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. 2020 May 9;21(9):3360. doi: 10.3390/ijms21093360

Table 1.

Predictive capacity of bladder cancer biomarkers.

Protein Name Gene Symbol Purpose Diagnostic Value Prognostic Value FDA Approved Method Samples Used (No. Patients) Predicitive Capacity Reference
CYFRA 21.1 KRT19 Diagnostic and surveillance Both serum and urine CYFRA 21.1 levels provide an effective index for the diagnosis of BC. High risk of malignancy- significantly higher serum level of CYFRA 21.1 according to tumour stage (p < 0.01) and grade (p < 0.05). Patients with increased CYFRA 21.1 level had significantly worse disease-specific survival (p < 0.0001, log rank test) [19]. Moreover, patients with metastases had a higher CYFRA 21.1 level than those with locally invasive BC [14]. No Meta-analysis performed using STATA 12.0 on the base of studies had published before 2 November 2014 in EMBASE, Web of Science and Medline databases. Quality of the studies was assessed by revised QUADAS tools, all of selected studies were English language publications and evaluate diagnostic accuracy of CYFRA 21.1 in patients with BC. Systematic review included 13 studies and 1,262 BC and 1,233 non-bladder cancer patients. 8 studies measured urine and 5 serum level of CYFRA 21.1. In serum detection of CYFRA 21.1 471 BC and 296 non- bladder cancer patients were analyzed. Urine CYFRA 21.1 studies included 538 BC and 678 non-bladder cancer patients. Urine (n = 538 BC/678 control) Sensitivity = 82% Specificity = 80%
AUC = 0.87
[12,13,14,19]
Serum (n = 471 BC/296 control) Sensitivity = 42% Specificity = 94%
AUC = 0.88
DNA EXCISION REPAIR PROTEIN ERCC-1 ERCC1 Diagnostic and surveillance 71.3% (308/432) of cases was ERCC1 positive. Ta = 3.2% T1 = 11.7% T2 = 21.4% T3 = 45.1% T4 = 18.5%
CIS = 8.1%
LG = 20.8%
HG = 79.2%
ERCC positive tumour had significantly better disease-free survival (HR 0.7, p = 0.028) than ERCC1 negative tumours. ERCC1 positive tumours has significantly reduced risk of recurrences (HR 0.71, p = 0.021). The 5-year DFS and CSS were better for ERCC1 positive than negative, and were respectively 62% vs 49% and 70% vs 59%. However, there was no important outcomes of adjuvant cisplatin-based chemotherapy by ERCC1 status. No Study cohort had 432 patients and 308 of tumours expressed ERCC1. Staining was conducted using Abcam® mouse monoclonal antibody and expression of ERCC1was evaluated by 2 pathologists. Chi-square test was made to assessed differences between ERCC1 expression. All analyses were performed with STATA®, version 13.1.
Primary tumour samples collected at RC, cells were lysed and total RNA was extracted with Qiagen® kit. ERCC1 mRNA expression was measured by RNA sequencing and confirmed by qPCR using TaqMan® gene expression assays.
UCB cell lines in vitro (n = 432) No data [22]
TUMOR SUPPRESSOR P53 TP53 gene Diagnostic (as a complementary tool) and surveillance 54% (56/103) of cases had TP53 mutations.
Ta = 40%
T1 = 52%
T2 = 80%
CIS = 55%
LG = 34%
HG = 62%
High risk of malignancy-significant difference of TP53 mutations according to tumour stage (p = 0.005) and to cellular grade (p < 0.001). No Sample collection of urine and tumours from 103 patients. Extraction of mRNA was made by Micro mRNA Purification Kit. Then Verso Kit® were used to reverse transcription, amplification was performed by PCR PrimeStar®. FASAY assay was used to detect TP53 mutations in tumour tissues and urinary cells. Statistical test was performed using SPSS software®, version 17. Primary bladder tumours and associated urine (n = 103) Sensitivity = 34% Specificity = 87%
PPV = 0.76
NPV = 0.53
[23]
FIBROBLAST GROWTH FACTOR RECEPTOR 3 FGFR3 gene Diagnostic (as a complementary tool) and surveillance 36% (37/103) of cases had FGFR3 mutations. Ta = 55%
T1 = 29%
T2 = 19%
CIS = 10%
LG = 62%
HG = 26%
Low risk of malignancy-negative association of FGFR3 mutations based on tumour stage (p = 0.002) and cellular grade (p < 0.001) [23]. Low level of FGFR3 expression is an independent predictor of cancer progression and is associated with HG tumours [24]. No * Sample collection of urine and tumours from 103 patients. Extraction of genomic DNA was performed by QIAamp Viral RNA® Mini kit. Multiplex PCR Kit were used to amplification. Snapshot ® kit was used to detect FGFR3 eight most frequent mutations hotspots in tumour tissues and urinary cells (two independent analysis were carried out). Statistical test was performed using SPSS software®, version 17. Primary bladder tumours and associated urine (n = 103) Sensitivity = 43%
Specificity = 98%
PPV = 0.94
NPV =0.76
[23]
Sensitivity = 97.6%
Specificity = 84.8%
AUC = 0.96
NPV = 0.996 (1)
[25]
TUMOR-ASSOCIATED TRYPSIN INHIBITOR SPINK1 gene Diagnostic and surveillance 49.1% (54/110) of cases had TATI expression.
Stage <T2 = 66.7%
Stage ≥T2 = 44.9% LG = 76.2% HG = 44.9%
Low risk of malignancy- negative association of TATI expression was positively correlated based on tumour stage (p = 0.048) and poor differentiation (p = 0.013). Significant differences were observed between TATI-positive and negative specimens in PFS and OS (Log-rank test, p = 0.003, 0.003). In a group of patients with BC undergoing RC TATI expression was independent protective factor. Moreover, TATI expression could enhance prognostic value of p53. No Study cohort had 110 patients and 54 of tumours, undergone RC, expressed TATI. Staining was conducted using Abcam® anti-TATI monoclonal antibody and expression of TATI was evaluated by 2 pathologists. Proportion of immune-positive cells and their staining intensity was scored in two scales and used to evaluation of TATI expression. All analyses were performed with SPSS software, version 21. Tissue microarrays from UCB (n = 110) No data [26]
Study cohort consisted of 160 patients, divided into 3 groups. Group 1 had 80 primary HG UBC. Group 2 of 40 healthy volunteers and group 3 of 40 benign UBC. TATI was measured using a radioimmunoassay according to the manufacturer’s instructions (Orion Diagnostica). Analyses were performer with STATA®, statistical software, version 6.0 Urine (n = 160) Sensitivity = 85.7%
Specificity = 77.5%
[27]

(1) Using a logistic regression analysis with a model consisting of the 3 markers’ methylation values, FGFR3 status, age and known smoker status at the diagnosis time. * It is available THERASCREEN® FGFR RGQ RT-PCR KIT. Abbreviations: HR—Hazard Ratio, n—number of patients participating in study, p—calculated probability, CIS—carcinoma in situ, HG—high grade, LG—low grade, FASAY—Functional Analysis of Separated Allele in Yeast, ELISA—enzyme-linked immunosorbent assay, IHC—immunohistochemistry, RC—radical cystectomy, BC—bladder cancer, CCS—cancer specific survival, DFS—disease-free survival, UCB—urothelial carcinoma of bladder, qPCR—quantitative polymerase chain reaction, PPV—positive predictive value, NPV—negative predictive value.