Autoantibodies: Potential clinical applications in early detection of esophageal squamous cell carcinoma and esophagogastric junction adenocarcinoma

Table 1 A brief summary of the biological significance of some common tumor-associated autoantibodies

Representative tumor-associated autoantigens	Authors, year	Tumor type	Biological significance
p53	Chapman et al[11], 2012	Lung	Early detection
	Takeda et al[14], 2001	Colorectal	Increased recurrence
	Anderson et al[15], 2010	Ovarian	Increased survival
NY-ESO-1	Shan et al[16], 2013	Lung	Early detection
	Fosså et al[17], 2004	Prostate	Decreased survival
	Elke et al[18], 1999	Melanoma	Therapeutic monitoring
MUC1	Pedersen et al[19], 2014	Ovarian	Early detection
	Kurtenkov et al[20], 2007	Gastric	Increased survival
Hu	Chapman et al[11], 2011	Lung	Early detection
	Graus et al[21], 1997	Lung	Therapeutic monitoring and increased survival

MUC1: Mucin-1.

Table 2 Diagnostic performance of single tumor-associated autoantibody biomarkers in esophageal squamous cell carcinoma

Target antigen of auto-anti-bodies	Authors, year	ESCC cases, n	Stage, n					Con-trols, n	P value	Sensiti-vity, all stages/ early stage	Specifi-city, all stages/ early stage	AUC, all stages/ early stage	Method
			0/I	II	III	IV	Tx
Survivin	Xiu et al[57], 2018	159	-	-	-	-	159	362	0.524	14.5%/-	90.0%/-	0.327/-	ELISA
	Qin et al[58], 2014	174	3/8	79	52	18	-	242	< 0.05	12.1%/-	99.6%/-	99.6/-	ELISA
	Zhou et al[44], 2014	88	-	-	-	-	88	200	0.06	9.0%/-	96.0%/-	-	ELISA
	Meglior-ino et al[59], 2005	77	-	-	-	-	77	82	< 0.05	10.4%/-	97.6%/-	-	ELISA
TOPO48	Zhang et al[60], 2018	112	29	28	28	27	-	112 healthy volunte-ers and 75 esopha-geal benign tumor patients	0.001	49.1%/ 61.4%	100%/ 100%	-/0.860	ELISA
L1CAM	Xu et al[61], 2017	191 (Cohort 1)	10	104	77	-	-	94 (Cohort 1)	0.005	26.2%/ 25.2%	90.4%/ 90.4%	0.603/ 0.611	ELISA
		47 (Cohort 2)	5	18	24	-	-	47 (Cohort 2)	0.032	27.7%/ 33.3%	91.5%/ 91.5%	0.628/ 0.636	ELISA
Ezrin	Li et al[62], 2017	149	4/14	57	71	3	149	98	< 0.0001	27.5%/ 27.8%	95.9%/ 95.9%	-	ELISA
STIP1	Xu et al[63], 2017	148 (Train-ing)	3/17	48	76	4	148	111 (Train-ing)	< 0.001	41.9%/ 35.7%	90.1%/ 90.1%	0.682/ 0.684	ELISA
		60 (Valida-tion)	1/8	20	30	1	60	40 (Valida-tion)	< 0.001	40.0%/ 38.5%	92.5%/ 92.5%	0.710/ 0.756	ELISA
Fascin	Chen et al[64], 2017	149	4/14	57	71	3	149	98	< 0.001	24.8%/ 20.6%	99.0%/ 99.0%	0.636/ 0.632	ELISA
DKK-1	Peng et al[65], 2016	185 (Train-ing)	4/23	69	85	4	185	97 (Train-ing)	< 0.0001	33.5%/ 34.6%	91.8%/ 91.8%	0.643/ 0.640	ELISA
		104 (Valida-tion)	1/12	35	53	3	104	53 (Valida-tion)	< 0.0001	33.7%/ 26.9%	92.5%/ 92.5%	0.629/ 0.603	ELISA
P16	Zhang et al[55], 2016	324 (Train-ing)	5/13	130	50	39	87	324 (Train-ing)	< 0.001	29.3%/-	81.8%/-	0.60/-	ELISA
		186 (Valida-tion)	1	29	14	46	96	186 (Valida-tion)	< 0.01	-	-	-	ELISA
	Jin et al[66], 2015	88	24	42	15	2	5	208	0.0052	5.7%/-	99.1%/-	-	ELISA
	Qin et al[58], 2014	174	3/8	79	52	18	-	242	< 0.05	18.4%/-	98.8%/-	0.6/-	ELISA
	Zhou et al[44], 2014	88	-	-	-	-	88	200	0.004	11.0%/-	97.0%/-	-	ELISA
	Looi et al[67], 2006	71	-	-	-	-	-	82	< 0.05	14.1%/-	98.8%/-	-	ELISA
p53	Zhang et al[55], 2016	324 (Train-ing)	5/13	130	50	39	87	324 (Train-ing)	< 0.001	55.9%/-	89.5%/-	0.784/-	ELISA
		186 (Valida-tion)	1	29	14	46	96	186 (Valida-tion)	< 0.001	-/-	-/-	-/-	ELISA
	Xu et al[43], 2014	388 (Test)	2/29	96	229	27	5	125 (Test)	< 0.0001	30.0%/-	98.0%/-	-	ELISA
		237 (Valida-tion)	2/31	114	90	-	-	134 (Valida-tion)	< 0.0001	29.0%/-	97.0%/-	-	ELISA
	Qin et al[58], 2014	174	3/8	79	52	18	-	242	< 0.05	21.8%/-	96.3%/-	0.6/-	ELISA
	Chai et al[68], 2014	157	-	-	-	-	157	85	< 0.01	22.9%/-	100%/-	-	ELISA
	Zhou et al[44], 2014	88	-	-	-	-	88	200	< 0.001	22.0%/-	98.0%/-	-	ELISA
	Cai et al[69], 2008	46	10	17	14	5	-	30	< 0.0001	39.1%/ 22.2%	100%/ 100%	-	ELISA
	Looi et al[67], 2006	71	-	-	-	-	71	82	< 0.05	7%/-	98.8%/-	-	ELISA
	Müller et al[70], 2006	50	-	-	-	-	50	436	< 0.05	20.0%/-	100%/-	-	Western blot
	Meglior-ino et al[59], 2005	77	-	-	-	-	77	82	< 0.01	14.3%/-	97.6%/-	-	ELISA
	Shimada et al[71], 2003	301	-	-	-	-	301	205	< 0.05	30.0%/-	95.5%/-	-	ELISA
	Shimada et al[72], 2002	105	50	24	21	10	-	153	< 0.001	26.7%/ 20.0%	95.5%/ 95.5%	-	ELISA
	Ralhan et al[73], 2000	60	-	-	-	-	60	50	< 0.05	60.0%/-	92.0%/-	-	ELISA
	Shimada et al[74], 2000	35	-	-	-	-	35	69	< 0.0001	40.0%/-	100.0%/-	-	ELISA
	Hagi-wara et al[75], 2000	46	6	15	24	2	-	13	< 0.05	28.0%/ 28.6%	100%/ 100%	-	ELISA
	Shimada et al[76], 1998	57	6/9	9	11	11	1	208	< 0.05	58.0%/-	99.0%/-	-	ELISA
	Sobti et al[77], 1998	20	-	-	-	-	20	20	0.0202	30.0%/-	100%/-	-	ELISA
	Cawley et al[78], 1988	23	-	-	-	-	23	19	0.0372	34.8%/-	94.7%/-	-	ELISA
NY-ESO-1	Xu et al[43], 2014	388 (Test)	2/29	96	229	27	5	125 (Test)	< 0.0001	26.0%/-	100%/-	-	ELISA
		237 (Valida-tion)	2/31	114	90	-	-	134 (Valida-tion)	< 0.0001	24.0%/-	99.0%/-	-	ELISA
	Oshima et al[79], 2016	172	-	-	-	-	172	74	< 0.001	32.0%/ 16.0%	100%/ 100%	-	ELISA
	Fujita et al[80], 2004	51	-	-	-	-	51	29	0.532	3.9%/-	100%/-	-	ELISA
P90	Zhang et al[55], 2016	324 (Train-ing)	5/13	130	50	39	87	324 (Train-ing)	< 0.001	31.5%/-	84.9%/-	0.617/-	ELISA
		186 (Valida-tion)	1	29	14	46	96	186 (Valida-tion)	< 0.001	-	-	-	ELISA
Mmp-7	Xu et al[43], 2014	388 (Test)	2/29	96	229	27	5	125 (Test)	< 0.001	9.0%/-	100%/-	-	ELISA
		237 (Valida-tion)	2/31	114	90	-	-	134 (Valida-tion)	< 0.001	10.0%/-	100%/-	-	ELISA
	Zhou et al[81], 2011	50	-	-	-	-	50	58	< 0.001	78.0%	81.0%	0.87/-	ELISA
Hsp70	Xu et al[43], 2014	388 (Test)	2/29	96	229	27	5	125 (Test)	< 0.001	11.0%/-	99.0%/-	-	ELISA
		237 (Valida-tion)	2/31	114	90	-	-	134 (Valida-tion)	< 0.01	8.0%/-	99.0%/-	-	ELISA
	Zhang et al[82], 2011	69	-	-	-	-	69	76	> 0.01	39.1%/-	92.3%/-	-	ELISA
	Fujita et al[40], 2008	16	2	7	4	3	-	13	< 0.001	93.7%/-	100%/-	-	ELISA
PRDX 6	Xu et al[43], 2014	388 (Test)	2/29	96	229	27	5	125 (Test)	< 0.001	11.0%/-	100%/-	-	ELISA
		237 (Valida-tion)	2/31	114	90	-	-	134 (Valida-tion)	< 0.001	10.0%/-	100%/-	-	ELISA
	Fujita et al[83], 2006	30	7	8	11	4	-	30	< 0.05	50.0%/ 53.5%	93.4%/ 93.4%	-	Western blot
Bmi-1	Xu et al[43], 2014	388 (Test)	2/29	96	229	27	5	125 (Test)	< 0.01	11.0%/-	98.0%/-	-	ELISA
		237 (Valida-tion)	2/31	114	90	-	-	134 (Valida-tion)	< 0.01	8.0%/-	100%/-	-	ELISA
	Liu et al[84], 2010	159	6	72	69	12	-	102	< 0.001	39.0%/-	100%/-	-	ELISA
Imp1	Zhang et al[55], 2016	324 (Train-ing)	5/13	130	50	39	87	324 (Train-ing)	< 0.001	26.9%/-	81.2%/-	0.576/-	ELISA
		186 (Valida-tion)	1	29	14	46	96	186 (Valida-tion)	< 0.01	-	-	-	ELISA
	Qin et al[58], 2014	174	3/8	79	52	18	-	242	< 0.05	16.1%/-	98.3%/-	0.6/-	ELISA
	Zhou et al[44], 2014	88	-	-	-	-	88	200	< 0.001	14.0%/-	99.0%/-	-	ELISA
Cyclin B1	Qin et al[58], 2014	174	3/8	79	52	18	-	242	< 0.05	16.1%/-	97.9%/-	0.6/-	ELISA
	Zhou et al[44], 2014	88	-	-	-	-	88	200	0.02	10.0%/-	97.0%/-	-	ELISA
C-Myc	Zhang et al[55], 2016	324 (Train-ing)	5/13	130	50	39	87	324 (Train-ing)	< 0.001	49.1%/-	81.5%/-	0.699/-	ELISA
		186 (Valida-tion)	1	29	14	46	96	186 (Valida-tion)	< 0.001	-	-	-	ELISA
	Qin et al[58], 2014	174	3/8	79	52	18	-	242	< 0.05	15.5%/-	98.8%/-	0.6/-	ELISA
	Zhou et al[44], 2014	88	-	-	-	-	88	200	< 0.001	18.0%/-	96.0%/-	-	ELISA
	Looi et al[67], 2006	71	-	-	-	-	-	82	< 0.05	7%/-	100%/-	-	ELISA
	Meglio-rino et al[59], 2005	77	-	-	-	-	77	82	< 0.01	11.7%/-	100%/-	-	ELISA
RalA	Qin et al[58], 2014	174	3/8	79	52	18	-	242	< 0.05	15.5%/-	96.7%/-	0.6/-	ELISA
P62	Zhang et al[55], 2016	324 (Train-ing)	5/13	130	50	39	87	324 (Train-ing)	< 0.001	29.3%/-	81.8%/-	0.60/-	ELISA
		186 (Valida-tion)	1	29	14	46	96	186 (Valida-tion)	< 0.001	-	-	-	ELISA
	Qin et al[58], 2014	174	3/8	79	52	18	-	242	< 0.05	12.1%/-	95.9%/-	0.5/-	ELISA
	Zhou et al[44], 2014	88	-	-	-	-	88	200	0.001	13.0%/-	98.0%/-	-	ELISA
Koc	Zhang et al[55], 2016	324 (Train-ing)	5/13	130	50	39	87	324 (Train-ing)	< 0.001	35.8%/-	82.1%/-	0.63/-	ELISA
		186 (Valida-tion)	1	29	14	46	96	186 (Valida-tion)	< 0.05	-	-	-	ELISA
	Qin et al[58], 2014	174	3/8	79	52	18	-	242	< 0.05	11.5%/-	97.9%/-	0.5/-	ELISA
	Zhou et al[44], 2014	88	-	-	-	-	88	200	0.05	10.0%/-	96.0%/-	-	ELISA
Cyclin D1	Qin et al[58], 2014	174	3/8	79	52	18	-	242	< 0.05	10.3%/-	96.3%/-	0.5/-	ELISA
Cyclin E	Zhang et al[55], 2016	324 (Train-ing)	5/13	130	50	39	87	324 (Train-ing)	< 0.001	26.5%/-	83.0%/-	0.581/-	ELISA
		186 (Valida-tion)	1	29	14	46	96	186 (Valida-tion)	< 0.05	-	-	-	ELISA
	Qin et al[58], 2014	174	3/8	79	52	18	-	242	< 0.05	10.3%/-	99.2%/-	0.5/-	ELISA
HCCR	Zhang et al[55], 2016	324 (Train-ing)	5/13	130	50	39	87	324 (Train-ing)	< 0.001	34.6%/-	80.0%/-	0.596/-	ELISA
		186 (Valida-tion)	1	29	14	46	96	186 (Valida-tion)	< 0.001	-	-	-	ELISA
GSTO1	Li et al[85], 2014	67	-	-	-	-	67	90	< 0.01	44.8%/-	93.3%/-	-	ELISA
MDM2	Chai et al[68], 2014	157	-	-	-	-	157	85	< 0.01	14.0%/-	98.8%/-	-	ELISA
HSP105	Gao et al[51], 2014	46	7	-	-	-	39	40	< 0.01	39.1%/ 42.9%	95%/95%	0.794/-	Western blot
TIM	Gao et al[51], 2014	46	7	-	-	-	39	40	< 0.01	34.8%/ 28.6%	95%/95%	0.786/-	Western blot
Prdx1	Ren et al[86], 2013	68	-	-	-	-	68	89	< 0.01	13.2%/-	100%/-	-	ELISA, Western blot
FOXP3	Ye et al[87], 2013	97	26	45	19	2	5	227	< 0.0001	22.7%/-	95.2%/-	0.70/-	ELISA,
CD25	Guan et al[88], 2013	97	26	45	17	3	6	226	< 0.001	37.2%/-	90.0%/-	0.69/-	ELISA
ABCC3 (IgA)	Cheng et al[89], 2013	114	-	-	-	-	-	226	< 0.001	13.2%/-	>95%/-	0.65/-	ELISA
LY6K	Zhang et al[90], 2012	62	13		27	22	-	58	< 0.001	80.6%/ 73.2%	78.7%/ 78.7%	0.85/-	ELISA
HMGB1	Zhang et al[82], 2011	69	-	-	-	-	69	76	> 0.05	7.2%/-	98.7%/-	-	ELISA
ESCA-1	Kagaya et al[91], 2011	146	32	29	42	43	-	118	0.0001	21.2%/-	98.3%/-	-	ELISA
ESCA-2	Kagaya et al[91], 2011	72	37		35		72	98	0.0026	15.3%/ 8.1%	99.0%/ 99.0%	-	ELISA
ESCA-3	Kagaya et al[91], 2011	68	-	-	-	-	68	74	0.0079	16.2%/-	98.6%/-	-	ELISA
CDC25B	Dong et al[92], 2010	134	80		54		-	134	< 0.001	56.7%/-	91.0%	0.87/-	ELISA
	Liu et al[93], 2008	124	-	-	-	-	123	102	< 0.05	36.3%/-	100%/-	-	ELISA
GRP78	Tsunemi et al[94], 2010	15	-	-	-	-	15	20	< 0.05	26.7%/-	100%/-	-	Western blot
Makorin 1	Shimada et al[95], 2009	73	1/13	21	27	11	-	43	< 0.05	25.0%/ 22.9%	100%/ 100%	-	Western blot
CUEC-23	Shimada et al[96], 2009	54	7	13	18	16	-	46	< 0.05	26.0%/ 33.3%	96.0%/-	-	Western blot
	Shimada et al[96], 2009	29	1	11	8	9	-	46	0.036	17.0%/-	100%/-	-	ELISA
MMGL	Shimada et al[97], 2007	91	21	22	35	13	-	45	< 0.05	47.0%/ 38.0%	97.8%/ 97.8%	-	Western blot
TRIM21	Kubo-shima et al[98], 2006	91	39		52		-	42	< 0.05	20.0%/ 13.0%	100%/ 100%	-	Western blot
	Kubo-shima et al[98], 2006	54	-	-	-	-	54	42	0.013	15.0%/-	98.0%/-	-	ELISA
SLC2A1	Kubo-shima et al[99], 2006	57	19	6	13	19	-	31	< 0.001	21.0%/ 22.0%	100%/ 100%	-	ELISA
SURF1	Shimada et al[50], 2005	21	-	3	13	5	-	37	0.0003	48%/-	95%/-	-	ELISA
LOC 146223	Shimada et al[50], 2005	21	-	3	13	5	-	37	0.0028	38%/-	95%/-	-	ELISA
HOOK2	Shimada et al[50], 2005	21	-	3	13	5	-	37	0.0431	14%/-	100%/-	-	ELISA
AGENCOURT_7565913	Shimada et al[50], 2005	21	-	3	13	5	-	37	0.0431	14%/-	100%/-	-	ELISA
TROP2	Naka-shima et al[100], 2004	75	14	14	24	23	-	43	< 0.05	31.0%/ 21.0%	97.7%/ 97.7%	-	Western blot

ESCC: Esophageal squamous cell carcinoma; AUC: Area under the curve; L1CAM: L1-cell adhesion molecule; STIP1: Stress induced phosphoprotein 1; DKK-1: Dickkopf 1; Mmp-7: Matrix metallopeptidase 7; Hsp70: Heat shock protein 70; PRDX 6: Peroxiredoxin 6; Bmi-1: BMI1 proto-oncogene, polycomb ring finger; Imp1: Insulin-like growth factor 2 mRNA binding protein 1; C-Myc: MYC proto-oncogene, bHLH transcription factor; Koc: Insulin-like growth factor 2 mRNA binding protein 3; HCCR: LETM1 domain containing 1; GSTO1: Glutathione S-transferase omega 1; MDM2: MDM2 proto-oncogene; HSP105: Heat shock protein family H (Hsp110) member 1; TIM: Rho guanine nucleotide exchange factor 5; Prdx1: Peroxiredoxin 1; FOXP3: Forkhead box P3; CD25: Interleukin 2 receptor subunit alpha; ABCC3: ATP binding cassette subfamily C member 3; LY6K: Lymphocyte antigen 6 family member K; HMGB1, high mobility group box 1; CDC25B: Cell division cycle 25B; GRP78: Heat shock protein family A (Hsp70) member 5; Makorin 1: Makorin ring finger protein 1; MMGL: Myomegalin; TRIM21: Tripartite motif containing 21; SLC2A1: Solute carrier family 2 member 1; SURF1: SURF1 cytochrome c oxidase assembly factor; HOOK2: Hook microtubule tethering protein 2; TROP2: Tumor-associated calcium signal transducer 2.

Table 3 Diagnostic performance of single tumor-associated autoantibody biomarkers in esophagogastric junction adenocarcinoma

Target antigen of auto-anti-bodies	Authors, year	EGJA cases, n	Stage, n					Con-trols, n	P value	Sensiti-vity, all stages/ early stage	Specifi-city, all stages/ early stage	AUC, all stages/ early stage	Method
			I	II	III	IV	Tx
p53	Xu et al[42], 2019	122 (Train-ing)	2	16	87	17	122	169 (Valida-tion)	< 0.0001	35.2%/ 33.3%	90.5%/ 90.5%	0.718/ 0.648	ELISA
		70 (Train-ing)	11	14	30	15	80	80 (Valida-tion)	< 0.0001	35.7%/ 40.0%	96.3%/ 96.3%	0.766/ 0.799	ELISA
	Zhou et al[41], 2015	75	-	-	-	-	75	140	< 0.001	24.0%/-	92%/-	0.67/-	ELISA
NY-ESO-1	Xu et al[42], 2019	122 (Train-ing)	2	16	87	17	122	169 (Valida-tion)	< 0.0001	37.7%/ 27.8%	90.5%/ 90.5%	0.718/ 0.654	ELISA
		70 (Train-ing)	11	14	30	15	80	80 (Valida-tion)	< 0.0001	34.3%/ 28.0%	95.0%/ 95.0%	0.747/ 0.714	ELISA
PRDX6	Xu et al[42], 2019	122 (Train-ing)	2	16	87	17	122	169 (Valida-tion)	0.033	34.4%/ 38.9%	90.5%/ 90.5%	0.573/ 0.602	ELISA
		70 (Train-ing)	11	14	30	15	80	80 (Valida-tion)	0.002	30.0%/ 28.0%	90.0%/ 90.0%	0.647/ 0.629	ELISA
MMP-7	Xu et al[42], 2019	122 (Train-ing)	2	16	87	17	122	169 (Valida-tion)	0.005	30.3%/ 33.3%	90.5%/ 90.5%	0.597/ 0.575	ELISA
		70 (Train-ing)	11	14	30	15	80	80 (Valida-tion)	0.036	24.3%/ 28.0%	95.0%/ 95.0%	0.599/ 0.609	ELISA
Hsp70	Xu et al[42], 2019	122 (Train-ing)	2	16	87	17	122	169 (Valida-tion)	< 0.0001	18.0%/ 16.7%	90.5%/ 90.5%	0.652/ 0.697	ELISA
		70 (Train-ing)	11	14	30	15	80	80 (Valida-tion)	< 0.0001	28.6%/ 32.0%	86.3%/ 86.3%	0.686/ 0.702	ELISA
Bmi-1	Xu et al[42], 2019	122 (Train-ing)	2	16	87	17	122	169 (Valida-tion)	< 0.0001	22.1%/ 27.8%	90.5%/ 90.5%	0.686/ 0.685	ELISA
		70 (Train-ing)	11	14	30	15	80	80 (Valida-tion)	< 0.0001	54.3%/ 40.0%	90.0%/ 90.0%	0.711/ 0.682	ELISA
Koc	Zhou et al[41], 2015	75	-	-	-	-	75	140	0.05	19.0%/-	91%/-	-	ELISA
P62	Zhou et al[41], 2015	75	-	-	-	-	75	140	0.02	16.0%/-	94%/-	-	ELISA
C-Myc	Zhou et al[41], 2015	75	-	-	-	-	75	140	0.18	11.0%/-	94%/-	-	ELISA
IMP1	Zhou et al[41], 2015	75	-	-	-	-	75	140	0.04	13.0%/-	95%/-	-	ELISA
Survivin	Zhou et al[41], 2015	75	-	-	-	-	75	140	0.002	17.0%/-	96%/-	-	ELISA
P16	Zhou et al[41], 2015	75	-	-	-	-	75	140	0.01	15.0%/-	96%/-	-	ELISA
Cyclin B1	Zhou et al[41], 2015	75	-	-	-	-	75	140	0.01	12.0%/-	97%/-	-	ELISA

EGJA: Esophagogastric junction adenocarcinoma; AUC: Area under the curve; PRDX 6: Peroxiredoxin 6; Mmp-7: Matrix metallopeptidase 7; Hsp70: Heat shock protein 70; Bmi-1: BMI1 proto-oncogene, polycomb ring finger; Koc: Insulin-like growth factor 2 mRNA binding protein 3; C-Myc: MYC proto-oncogene, bHLH transcription factor; IMP1: Insulin-like growth factor 2 mRNA binding protein 1.

Table 4 Diagnostic performance of tumor-associated autoantibody panel in esophageal squamous cell carcinoma

Target antigen of auto-anti-bodies	Authors, year	ESCC cases, n	Stage, n					Con-trols, n	Sensiti-vity, all stages/ early stage	Specifi-city, all stages/ early stage	AUC, all stages/ early stage	Method
			0/I	II	III	IV	Unknown
c-Myc, HCCR, IMP1, Koc, p53 and p62	Zhang et al[55], 2016	324 (Train-ing)	5/13	130	50	39	87	324 (Train-ing)	67.9%/ 66.9%	86.7%/ 86.7%	0.838/ 0.829	ELISA
		186 (Valida-tion)	1	29	14	46	96	186 (Valida-tion)	67.7%/ 56.7%	85.5%/ 85.5%	0.859/ 0.818	ELISA
c-Myc, HCCR, p53 and p62	Zhang et al[55], 2016	324 (Train-ing)	5/13	130	50	39	87	324 (Train-ing)	67.6%/ 67.6%	86.4%/ 86.4%	0.838/ 0.831	ELISA
		186 (Valida-tion)	1	29	14	46	96	186 (Valida-tion)	72.0%/ 63.3%	85.0%/ 85.0%	0.872/ 0.837	ELISA
MAGEA4, CTAG1, TP53, SDCCAG8 and ERBB2_C	Werner et al[101], 2016	31	-	-	-	-	31	321	26.0%/-	88.5%/-	-	Bead-based multiplex serology
p53 and MDM2	Chai et al[68], 2014	157	-	-	-	-	157	85	35.0%/-	98.8%/-	-	ELISA
p53, pl6, Imp-l, CyclinB1, c-Myc, RalA, p62, Survivin, Koc, Cyclin D1 and Cyclin E	Qin et al[58], 2014	174	3/8	79	52	18	-	242	75.3%/-	81.0%/-	0.78/-	ELISA
p53, NY-ESO-1, MMP-7, Hsp70, PRDX 6 and Bmi-1	Xu et al[43], 2014	388 (Test)	2/29	96	229	27	5	125 (Test)	57.0%/ 45.0%	95.0%/ 95.0%	-	ELISA
		237 (Valida-tion)	2/31	114	90	-	-	134 (Valida-tion)	51.0%/ 46.0%	96.0%/ 96.0%	-	ELISA
p53, NY-ESO-1, Hsp70 and PRDX 6	Xu et al[43], 2014	388 (Test)	2/29	96	229	27	5	125 (Test)	55.0%/ 45.0%	98.0%/ 98.0%	-	ELISA
		237 (Valida-tion)	2/31	114	90	-	-	134 (Valida-tion)	48.0%/ 45.0%	96.0%/ 96.0%	-	ELISA
p53, IMP1, P16, Cyclin B1, P62, and C-myc	Zhou et al[44], 2014	88	-	-	-	-	88	200	64.0%/-	94.0%/-	0.78/-	ELISA
HSP105 and TIM	Gao et al[51], 2014	46	7	-	-	-	39	40	54.3%/-	95.0%/-	0.823/-	Western blot
p16, c-Myc and p53	Looi et al[67], 2006	71	-	-	-	-	71	82	7%/-	100%/-	-	ELISA
SURF1, LOC146223, HOOK2 and AGENCOURT_7565913	Shimada et al[50], 2005	21	-	3	13	5	-	37	86%/-	100%/-	-	ELISA
Survivin, p53 and C-myc	Meglio-rino et al[59], 2005	77	-	-	-	-	77	82	29.9%/-	95.1%/-	-	ELISA

ESCC: Esophageal squamous cell carcinoma; AUC: Area under the curve; C-Myc: MYC proto-oncogene, bHLH transcription factor; HCCR: LETM1 domain containing 1; IMP1: Insulin-like growth factor 2 mRNA binding protein 1; Koc: Insulin-like growth factor 2 mRNA binding protein 3; MAGEA4: MAGE family member A4; CTAG1: Cancer/testis antigen 1B; SDCCAG8: Serologically defined colon cancer antigen 8; ERBB2: Erb-b2 receptor tyrosine kinase 2; MDM2: MDM2 proto-oncogene; HSP105: Heat shock protein family H (Hsp110) member 1; TIM: Rho guanine nucleotide exchange factor 5; SURF1: SURF1 cytochrome c oxidase assembly factor; HOOK2: Hook microtubule tethering protein 2.

Table 5 Diagnostic performance of tumor-associated autoantibody panel in esophagogastric junction adenocarcinoma

Target antigen of auto-anti-bodies	Authors, year	EGJA cases, n	Stage, n					Con-trols, n	Sensiti-vity, all stages/ early stage	Specifi-city, all stages/ early stage	AUC, all stages/ early stage	Method
			0/I	II	III	IV	Unknown
p53, NY-ESO-1, MMP-7, Hsp70, PRDX6 and Bmi-1	Xu et al[42], 2019	122 (Train-ing)	2	16	87	17	122	169 (Valida-tion)	59.0%/ 50.0%	90.5%/ 90.5%	0.818/ 0.786	ELISA
		70 (Valida-tion)	11	14	30	15	80	80 (Valida-tion)	61.4%/ 56.0%	90.0%/ 90.0%	0.815/ 0.786	ELISA
p53, NY-ESO-1 and Bmi-1	Xu et al[42], 2019	122 (Train-ing)	2	16	87	17	122	169 (Valida-tion)	53.5%/ 55.6%	90.5%/ 90.5%	0.814/ 0.744	ELISA
		70 (Valida-tion)	11	14	30	15	80	80 (Valida-tion)	60.0%/ 52.0%	93.7%/ 93.7%	0.823/ 0.773	ELISA
p53, Koc, P62, c-Myc, IMP1, Survivin and P16	Zhou et al[41], 2015	75	-	-	-	-	75	140	64.0%/-	87.0%/-	0.73/-	ELISA

EGJA: Esophagogastric junction adenocarcinoma; AUC: Area under the curve; Mmp-7: Matrix metallopeptidase 7; Hsp70: Heat shock protein 70; PRDX 6: Peroxiredoxin 6; Bmi-1: BMI1 proto-oncogene, polycomb ring finger; Koc: Insulin-like growth factor 2 mRNA binding protein 3; C-Myc: MYC proto-oncogene, bHLH transcription factor; IMP1: Insulin-like growth factor 2 mRNA binding protein 1.