mixed‐methods approach to exploring patients’ perspectives on the acceptability of a urinary biomarker test in replacing cystoscopy for bladder cancer surveillance

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