MicroRNA-371-3 cluster as biomarkers for the diagnosis and prognosis of cancers

Figures & data

Figure 1 Flow diagram of the study selection process.

Table 1 Characteristics of the studies included for diagnosis in the meta-analysis

Author	Year	microRNA	Ethnicity	Cancer type	Cancer grade	Sample type	Mean/Median age (years)		Sample size		Diagnostic power				Sensitivity	Specificity	AUC	Cut-off value	Method
							Ca	Co	Ca	Co	TP	FP	TN	FN
Dieckmann	2017	miR-371–3p	Caucasian	Germ cell tumours	CS1	Serum	38.5	38	107	106	87	8	98	20	81.40%	92.50%	/	Median	qRT-PCR
					CS2-CS3				43		42	8	98	1	98.60%	92.50%	/
Syring	2014	miR-371-3p	Caucasian	Testicular germ cell cancer		Serum	NM	NM	59	101	50	1	100	9	84.70%	99.00%	0.929	0.004	qRT-PCR
Liu	2012	miR-371-5p	Asian	Gastric cancer	I–IV	Serum	56	58	40	41	30	15	26	10	75.00%	63.41%	0.715	6.66	qRT-PCR
Hua	2017	miR-373	Asian	Pancreatic cancer	I–IV	Serum	NM	NM	103	50	83	8	42	20	80.60%	84.30%	0.852	Median	qRT-PCR
Eichelser	2013	miR-373	Caucasian	Breast cancer	M0	Serum	65	65	120	40	92	0	40	28	76.60%	100.00%	0.879	/	qRT-PCR
					M1				32		31	2	38	1	96.80%	94.10%	/	/
Chen	2013	miR-373	Caucasian	Breast ductal carcinoma	I–IV	Plasma	49	47	35	25	24	3	22	11	68.00%	89.00%	0.84	6.97	qRT-PCR

Notes: M0, patients with primary breast cancer after surgery and before chemotherapy; M1, patients with distant metastases at diagnosis (We roughly incorporated M0 into the early stage, and correspondingly incorporate M1 into the late stage.); qRT-PCR, quantitative real-time PCR.

Abbreviations: NM, not mentioned; CS, clinical stage.

Figure 2 Diagnostic value of miR-371. (A) Forest plots. (B) SROC curve.

Figure 3 Diagnostic value of miR-373. (A) Forest plots. (B) SROC curve.

Table 2 Characteristics of the studies included for miR-372 prognosis in tissue

First author	Year	Ethnicity	Age(median/mean)	Malignant disease	Survival indicator	Follow up months	Method	Cut-off value	Case number		OS		RFS/PFS/DFS		NOS sore
									H	L	HR(95%CI)(U/M)	P-value	HR (95%CI) (U/M)	P-Value
Bellmunt	2016	Caucasian	NM	UC	PFS	24	qRT-PCR	Median	40	40			1.73 (1.04, 2.89) U/ 1.70 (1.00, 2.89) M	0.05 U	5
Tu	2015	Asian	52.6	OSCC	DFS	160	qRT-PCR	Median	50	50			2.57 (1.20–5.48) U	0.002 U	6
Wu	2015	Asian	NM	HCC	OS	70	ISH	Mean	33	87	0.57 (0.38–0.85) U/ 0.53 (0.35–0.83) M	0.006 U/0.005 M			6
Li	2013	Asian	42	Gliomas	RR	148	qRT-PCR	Mean	78	50	4.37 (2.11–8.93) M	0.008 M			7
Yamashita	2012	Asian	66.8	CRC	OS	70	qRT-PCR	Median	72	72	2.03 (1.006–4.351) U/ 2.76 (1.322–6.110) M	0.048 U/0.006 M			6
Gu	2012	Asian	NM	HCC	OS/RFS	38	qRT-PCR	Median	65	43	20.36 (2.90–42.32) U/ 9.53 (1.74–28.67) M	0.001 U/0.008 M	12.73 (2.31–30.87) U/ 6.83 (1.51–19.05) M	0.0006 U/ 0.01 M	6

Note: qRT-PCR, quantitative real-time PCR; ISH, in situ hybridization; H, high expression; L, low expression; U, univariate analysis, M, multivariate analysis.

Abbreviations: NM, not mentioned; UC, urothelial carcinoma; OSCC, oral squamous cell carcinoma; HCC, hepatocellular carcinoma; CRC, colorectal cancer.

Table 3 Characteristics of the studies included for miR-373 prognosis in the meta-analysis

First author	Year	Dominant ethnicity	Age(median/mean)	Malignant disease	Detected sample	Survival analysis	Source of HR	Follow-up months	Male/ Female	Cut-off value	Case number		OS		RFS/PFS/DFS		NOS score
											H	L	HR (95%CI)(U/M)	P-value	HR(95%CI) (U/M)	P-value
Zhang	2017	Asian	NM	BCa	Tissues	OS	Reported	24	27/13	NM	40	40	0.441 (0.210–0.699)U	0.17 U			7
Hua	2017	Asian	NM	Pancreatic cancer	Serum	OS	Reported	70	62/41	Median	50	53	0.192 (0.119–0.472) M	0.014 M			5
Wang	2017	Asian	58.67	NSCLC	Tissues	OS	SC	70	56/36	Median	46	46	0.37 (0.15,0.92)	<0.001			6
Jing	2017	Asian	NM	Gliomas	Tissues	OS/RFS	SC	60	113/57	NM	83	87	0.40 (0.145–0.549) M	0.0007	0.3 (0.157,0.613)M	<0.001	7
Tu	2015	Asian	52.6	OSCC	Tissues	DFS	Reported	160	47/3	Median	50	50			2.62 (1.47–4.64) U	0.001 U	6
Meng	2015		60	EOC	Serum	OS/PFS	Reported	136	/	NM	47	46	2.1 (1.0–4.3)U/ 2.9 (1.3–6.8)M	0.033 U/ 0.012 M	1.6 (0.9–2.9) U	0.099 U	8

Abbreviations: NM, not mentioned; SC, survival curve; R, retrospective; qRT-PCR, quantitative real-time PCR; H, high expression; L, low expression; U, univariate analysis, M, multivariate analysis; BCa, bladder cancer; NSCLC, non-small cell lung cancer; OSCC, oral squamous cell carcinoma; EOC, epithelial ovarian cancer.

Figure 4 Forest plot of extracted HR for the association of miR-372 and miR-373 expression with OS/RFS/PFS/DFS.

Table 4 The pooled associations between characteristic subgroups of miR-371––3 expression and prognosis of patients

microRNA	Subgroup	Number of studies	Number of cases (High/low)	HR (95% CI)	Heterogeneity (I^2)	P-values
miR-372	Total	6	338/342	2.31 (1.04,5.14)	87.9%	<0.001
	Race
	Asian	5	298/302	2.55 (0.90,7.25)	90.2%	<0.001
	Caucasian	1	40/40	1.70 (1.00,2.89)	/	/
	Method
	qRT-PCR	5	305/255	2.94 (1.82,4.74)	48.4%	0.101
	ISH	1	33/87	0.53 (0.35,0.83)	/	/
	Cutoff
	Median	4	227/208	2.62 (1.54,4.46)	45.3%	0.139
	Mean	2	111/137	1.50 (0.19,11.74)	95.8%	<0.001
miR-373	Total	6	316/322	0.68 (0.27,1.68)	90.04%	<0.001
	Race
	Asian	5	269/276	0.51 (0.20, 1.31)	89.8%	<0.001
	Caucasian	1	47/46	2.90 (1.27,6.63)	/	/
	Sample source
	Tissue	4	172/177	0.66 (0.24,1.79)	88.9%	<0.001
	Serum	2	97/99	0.74 (0.05,10.57)	95.9%	<0.001
	Cutoff
	NM	3	170/173	0.78 (0.25,2.42)	87.7%	<0.001
	Median	3	146/149	0.58 (0.27,1.69)	94.4%	<0.001

Abbreviations: NM, not mentioned; qRT-PCR, quantitative real-time PCR; ISH, in situ hybridization.

Table S1 Characteristics of studies included in the meta-analysis

First author	Year	miRNA	Ethnicity	Cancer type	Sample type	Method	Cancer grade	Case (H)	Control (L)
Liu	2012	miR-371-5p	Asian	Gastric cancer	Serum	qRT-PCR	I–IV	40	41
Yamashita	2012	miR-372	Asian	CRC	Tissue	qRT-PCR	\	72	72
Gu	2012	miR-372	Asian	HCC	Tissue	qRT-PCR	\	65	43
Li	2013	miR-372	Asian	Gliomas	Tissue	qRT-PCR	\	78	50
Eichelser	2013	miR-373	Caucasian	Breast cancer	Serum	qRT-PCR	M0	120	40
							M1	32
Chen	2013	miR-373	Caucasian	Breast ductal carcinoma	Plasma	qRT-PCR	I–IV	35	25
Syring	2014	miR-371-3p	Caucasian	Testicular germ cell cancer	Serum	qRT-PCR	\	59	101
Tu	2015	miR-372	Asian	OSCC	Tissue	qRT-PCR	\	50	50
Tu	2015	miR-373	Asian	OSCC	Tissues	qRT-PCR	\	50	50
Meng	2015	miR-373	Caucasian	EOC	Serum	qRT-PCR	\	47	46
Wu	2015	miR-372	Asian	HCC	Tissue	ISH	\	33	87
Bellmunt	2016	miR-372	Caucasian	UC	Tissue	qRT-PCR	\	40	40
Dieckmann	2017	miR-371-3p	Caucasian	Germ cell tumours	Serum	qRT-PCR	CS1	107	106
							CS2-CS3	43
Hua	2017	miR-373	Asian	Pancreatic cancer	Serum	qRT-PCR	I–IV	103	50
Zhang	2017	miR-373	Asian	BCa	Tissues	qRT-PCR	\	40	40
Hua	2017	miR-373	Asian	Pancreatic cancer	Serum	qRT-PCR	\	50	53
Jing	2017	miR-373	Asian	Gliomas	Tissues	qRT-PCR	\	83	87
Wang	2017	miR-373	Asian	NSCLC	Tissues	qRT-PCR	\	46	46

Note: M0, patients with primary breast cancer after surgery and before chemotherapy; M1, patients with distant metastases at diagnosis (We roughly incorporated M0 into the early stage, and correspondingly incorporate M1 into the late stage).

Abbreviations: qRT-PCR, quantitative real-time PCR; H, high expression; L, low expression; CS, clinical stage; UC, urothelial carcinoma; OSCC, oral squamous cell carcinoma; HCC, hepatocellular carcinoma; CRC, colorectal cancer; BCa, bladder cancer; NSCLC, non-small cell lung cancer; EOC, epithelial ovarian cancer.

Figure 5 Forest plots of the miR-372 according to subgroup. (A) Cutoff value subgroup. (B) Detection method subgroup. (C) Race subgroup.

Figure 5 (Continued).

Figure 6 Forest plots of the miR-373 according to subgroup. (A) Cutoff value subgroup. (B) Race subgroup. (C) Sample source subgroup.

Figure 6 (Continued).

Figure 7 Sensitivity analyses. (A) miR-372. (B) miR-373.

Figure 8 Publication bias analysis. (A) miR-372. (B) miR-373.

Figure S1 The genomic localization chart and sequences of miR-371-3 cluster.