Blood-based biomarkers for early detection of esophageal squamous cell carcinoma

Table 1 Technologies for detection of esophageal squamous cell carcinoma

Technology	Quantitative	Qualitative	Advantages	Disadvantage	Ref.
Endoscopy	-	+	(1) Obvious observation of esophageal mucosal changes, lesion changes, and lesion size and morphology; and (2) Low false negative rate and false positive rate	(1) Invasiveness; (2) Easy to cause complications such as sore throat after examination; and (3) High cost	[15,16]
Blood-based biomarker	+	+	(1) Non-invasive; (2) Easy to operate; (3) Low cost; (4) Suitable as a screening tool; and (5) Identification of asymptomatic patients at risk	High false Negative rate and false positive rate	[16-18]

Table 2 Diagnostic performance of tumor-associated autoantibodies in esophageal squamous cell carcinoma

Target antigen of autoanti-body	Ref.	Year of publication	ESCC, n	Controls, n	All stages/early stage			P value	Detection method
					Sensitivity (%)	Specificity (%)	AUC
p53	Zhang et al[38]	2016	324 (Training)	324 (Training)	55.9/-	89.5/-	0.784/-	< 0.001	ELISA
			186 (Validation)	186 (Validation)				< 0.001	ELISA
	Xu et al[39]	2014	388 (Test)	125 (Test)	30.0/-	98.0/-		< 0.0001	ELISA
			237 (Validation)	134 (Validation)	29.0/-	97.0/-		< 0.0001	ELISA
	Qin et al[40]	2014	174	242	21.8/-	96.3/-	0.6/-	< 0.05	ELISA
	Chai et al[41]	2014	157	85	22.9/-	100/-		< 0.01	ELISA
	Zhou et al[42]	2014	88	200	22.0/-	98.0/-		< 0.01	ELISA
	Cai et al[43]	2008	46	30	39.1/22.2	100/100		< 0.001	ELISA
	Looi et al[44]	2006	71	82	7.0/-	98.8/-		< 0.05	ELISA
	Müller et al[45]	2006	50	436	20.0/-	100/-		< 0.05	Western blot
	Megliorino et al[46]	2005	77	82	14.3/-	97.6/-		< 0.01	ELISA
	Shimada et al[47]	2003	301	205	30.0/-	95.5/-		< 0.05	ELISA
	Shimada et al[48]	2002	105	153	26.7/20.0	95.5/95.5		< 0.001	ELISA
	Ralhan et al[49]	2000	60	50		60.0/-	92.0/-	< 0.05	ELISA
	Shimada et al[50]	2000	35	69	40.0/-	100/-		< 0.001	ELISA
	Hagiwara et al[51]	2000	46	13	28.0/28.6	100/100		< 0.05	ELISA
	Shimada et al[52]	1998	57	208	58.0/-	99.0/-		< 0.05	ELISA
	Sobti et al[53]	1998	20	20	30.0/-	100/-		0.02	ELISA
	Cawley et al[54]	1998	23	19	34.8/-	94.7/-		0.037	ELISA
p16	Zhang et al[38]	2016	324 (Training)	324 (Training)	29.3/-	81.8/-	0.60/-	< 0.001	ELISA
			186 (Validation)	186 (Validation)				< 0.01
	Jin et al[55]	2015	88	208				0.05	ELISA
	Qin et al[40]	2014	174	242	18.4/-	98.8/-	0.6/-	< 0.05	ELISA
	Zhou et al[42]	2014	88	200	11.0/-	97.0/-		0.004	ELISA
	Looi et al[44]	2006	71	82	14.1/-	98.8/-		< 0.05	ELISA
c-Myc	Zhang et al[38]	2016	324 (Training)	324 (Training)	49.1/-	81.5/-	0.699/-	< 0.001	ELISA
			186 (Validation)	186 (Validation)				< 0.001	ELISA
	Qin et al[40]	2014	174	242	15.5/-	98.8/-	0.6/-	< 0.05	ELISA
	Zhou et al[42]	2014	88	200	18.0/-	96.0/-		< 0.001	ELISA
	Looi et al[44]	2006	71	82	7.0/-	100/-		< 0.05	ELISA
	Megliorino et al[46]	2005	77	82	11.7/-	100/-		< 0.01	ELISA
Survivin	Xiu et al[56]	2018	159	362	14.5/-	90.0/-	0.327/-	0.524	ELISA
	Qin et al[40]	2014	174	242	12.1/-	99.6/-		< 0.05	ELISA
	Zhou et al[42]	2014	88	200	9.0/-	96.0/-		0.06	ELISA
	Megliorino et al[46]	2005	77	82	10.4/-	97.6/-		< 0.05	ELISA
NY-ESO-1	Oshima et al[57]	2016	172	74	32.0/16.0	100/100		< 0.001	ELISA
	Xu et al[39]	2014	388 (Test)	125 (Test)	26.0/-	100/-		< 0.0001	ELISA
			237 (Validation)	134 (Validation)	24.0/-	99.0/-		< 0.0001	ELISA
	Fujita et al[58]	2004	51	29	3.9/-	100/-		0.532	ELISA
Hsp 70	Xu et al[39]	2014	388 (Test)	125 (Test)	11.0/-	99.0/-		< 0.001	ELISA
			237 (Validation)	134 (Validation)	8.0/-	99.0/-		< 0.01	ELISA
	Zhang et al[59]	2011	69	76	39.1/-	92.3/-		> 0.01	ELISA
	Fujita et al[60]	2008	16	13	93.7/-	100/-		< 0.001	ELISA

Table 3 Diagnostic performance of microRNAs in esophageal squamous cell carcinoma

MicroRNA	Ref.	Year of publication	ESCC, n	Controls, n	All stages/early stage			P value	Detection method
					Sensitivity (%)	Specificity (%)	AUC
miR-21	Wang et al[76]	2018	31	32	71.0/-	96.9/-	0.88/-	< 0.001	qRT-PCR
	Sharma et al[77]	2018	24	21	83.3/-	57.2/-	0.692/-	0.027	qRT-PCR
	Zhang et al[78]	2018	125	125	74.0/-	78.0/-	0.80/0.86	< 0.001	RT-qPCR
	Lv et al[79]	2016	126	80			0.796/ 0.812	0.021	qRT-PCR
	Li et al[80]	2015	38	19			0.690/-	0.017	qRT-PCR
	Ye et al[81]	2014	100	50	/97.0	/56.0	/0.837	< 0.001	qRT-PCR
	Kurashige et al[82]	2012	71	39				< 0.001	qRT-PCR
	Wang et al[83]	2012	174	39	71.0/-	69.2/-	0.740/-	< 0.001	qRT-PCR
	Komatsu et al[84]	2011	50	20			0.618/-	0.022	qRT-PCR
miR-223	Zhang et al[78]	2017	125	125	0.68/-	0.68/-	0.73/0.83	< 0.001	RT-qPCR
	Zhou et al[85]	2017	137	155			0.649/-	< 0.001	RT-qPCR
	Wu et al[86]	2014	194	98			0.734/-	0.001	RT-qPCR
	Wu et al[87]	2014	20 (Test)	20 (Validation)			0.90/-	< 0.001	RT-qPCR
			63 (Test)	63 (Validation)			0.77/-	< 0.001	RT-qPCR
	Zhang et al[73]	2010	149	100	83.2/-	83.0/-	0.911/-	< 0.05	RT-qPCR
miR-375	Zhang et al[78]	2017	125	125	0.78/-	0.59/-	0.69/0.87	< 0.001	RT-qPCR
	Lv et al[79]	2016	126	80			0.712/ 0.739	0.023	qRT-PCR
	Li et al[80]	2015	38	19			0.921/-	< 0.0001	qRT-PCR
	Wu et al[86]	2014	194	98			0.720/-	0.007	RT-qPCR
	Komatsu et al[84]	2011	50	20			0.807/-	0.005	qRT-PCR
miR-25	Wang et al[76]	2018	31	32	71.0/-	68.8/-	0.72/-	< 0.001	qRT-PCR
	Zhang et al[78]	2017	125	125	0.54/-	0.57/-	0.55/-	0.025	RT-qPCR
	Wu et al[87]	2014	20 (Test)	20 (Validation)			0.94/-	< 0.001	RT-qPCR
			63 (Test)	63 (Validation)			0.78/-	< 0.001	RT-qPCR
	Wu et al[86]	2014	194	98	47.1/-	71.6/-	0.593/-	0.009	RT-qPCR
	Komatsu et al[88]	2014	20	50	85.0/-	86.0/-	0.856/-	< 0.0001	RT-qPCR
miR-100	Zhang et al[78]	2017	125	125	0.58/-	0.58/-	0.58/0.79	0.164	RT-qPCR
	Wu et al[87]	2014	20 (Test)	20 (Validation)			0.88/-	< 0.001	RT-qPCR
			63 (Test)	63 (Validation)			0.75/-	< 0.001	RT-qPCR
	Zhang et al[73]	2010	149	100	63.8/-	81.0/-	0.817/-	< 0.05	RT-qPCR

ESCC: Esophageal squamous cell carcinoma; AUC: Area under the curve.

Table 4 Diagnostic performance of long non-coding RNAs in esophageal squamous cell carcinoma

LncRNA	Ref.	Year of publication	ESCC, n	Controls, n	All stages/early stage			P value	Detection method
					Sensitivity (%)	Specificity (%)	AUC
POU3F3	Hu et al[102]	2016	205	210			0.584/-	< 0.01	qRT-PCR
	Tong et al[103]	2015	147	123	72.8/69.2	89.4/-	0.842/-	< 0.001	qPCR
HOTAIR	Wang et al[104]	2017	50	20	56.0/-	90.0/-	0.793/-	< 0.01	qRT-PCR
HNF1A-AS1	Tong et al[103]	2015	147	123	32.7/-		0.781/-	< 0.001	qPCR
SPRY4-IT1	Tong et al[103]	2015	147	123	48.2/-		0.800/-	< 0.001	qPCR
linc00152	Hu et al[102]	2016	205	210			0.698/-	< 0.01	qRT-PCR
CFLAR-AS1	Hu et al[102]	2016	205	210			0.651/-	< 0.01	qRT-PCR
PGM5-AS1	Zhihua et al[105]	2019	41	26			0.894/-	< 0.001	qRT-PCR

ESCC: Esophageal squamous cell carcinoma; AUC: Area under the curve; lncRNA: Long noncoding RNA; POU3F3: POU class 3 homeobox 3; HOTAIR: HOX transcript antisense RNA; HNF1A‐AS1: Hepatocyte nuclear factor 1 homeobox A antisense RNA 1; SPRY4-IT1: SPRY4 intronic transcript 1; Linc00152: long intergenic non-protein-coding RNA. CFLAR-AS1: CFLAR antisense RNA 1; PGM5-AS1: PGM5 antisense RNA 1.

Table 5 Diagnostic performance of cytokines in esophageal squamous cell carcinoma

Cytokine	Ref.	Year of publication	ESCC, n	Controls, n	All stages/early stage			P value	Detection method
					Sensitivity (%)	Specificity (%)	AUC
VEGF-A	Kozłowski et al[139]	2013	89	30	83.0/-	70.0/-	0.865/-	< 0.001	ELISA
	Krzystek-Korpacka et al[140]	2008	70	42	72.5/-	66.0/-	0.739/-	< 0.001	ELISA
	Krzystek-Korpacka et al[141]	2007	70	47	70.0/-	81.0/-	0.837/-	< 0.001	ELISA
	Ren et al[142]	2005	72	15				< 0.001	ELISA
	Shimada et al[143]	2001	96	24	79.0/-	48.0/-		0.001	ELISA
VEGF-C	Kozlowski et al[144]	2010	110	30	60.0/-	80.0/-		< 0.001	ELISA
	Krzystek-Korpacka et al[140]	2008	70	42	78.6/-	76.6/-	0.841/-	< 0.001	ELISA
IL-8	Tong et al[145]	2018	10	10				< 0.05	ELISA
	Krzystek-Korpacka et al[140]	2008	70	42	77.1/-	74.4/-	0.782/-	< 0.001	ELISA
	Ren et al[146]	2005	149	35				< 0.001	ELISA
	Ren et al[142]	2005	72	15				< 0.001	ELISA
IL-6	Tong et al[145]	2018	10	10				< 0.05	ELISA
	Łukaszewicz-Zając et al[147]	2011	30	90	87.0/-	92.0/-	0.924/-	< 0.001	ELISA

ESCC: Esophageal squamous cell carcinoma; AUC: Area under the curve; VEGF-A: Vascular endothelial growth factor A; VEGF-C: Vascular endothelial growth factor C; IL-8: Interleukin-8; IL-6: Interleukin-6.