Noninvasive diagnosis of colorectal adenoma: The emerging potential of blood-based biomarkers

Table 1 Diagnostic potential of noncoding RNAs in blood for colorectal adenomas[18,19,21-23,25,26,31,34,77,83-92]

Ref.	Study type and population	Biomarkers	Grouped control	AUC	Sensitivity (%)	Specificity (%)
Min et al[23]	Prospective observational study; 24 CAA; 53 NC	EV-delivered 9 RNAs, 3 miRNAs, 4 mRNAs, 2 lncRNAs	CAA/NC	0.880
Shi et al[22]	Prospective observational study; 29 CRC; 24 CAA; 22 NC	EV-delivered miR-185-5p	CRC/CAA	0.700	75.86
			CAA/NC	0.737	65.52	81.82
Raut et al[21]	Retrospective observational study; 52 CRC; 100 CAA; 88 NAA; 173 NC	7 serum miRNAs, let-7 g-5p, miR-19a-3p, miR-23a-3p, miR-92a-3p, miR-144-5p, miR-21-5p, miR-27a-3p	CRC/CAA	0.380
			CAA/NAA	0.590
			NAA/NC	0.440
Zaki et al[19]	Prospective observational study; 54 CRC; 15 CRA; 15 NC	miR-92a	CRC/CRA	0.993	92.6	93.3
			CRA/NC	0.529	73.3	46.7
Qi et al[26]	Clinical experimental study; 80 CRC; 80 CRA	3 plasma circRNAs, hsa-circ-001978, hsa-circ-105039, hsa-circ-103627	CRC/CRA	0.966
Han et al[83]	Observational study; 81 CRC; 67 CRA	EV-delivered 3 miRNAs, miR-15b, miR-16, miR-21	CRC/CRA		85.19	82.09
Wang et al[84]	Case-control study and retrospective cohort study; 42 CRA; 36 NC	miR-1207-5p	CRA/NC	0.953	90.48	80.56
Pan and Miao[85]	Experimental study; 50 CAA; 50 NC	miR-592	CAA/NC	0.747	68.60	78.1
Li et al[25]	Retrospective observational study; 102 CRC; 30 CRA	CircPanel, hsa-circ-0001900, hsa-circ-0001178, hsa-circ-0005927	CRC/CRA	0.818	84.31	70.0
Xu et al[34]	Experimental study; 30 CRA; 42 NC	SNHG11, ZFAS1	CRA/NC	0.868
			CRA/NC	0.850
Wang et al[31]	Case-control study; 40 CRA; 40 NC	piR-020619, piR-020450, piR-020619 + piR-020450	CRA/NC	0.701	82.50	55.90
			CRA/NC	0.689	67.50	72.50
			CRA/NC	0.779	72.50	76.60
Marcuello et al[86]	Prospective observational study; 74 CAA; 80 NC	6 serum miRNAs, miR-15b-5p, miR-18a-5p, miR-29a-3p, miR-335-5p, miR-19a-3p, miR-19b-3p	CAA/NC	0.800	81	63
Liu et al[87]	Observational study and experimental study; 80 CRC; 50 CRA; 30 NC	miR-1290, miR-320d, miR-1290 + miR-320d	CRA/NC	0.780	75.53	87.41
			CRA/NC	0.740	79.64	71.55
			CRA/NC	0.820	77.46	88.69
Roberts et al[77]	Cross-sectional study; 7 CRA; 12 NC	2 small RNAs, a miR-335-5p isoform, an unannotated small RNA	CRA/NC	0.833
Uratani et al[88]	Retrospective observational study; 26 CRA; 47 NC	miR-21, miR-29a, miR-92a	CRA/NC	0.755	73.1	68.1
			CRA/NC	0.676	72.0	66.0
			CRA/NC	0.747	65.4	78.7
Carter et al[89]	Prospective observational study; 25 CRC; 25 CAA	4 plasma miRNAs, miR-29c, miR-122, miR-192, miR-374a	CRC/CAA	0.980	72.0-80.0	100
Zheng et al[90]	Prospective observational study; 117 CAC; 73 CRA; 102 NC	4 serum miRNAs, miR-19a-3p, miR-223-3p, miR-92a-3p, miR-422a	CAC/CRA	0.886
			CRA/NC	0.765
Wang et al[91]	Case-control study; 43 CAA; 58 NC	miR-601, miR-760, miR-601 + miR-760	CAA/NC	0.638	72.1	51.7
			CAA/NC	0.682	69.8	62.1
			CAA/NC	0.683	72.1	62.1
Kanaan et al[92]	Retrospective observational study; 45 CRC; 16 CRA; 26 NC	8 plasma miRNAs, miR-532-3p, miR-331, miR-195, miR-17, miR-142-3p, miR-15b, miR-532, miR-652. 5 plasma miRNAs, miR-331, miR-15b, miR-21, miR-142-3p, miR-339-3p	CRA/NC	0.868	88	64
			CRC/CRA	0.856	91	69
Huang et al[18]	Retrospective observational study; 37 CAA; 59 NC	miR-29a, miR-92a, miR-29a + miR-92a	CAA/NC	0.769	62.2	84.7
			CAA/NC	0.749	64.9	81.4
			CAA/NC	0.773	73.0	79.7

AUC: Area under the curve; CAA: Colorectal advanced adenoma; NC: Normal controls; CRC: Colorectal cancer; NAA: Nonadvanced colorectal adenoma; CRA: Colorectal adenoma; miRNA: MicroRNA; EV: Extracellular vesicle; lncRNA: Long noncoding RNA; mRNA: Messenger RNA; CAC: Colorectal adenocarcinoma.

Table 2 Methylation in the diagnostic potential of adenomas[50,51,53,93-98]

Ref.	Study type	Biomarkers	AUC	Sensitivity (%)	Specificity (%)
Wang et al[93]	Cross-sectional study	MethyDT test: Methylation levels of NTMT1 and MAP3K14-AS1	0.679	43.5
Wu et al[94]	Prospective study	ColonUSK test: Two CpG-rich subregions in the promoter of the Septin9 gene		25.26	93.53
Zhao et al[53]	Prospective cohort study	ColonSecure test: 149 hypermethylated CpG sites			89.7
Cai et al[51]	Clinical experimental study	ColonAiQ test: 6 methylation markers	0.84	42.1
Wu et al[95]	Retrospective observational study	cfDNA methylation model: 11 methylation biomarkers	0.85	76.5	82.7
Zhao et al[50]	Clinical experimental study	SpecColon test: Methylated SFRP2 and SDC2		58.3	87.9
Zhao et al[96]	Clinical experimental study	ColoDefense test: Methylated SEPT9 and SDC2	0.754	47.8	92.8
Potter et al[97]	Prospective clinical study	Epi proColon test: Methylation of the SEPT9 gene promoter region		22	78.8
Church et al[98]	Prospective observational study	Epi proColon test: Methylated SEPT9 DNA		14.4	88.4

AUC: Area under the curve; cfDNA: Cell-free DNA.

Table 3 Potential of proteomics-based differential markers in the diagnosis of adenomas[56,57,59,99]

Ref.	Detection methods	Biomarkers	AUC	Sensitivity (%)	Specificity (%)
Jin et al[99]	PEA + ML	TGM2, MMP7, GDF15, RNASE3, REG1B	0.921
Zhang et al[56]	DIA-MS + ML	APOA4, SERPINA3, GPX3, SNCA, YKT6, RAN, ENPP2, ANTXR1, THBS4, SPP2	1.0
Hua et al[59]	DDA + DIA + MRM + ML	LRG1, C9, IGFBP2, CNDP1, ITIH3, SERPINA1, ORM1		49
Huang et al[57]	4D-DIA + CRC-EV array + ML	EVs-FIBG, EVs-PDGF-β, EVs-TGF-β	0.822 (training set); 0.767 (testing set)	68.0 (training set); 56.0 (testing set)	94.9 (training set); 89.3 (testing set)

AUC: Area under the curve; PEA: Proximity extension assay; ML: Machine learning; DIA-MS: Data-independent acquisition mass spectrometry; DDA: Data-dependent acquisition; DIA: Data-independent acquisition; MRM: Multiple reaction monitoring; 4D-DIA: Four-dimensional data-independent acquisition; CRC-EV: Colorectal cancer-extracellular vesicle antibody microarray; EV: Extracellular vesicle; FIBG: Fibrinogen; PDGF: Platelet-derived growth factor; TGF: Transforming growth factor.

Table 4 Diagnostic potential of metabolites for adenomas[66,70,100,101]

Ref.	Study type and population	Biomarkers	Grouped control	AUC	Sensitivity (%)	Specificity (%)
Huang et al[100]	Retrospective multi-center case-control study; 219 CRC; 164 CRA	6 plasma metabolites, 3 lipids and lipid-like molecules, 2 organic oxygen compounds, 1 phenylpropanoid	CRC/CRA	0.905	84.0	81.7
Huang et al[100]	Retrospective multi-center case-control study; 164 CRA; 219 NC	7 plasma metabolites, 5 lipids and lipid-like molecules, 1 organic nitrogen compound, 1 organic acid	CRA/NC	0.997	97.0	97.7
Sun et al[70]	Multi-center case-control study; 111 CRC; 143 CRA; 119 NC	17 plasma metabolites	CRC/CRA	0.928	89.0	88.7
			CRA/NC	0.968	87.0	97.2
Guo et al[101]	Observational study; 19 CRC; 26 CRA; 20 NC	5 serum metabolites and 5 gut bacteria, 7 serum metabolites and 6 gut bacteria	CRC/CRA	0.850	84.21	76.92
			CRA/NC	0.880	75.00	96.15
Zhang et al[66]	Clinical case-control study; 200 CRC; 160 CRA	3 plasma metabolites ribitol, beta-hydroxybutyric acid, lactic acid	CRC/CRA	0.960

AUC: Area under the curve; CRC: Colorectal cancer; CRA: Colorectal adenoma; NC: Normal controls.