Emerging biomarkers for the diagnosis and monitoring of urothelial carcinoma

Figures & data

Figure 1 Main liquid biopsies in urothelial carcinoma of the bladder and upper urinary tract carcinoma

Notes: Several materials are available as liquid biopsy samples. In urothelial carcinoma, two main liquid biopsies are widely used for initial detection of primary tumors and monitoring systems after treatment. Urine sample is mostly used for non-muscle disease, whereas serum and plasma allow the follow-up and prediction of treatment response predominantly in advanced diseases. The commercially available assays that are approved by the US Food and Drug Administration and/or Japanese health insurance are indicated by rectangles.
Abbreviations: BTA, bladder tumor antigen; CTC, circulating tumor cells; UBC, urinary bladder cancer.

Table 2 Urine-based tests to diagnosis and post-RNU monitoring for upper tract urothelial carcinoma

Name of assay	Biomaterial	Marker description	Assay	Application purpose	Diagnostic accuracy (%)		Reference
					Sensitivity	Specificity
Urine cytology	Sediment (voiding urine)	Morphology	Staining and microscopical exam	Diagnosis	50–59	83–100	^Citation69, ^Citation71
				Monitoring the intravesical recurrence	50	100	^Citation70
	Sediment (ureteral catheterization)	Morphology	Staining and microscopical exam	Diagnosis	75	67	^Citation71
ImmunoCyt/uCyt+	Sediment (voiding urine)	Tumor-associated cellular antigens (M344, LDQ10, 19A11)	Immunofluorescence	Diagnosis	75	95	^Citation69
	Sediment (ureteral catheterization)	Tumor-associated cellular antigens (M344, LDQ10, 19A11)	Immunofluorescence	Diagnosis	91	100	^Citation69
UroVysion	Sediment (voiding urine)	Aneuploidy for chromosomes 3, 7, and 17 and loss of the 9p21 locus	Multitarget FISH	Diagnosis	77	95	^Citation72
NMP-22	Protein (voiding urine)	NuMA	Sandwich ELISA	Diagnosis	44	98	^Citation73
BTA stat	Protein (voiding urine)	hCFHrp	Dipstick immunoassay (POC)	Diagnosis	82	89	^Citation74
NA	DNA	CDH1, HSPA2, RASSF1A, TMEFF2, VIM, and GDF15 promoter methylations	Quantitative methylation-specific PCR	Diagnosis	84	91	^Citation81
NA	DNA	TERT promoter mutations	Sanger sequencing	Diagnosis	60	97	^Citation82
			Competitive allele-specific TaqMan PCR	Diagnosis	90	92	^Citation82
NA	DNA	GDF15, TMEFF2, and VIM promoter methylations	Quantitative methylation-specific PCR	Diagnosis	91	100	^Citation83

Abbreviations: BTA, bladder tumor antigen; FISH, fluorescence in situ hybridization; NA, not available; POC, point-of-care; RNU, radical nephroureterectomy; TERT, telomerase reverse transcriptase.

Table 1 Urine-based tests to diagnosis and post-TURBT monitoring for bladder cancer (BCa)

Name of assay	Biomaterial	Marker description	Assay	Application purpose	Diagnostic accuracy (%)		Approval		Reference
					Sensitivity	Specificity	FDA	Japanese health insurance
Urine cytology	Sediment	Morphology	Staining and microscopical exam	Diagnosis	38	98	Yes	Yes	^Citation31
				Monitoring	16–53	94–100	Yes	Yes	^Citation32, ^Citation33
ImmunoCyt/uCyt+	Sediment	Tumor-associated cellular antigens (M344, LDQ10, 19A11)	Immunofluorescence	Monitoring	73	66	Yes	No	^Citation35
UroVysion	Sediment	Aneuploidy for chromosomes 3, 7, and 17 and loss of the 9p21 locus	Multitarget FISH	Diagnosis	72	83	Yes	No	^Citation36
				Monitoring	50–92	72–93	Yes	Yes	^Citation37, ^Citation38
5-ALA-mediated fluorescent urine cytology	Sediment	Intracellular accumulation of protoporphyrin IV	Fluorescence detection devices	Diagnosis	70–87	68–80	No	No	^Citation43, ^Citation44
NMP-22	Protein	NuMA	Sandwich ELISA	Surveillance	40	99	Yes	Yes	^Citation45
NMP-22 BladderChek	Protein	NuMA	Dipstick immunoassay (POC)	Diagnosis and monitoring	68	79	Yes	No	^Citation46
BTA TRAK	Protein	hCFHrp	Sandwich ELISA	Monitoring	57–83	60–92	Yes	No	^Citation47, ^Citation48
BTA stat	Protein	hCFHrp	Dipstick immunoassay (POC)	Monitoring	58	72–95	Yes	No	^Citation47
UBC test	Protein	Cytokeratin 8/18 fragment	Sandwich ELISA	Diagnosis	64	80	No	Yes	^Citation49
CxBladder Detect	mRNA	IGFBP5, MDK, HOXA13, CDK1, and CXCR2	RT-PCR	Diagnosis	82	85	Yes	No	^Citation61
CxBladder Monitor	mRNA	IGFBP5, MDK, HOXA13, CDK1, and CXCR2	RT-PCR	Monitoring	91	96 (NPV)	Yes	No	^Citation62
Xpert Bladder Cancer Detection	mRNA	ABL1, CRH, IGF2, UPK1B, and ANXA10	RT-PCR	Diagnosis	77	85	Yes	No	^Citation64
Xpert Bladder Cancer Monitor	mRNA	ABL1, CRH, IGF2, UPK1B, and ANXA10	RT-PCR	Monitoring	84	91	Yes	No	^Citation65
FGFR3 gene mutation	DNA	FGFR3	PCR	Diagnosis	46% (Ta tumor) 53% (low-grade tumor)	NA	No	No	^Citation59
				Monitoring	78	100	No	No	^Citation53

Abbreviations: 5-ALA, 5-aminolevulinic acid; BTA, bladder tumor antigen; FDA, US Food and Drug Administration; FISH, fluorescence in situ hybridization; NPV, negative predictive value; POC, point-of-care; RT-PCR, reverse transcription-PCR; TURBT, transurethral resection of bladder tumor; UBC, urine bladder cancer.

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