Extracellular vesicle biomarkers for pancreatic cancer diagnosis: a systematic review and meta-analysis

Jia, Erna; Ren, Na; Shi, Xianquan; Zhang, Rongkui; Yu, Haixin; Yu, Fan; Qin, Shaoyou; Xue, Jinru

doi:10.1186/s12885-022-09463-x

BMC Cancer

Table 2 Diagnostic performance of proteins in extracellular vesicles for pancreatic cancer

From: Extracellular vesicle biomarkers for pancreatic cancer diagnosis: a systematic review and meta-analysis

Study	Country	study design	Cases vs Controls			Specimen	Stage	Status Controls	Detection Method	markers	SEN%	SPE%	AUC	P Value
			Number	Age	Male (%)
										MPs
Melo, 2015 [30]	Germany	Case–control	5/126	/	/	Serum	0-I	NC^b	Flow cytometry	GPC1	100	100	1.00	/
			18/126	/	/	Serum	IIa		Flow cytometry	GPC1	100	100	1.00	/
			117/126	/	/	Serum	IIb		Flow cytometry	GPC1	100	100	1.00	/
			11/126	/	/	Serum	III		Flow cytometry	GPC1	100	100	1.00	/
			41/126	/	/	Serum	IV		Flow cytometry	GPC1	100	100	1.00	/
		Case–control	56/26	70/NA	50/NA	Serum	I-IV		Flow cytometry	GPC1	100	100	1.00	/
Liang, 2017 [34] ^a	USA	Case–control	49/48	NA/62	NA/40	Plasma	I-III	HC	nPES assay	EphA2	94	85	0.96	< 0.001
			49/48	NA/52	NA/52	Plasma	I-III	CP	nPES assay	EphA2	89	85	0.94	< 0.001
			37/48	67/62	60/40	Plasma	I-II	HC	nPES assay	EphA2	91	85	0.96	< 0.001
			37/48	67/52	60/52	Plasma	I-II	CP	nPES assay	EphA2	86	85	0.93	< 0.001
Yang, 2017 [47]^a	USA	Prospective	22/21	/	/	plasma	/	NC^c	NPS chip	GPC1	82	52	/	/
										EGFR	59	76	/	/
										EPCAM	45	95	/	/
										HER2	59	85	/	/
										MUC1	36	90	/	/
Li, 2018 [82]	China	Case–control	34/32	NA/50	NA/69	Serum	/	HC	SERS immunosensor	GPC1	59	58	0.67	/
Li, 2018 [82]	China	Case–control	34/32	NA/50	NA/69	Serum	/	HC	SERS immunosensor	EGFR	57	56	0.63	/
Jin, 2018 [49, 83]	China	Case–control	24/46	61/49	33/50	Serum	I-IV	HC	ELISA	ZIP4	92	80	0.89	/
			24/32	61/44	33/28	Serum	I-IV	NC^d	ELISA	ZIP4	92	84	0.89	/
			24/32	61/63	33/53	Serum	I-IV	BD	ELISA	ZIP4	92	81	0.81	/
Xiao, 2019 [79]	China	Case–control	24/26	59/45	42/85	Plasma	/	HC	Flow cytometry	GPC1	72*	84*	0.89	/
			24/26	59/45	42/85	Plasma	/	HC	Flow cytometry	CD82	86*	66*	0.85	/
			24/6	59/73	42/83	Plasma	/	CP	Flow cytometry	GPC1	100*	66*	0.85	/
			24/6	59/73	42/83	Plasma	/	CP	Flow cytometry	CD82	100*	66*	0.90	/
Buscail, 2019 [24, 54, 66]	France	Prospective	22/28	70/58	59/28	Serum-CD63	I-III	NC^e	Flow cytometry	GPC1	50	90	0.68	/
Buscail, 2019 [24, 54, 66]	France	Prospective	22/28	70/58	59/28	Serum-CD63	I-III	NC^e	Flow cytometry	MPs
Rodrigues, 2019 [33] ^a	USA	Case–control	20/12	/	45/25	Serum	/	NC^k	nanoparticle-and dyebased fluorescent immunoassay	EpCAM	75*	100*	0.92
Rodrigues, 2019 [33] ^a	USA	Case–control	20/12	/	45/25	Serum	/	NC^k	nanoparticle-and dyebased fluorescent immunoassay	EphA2	95*	83*	0.93
Zhou, 2020 [62]	China	Case–control	30/10	60/58	/	Plasma	I-IV	NC^f	3D mircrofluidic chip	EphA2	69*	99*	0.85
Wei, 2020 [60]	China	Case–control	204/74	62/NA	/	serum	I-IV	HC	Enzyme-Linked Immunosorbent Assays	EphA2	83	94	0.94
			204/75	62/NA	/		I-IV	BPD		EphA2	81	94	0.92
			94/74	/	/		I-II	HC		EphA2	83	94	0.92
			94/75	/	/		I-II	BPD		EphA2	84	88	0.90
Fahrmann,2020 [58]^a	USA	Case–control	6/21	/	/	Plasma	IV	HC	SOMAscan assay	ASGR1	/	/	0.89	0.0026
										ANXA1	/	/	0.99	0.0000
										IL12RB2	/	/	0.85	0.0083
										ADAM9	/	/	0.98	0.0000
										TGFBR2	/	/	0.85	0.0083
										EDA	/	/	0.85	0.0083
										BMPR2	/	/	0.88	0.0034
										TYRO3	/	/	0.87	0.0043
										FLRT3	/	/	0.87	0.0054
										SLAMF6	/	/	0.95	0.0002
										CD4	/	/	0.87	0.0054
										RXFP1	/	/	0.87	0.0054
Li, 2021 [76] ^a	China	Case–control	21/29	54/62	43/55	plasma	/	HC	AbMB-bioChol paltform	EGFR	52*	93*	0.74
										EpCAM	94*	48*	0.68
										GPC1	43*	89*	0.72
										EphA2	47*	86*	0.64
										MPs
Moutinho-R, 2021 [75]	Portugal	prospective	60/29	67/54	55/76	serum	I-IV	CP	flow cytometry	GPC1	98	86	0.96	< 0.0001
			15/29	NA/54	NA /76		I				100*	96*	0.97
			45/29	NA /54	NA /76		II-IV				95*	97*	0.96
			45/29	NA /54	NA /76		II-IV			nMPs
Yang, 2017 [47] ^a	USA	Prospective	22/21	/	/	plasma	/	NC^c	NPS chip	WNT2	64	76	/	/
		Prospective	22/21	/	/	plasma	/	NC^c	NPS chip	GRP94	55	71	/	/
		Case–control	22/10	68/48	36/40	plasma	II-IV	HC	NPS chip	B7-H3	50	100	0.75	/
Li, 2018 [82]	China	Case–control	71/32	60/50	54/69	Serum	I-IV	HC	SERS immunosensor	MIF	63	76	0.89	/
Lux, 2019 [54, 81]	Germany	Case–control	55/34	67/NA	53/NA	Serum	I-IV	NC^g	Flow cytometry	c-Met	70	85	0.75*	/
Fahrmann,2020 [58]^a	USA	Case–control	6/21	/	/	Plasma	IV	HC	SOMAscan assay	IFNGR2	/	/	0.87	0.0054
Fahrmann,2020 [58]^a	USA	Case–control	6/21	/	/	Plasma	IV	HC	SOMAscan assay	TPSG1	/	/	0.94	0.0003
Yang, 2021 [69]	China	Case–control	62/42	/	48/ NA	plasma	I-IV	NC^h	Enzyme-linked immunosorbert assay	ALIX	53	84	0.73	0.0003
Zheng, 2022 [67]	China	Case–control	57/84	/	31/39	plasma	II-IV	HC	MALDI-TOF MS	SAA1	96	28	0.61	/
										FGG	40	87	0.62	/
												nMPs
Fahrmann,2020 [58]^a	USA	Case–control	6/21	/	/	Plasma	IV	HC	SOMAscan assay	MAPKAPK2	/	/	0.94	0.0004
										PDXK	/	/	0.94	0.0003
										PLCG1	/	/	0.94	0.0004
										INSR	/	/	0.94	0.0004
										IL34	/	/	0.93	0.0006
										AIP	/	/	0.93	0.0006
										YES1	/	/	0.93	0.0006
										DYNLRB1	/	/	0.93	0.0006
										IDE	/	/	0.93	0.0006
										CCL28	/	/	0.93	0.0006
										nMPs
Fahrmann,2020 [58]^a	USA	Case–control	6/21	/	/	Plasma	IV	HC	SOMAscan assay	C5 C6	/	/	0.92	0.0008
										CD109	/	/	0.92	0.0008
										CAMK2A	/	/	0.92	0.0008
										TNFSF14	/	/	0.91	0.0011
										MMP14	/	/	0.91	0.0011
										PRKCI	/	/	0.91	0.0011
										MAP2K1	/	/	0.91	0.0011
										KYNU	/	/	0.91	0.0011
										KIF23	/	/	0.91	0.0011
										IL27RA	/	/	0.91	0.0011
										IMPDH1	/	/	0.91	0.0011
										TNFRSF13B	/	/	0.91	0.0011
										SEMA6B	/	/	0.91	0.0011
										AIMP1	/	/	0.91	0.0011
										NMT1	/	/	0.90	0.0015
										EPHA5	/	/	0.90	0.0015
										MSLN	/	/	0.90	0.0015
										IBSP	/	/	0.90	0.0015
										TNFSF13B	/	/	0.90	0.0015
										CTF1	/	/	0.90	0.0015
										BCL2L1	/	/	0.90	0.0015
										IL1A	/	/	0.90	0.0015
										MAPK12	/	/	0.90	0.0015
										FABP1	/	/	0.90	0.0020
										CCL17	/	/	0.90	0.0020
										nMPs
Fahrmann,2020 [58]^a	USA	Case–control	6/21	/	/	Plasma	IV	HC	SOMAscan assay	SPARCL1	/	/	0.90	0.0020
										LCK	/	/	0.90	0.0020
										CCL3L1	/	/	0.90	0.0020
										PDE9A	/	/	0.90	0.0020
										PRDX5	/	/	0.90	0.0020
										CD300C	/	/	0.90	0.0020
										BCL2L2	/	/	0.90	0.0020
										CSRP3	/	/	0.90	0.0020
										GDF2	/	/	0.90	0.0020
										IL17RB	/	/	0.90	0.0020
										LGALS3BP	/	/	0.90	0.0020
										SEMA6A	/	/	0.90	0.0020
										CLEC11A	/	/	0.90	0.0020
										UBC	/	/	0.89	0.0026
										HIPK3	/	/	0.89	0.0026
										PARK7	/	/	0.89	0.0026
										MMP13	/	/	0.89	0.0026
										FGFR4	/	/	0.89	0.0026
										FGF5	/	/	0.89	0.0026
										DDR1	/	/	0.89	0.0026
										PDK1	/	/	0.89	0.0026
										CXCL8	/	/	0.89	0.0026
										GDF11	/	/	0.89	0.0026
										IDUA	/	/	0.89	0.0026
										CA3	/	/	0.89	0.0026
										nMPs
Fahrmann,2020 [58]^a	USA	Case–control	6/21	/	/	Plasma	IV	HC	SOMAscan assay	DYNLL1	/	/	0.89	0.0026
										ACVRL1	/	/	0.89	0.0026
										CXCL1	/	/	0.88	0.0034
										CRLF1/CLCF1	/	/	0.88	0.0034
										DHH	/	/	0.88	0.0034
										ENTPD5	/	/	0.88	0.0034
										UBE2G2	/	/	0.88	0.0034
										IFNG	/	/	0.88	0.0034
										CHEK2	/	/	0.88	0.0034
										LTA LTB	/	/	0.87	0.0043
										FAM107A	/	/	0.87	0.0043
										TNFRSF18	/	/	0.87	0.0043
										KLK6	/	/	0.87	0.0043
										PPP3R1	/	/	0.87	0.0043
										CD244	/	/	1.00	0.0000
										ETHE1	/	/	0.87	0.0043
										PDXP	/	/	0.87	0.0043
										IFNB1	/	/	0.87	0.0043
										IL36A	/	/	0.87	0.0043
										KLK14	/	/	0.87	0.0043
										IL1RN	/	/	0.87	0.0043
										F3	/	/	0.87	0.0043
										MAPK11	/	/	0.87	0.0054
										TNFRSF14	/	/	0.87	0.0054
										PRLR	/	/	0.87	0.0054
										nMPs
Fahrmann,2020 [58]^a	USA	Case–control	6/21	/	/	Plasma	IV	HC	SOMAscan assay	VEGFA	/	/	0.87	0.0054
										FABP5	/	/	0.87	0.0054
										CDH3	/	/	0.87	0.0054
										ISG15	/	/	0.87	0.0054
										CKM	/	/	0.87	0.0054
										ABL2	/	/	0.87	0.0054
										TNFSF11	/	/	0.86	0.0067
										CA10	/	/	0.86	0.0067
										EPHA2	/	/	0.86	0.0067
										HK2	/	/	0.86	0.0067
										STK16	/	/	0.86	0.0067
										CD47	/	/	0.86	0.0067
										PAK7	/	/	0.86	0.0067
										CDK2 CCNA2	/	/	0.86	0.0067
										ZAP70	/	/	0.86	0.0067
										CXCL5	/	/	0.86	0.0067
										MAPK8	/	/	0.86	0.0067
										IL17F	/	/	0.86	0.0067
										PDGFRA	/	/	0.86	0.0067
										FGF2	/	/	0.86	0.0067
										AFP	/	/	0.86	0.0067
										PECAM1	/	/	0.86	0.0067
										STAT6	/	/	0.85	0.0083
										TOP1	/	/	0.85	0.0083
										CRLF2	/	/	0.85	0.0083
										nMPs
Fahrmann,2020 [58]^a	USA	Case–control	6/21	/	/	Plasma	IV	HC	SOMAscan assay	TLR4	/	/	0.85	0.0083
										BCL2	/	/	0.85	0.0083
										TNF	/	/	0.85	0.0083
										C1QBP	/	/	0.85	0.0083
										CLEC11A	/	/	0.85	0.0083
										GDF9	/	/	0.85	0.0083
										ING1	/	/	0.85	0.0083
										BIRC5	/	/	0.85	0.0083
										B2M	/	/	0.85	0.0083
										ERP29	/	/	0.85	0.0083
										FLT3LG	/	/	0.85	0.0083
										NAPA	/	/	0.85	0.0083
										GCKR	/	/	0.85	0.0083
										EPHA1	/	/	0.85	0.0083
										HSD17B10	/	/	0.85	0.0083
										CEBPB	/	/	0.85	0.0083
										SSRP1	/	/	0.85	0.0083
										SPHK2	/	/	0.85	0.0083
										CCL22	/	/	0.85	0.0083
										GDF5	/	/	0.85	0.0083
										APOD	/	/	0.85	0.0083
										POR	/	/	0.99	0.0000
										LY9	/	/	0.97	0.0001
										IFNGR1	/	/	0.96	0.0001
										GSK3A/B	/	/	0.96	0.0001
										nMPs
Fahrmann,2020 [58]^a	USA	Case–control	6/21	/	/	Plasma	IV	HC	SOMAscan assay	FLT3	/	/	0.95	0.0002
										CSNK2A1	/	/	0.95	0.0002
										PIK3CA/R1	/	/	0.95	0.0002
										LIN7B	/	/	0.95	0.0002
										METAP1	/	/	0.95	0.0002
										MAPK13	/	/	0.90	0.0015
										FAS	/	/	0.94	0.0003

SENs, SPEs and AUCs in bold fonts represent results from validation set (non-bold fonts represent results without validation)
AUC area under the curve, BD Biliary disease, BPD benign pancreatic disease, CP chronic pancreatitis, HC healthy control, IPMN intraductal papillary mucinous neoplasm, NC noncancerous, nPES nanoplasmon-enhanced scattering, NPS nanoplasmonic sensor, SERS surface-Enhanced Raman Scattering, SOMAscan assay slow off-rate modified DNA aptamer, nMPs nonMembrane proteints, MPs Membrane proteins, SEN sensitivity, SPE specificity, MALDI-TOF MS matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, AbMB antibody-conjugated magnetic beads
^arepresent markers extracted from extracellular vesicles
^bBPD and HC
^cbenign pancreatic tumor, CP, and HC
^dbenign pancreatic tumor and pancreatitis
^eHC, CP, and IPMN
^fno history of cancer
^gserous cyst adenoma and CP
^hwell-differentiated pancratic neuroendocrine tumor, pancreatic cystic lesions, choronic pancreatitis, and HC
^kliver injury, pancreatitis, and cholangitis
^*represent estimated value
p value indicates the p value of AUC

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