Prognostic role of CD82/KAI1 in multiple human malignant neoplasms: a meta-analysis of 31 studies

Figures & data

Figure 1 Flow diagram of the study selection process.

Abbreviation: HRs, hazard ratios.

Table 1 Main characteristics of studies included in the meta-analysis

First author, publication year	Case nationality	Dominant ethnicity	Median or mean age	Study design	Malignant disease	Main type of pathology	Detected sample	Assay method	Survival analysis	Source of HR	Maximum months of follow-up
Zhu, 2017^Citation10	China	Asian	59.4	R	Colorectal carcinoma	AdenoCa	Tissue	IHC	OS	Reported	96
Lu, 2016^Citation12	China	Asian	57.7	R	Gastric carcinoma	AdenoCa	Tissue	IHC	OS	Reported	95
Singh, 2016^Citation11	India	Asian	49	R	Breast cancer	AdenoCa	Tissue	qRT-PCR	OS	SC	36
Guo, 2015^Citation16,a	China	Asian	48	R	Gastric carcinoma	AdenoCa	Tissue	IHC	OS	SC	60
Guo, 2015^Citation16,b	China	Asian	48	R	Gastric carcinoma	AdenoCa	Tissue	qRT-PCR	OS	SC	60
Wu, 2015^Citation32	China	Asian	62.1	R	Colorectal carcinoma	AdenoCa	Tissue	IHC	OS	Reported	108
Han, 2015^Citation36	China	Asian	45.6	R	Breast cancer	AdenoCa	Tissue	IHC	OS	Reported	NM
Yu, 2014^Citation13	China	Asian	62.1	R	LSCC	SqCa	Tissue	IHC	OS/DFS	Reported	NM
Kwon, 2014^Citation19	Korea	Asian	55.8	R	CCRCC	AdenoCa	Tissue	IHC	OS	Reported	223
Tang, 2014^Citation14,c	Canada	Caucasian	60	R	Melanoma	Melanoma	Tissue	IHC	OS	Reported	120
Tang, 2014^Citation14,d	Canada	Caucasian	60	R	Melanoma	Melanoma	Tissue	IHC	OS	Reported	60
Zhang, 2013^Citation37	China	Asian	58.7	R	LSCC	SqCa	Tissue	IHC	OS	SC	NM
Zhang, 2013^Citation38	China	Asian	59.6	R	LSCC	SqCa	Tissue	WB	OS	SC	84
Wu, 2012^Citation15	China	Asian	58.6	R	NSCLC	AdenoCa	Tissue	IHC	OS	Reported	88
Knoener, 2012^Citation33	Germany	Caucasian	NM	R	Gastric carcinoma	AdenoCa	Tissue	IHC	OS	SC	163
Guo, 2009^Citation39	China	Asian	60	R	Hepatocellular carcinoma	AdenoCa	Tissue	IHC	OS	SC	24
Protzel, 2008^Citation34	Germany	Caucasian	66.5	R	Penile carcinoma	SqCa	Tissue	IHC	OS	SC	125
Miyazaki, 2005^Citation40	Japan	Asian	61	R	ESCC	SqCa	Tissue	IHC	OS	SC	60
Leavey, 2005^Citation17	America	Caucasian	11	R	Osteosarcoma	Sarcoma	Tissue	IHC	OS/PFS	SC	NM
Farhadieh, 2004^Citation41	Australia	Caucasian	65	R	OSCC	SqCa	Tissue	IHC	OS/DFS	Reported	258
Goncharuk, 2004^Citation42	America	Caucasian	65	R	NSCLC	AdenoCa	Tissue	IHC	OS	SC	NM
Su, 2004^Citation50	Japan	Asian	64	R	Bladder cancer	TCC	Tissue	IHC	RFS	Reported	78
Hashida, 2003^Citation18	Japan	Asian	62.8	R	Colorectal carcinoma	AdenoCa	Tissue	IHC	OS/DFS	Reported	85.9
Imai, 2002^Citation43	Japan	Asian	62.6	R	OSCC	SqCa	Tissue	qRT-PCR	OS	SC	60
Schindl, 2001^Citation44	Austria	Caucasian	56.8	R	Epithelial ovarian cancer	AdenoCa	Tissue	IHC	OS/DFS	Reported	130
Miyazaki, 2000^Citation45	Japan	Asian	61.8	R	ESCC	SqCa	Tissue	IHC	OS	SC	195.2
Yang, 2000^Citation46	America	Caucasian	NM	R	Breast cancer	AdenoCa	Tissue	IHC	OS	SC	NM
Sho, 1998^Citation47	Japan	Asian	66	R	Pancreatic cancer	AdenoCa	Tissue	IHC	OS	SC	62
Huang, 1998^Citation48	Japan	Asian	50	R	Breast cancer	AdenoCa	Tissue	IHC	OS/DFS	Reported	NM
Higashiyama, 1997^Citation35	Japan	Asian	63.7	R	NSCLC	AdenoCa	Tissue	IHC	OS	Reported	61.3
Adachi, 1996^Citation49	Japan	Asian	60	R	NSCLC	AdenoCa	Tissue	qRT-PCR	OS	Reported	58

Notes:

a,b Data extracted from one study due to different assay methods (IHC and qRT-PCR).

c,d Data extracted from one study due to different follow-up times (120 and 60 months). Study design is described as retrospective.

Abbreviations: AdenoCa, adenocarcinoma; CCRCC, clear cell renal cell carcinoma; DFS, disease-free survival; ESCC, esophageal squamous cell carcinoma; HR, hazard ratio; IHC, immunohistochemistry; LSCC, laryngeal squamous cell carcinoma; NM, not mentioned; NSCLC, non-small-cell lung cancer; OS, overall survival; OSCC, oral squamous cell carcinoma; PFS, progression-free survival; qRT-PCR, quantitative reverse transcription-polymerase chain reaction; R, retrospective; RFS, recurrence-free survival; SC, survival curve; SqCa, squamous carcinoma; TCC, transitional cell carcinoma; WB, Western-blot.

Table 2 HRs and 95% CIs of patient survival or cancer progression relating to CD82 expression in eligible studies

First author, publication year	Assay method	Cutoff point	Case number		OS		DFS/RFS/PFS
			High expression	Low expression	HR (95% CI) (U/M)	p-value	HR (95% CI) (U/M)	p-value
Zhu, 2017^Citation10	IHC	IRS scores ≥3 (range of 0–12)	65	139	0.302 (0.184–0.497)M	<0.001	NM	NM
Lu, 2016^Citation12	IHC	IRS scores ≥3 (range of 0–12)	134	191	0.648 (0.492–0.854)M	0.002	NM	NM
Singh, 2016^Citation11	qRT-PCR	NM	46	29	0.66 (0.26–1.68)Ue	0.047	NM	NM
Guo, 2015^Citation16,a	IHC	>10% of tumor cells stained	28	100	1.07 (0.22–5.24)Ue	<0.05	NM	NM
Guo, 2015^Citation16,b	qRT-PCR	NM	40	88	0.62 (0.19–1.98)Ue	<0.05	NM	NM
Wu, 2015^Citation32	IHC	IRS scores ≥3 (range of 0–12)	56	118	0.430 (0.269–0.687)M	<0.001	NM	NM
Han, 2015^Citation36	IHC	IRS scores ≥3 (range of 0–12)	137	188	0.617 (0.462–0.823)M	0.001	NM	NM
Yu, 2014^Citation13	IHC	IRS scores ≥3 (range of 0–12)	34	49	0.226 (0.094–0.545)M	0.001	0.278 (0.119–0.647)M	0.003
Kwon, 2014^Citation19	IHC	.0% of tumor cells stained	98	546	1.513 (1.057–2.165)M	0.024	f	f
Tang, 2014^Citation14,c	IHC	IRS scores ≥8 (range of 0–12)	114	303	0.42 (0.29–0.63)M	0.0000147	NM	NM
Tang, 2014^Citation14,d	IHC	IRS scores ≥8 (range of 0–12)	114	303	0.59 (0.36–0.96)M	0.029	NM	NM
Zhang, 2013^Citation37	IHC	Accumulated points ≥80	52	48	0.54 (0.27–1.05)Ue	NM	NM	NM
Zhang, 2013^Citation38	WB	NM	43	43	0.36 (0.17–0.77)Ue	NM	NM	NM
Wu, 2012^Citation15	IHC	IRS scores >1 (range of 0–12)	19	31	0.039 (0.007–0.236)M	0.00	NM	NM
Knoener, 2012^Citation33	IHC	IRS scores ≥3 (range of 0–12)	168	103	0.77 (0.55–1.07)Ue	0.2305	NM	NM
Guo, 2009^Citation39	IHC	>10% of tumor cells stained	21	59	0.81 (0.28–2.32)Ue	0.022	NM	NM
Protzel, 2008^Citation34	IHC	>50% of tumor cells stained	17	13	0.34 (0.02–4.90)Ue	0.0042	NM	NM
Miyazaki, 2005^Citation40	IHC	Ki index ≥39	48	43	0.48 (0.22–1.03)Ue	0.0023	NM	NM
Leavey, 2005^Citation17	IHC	NM	16	31	1.14 (0.27–4.81)Ue	0.28	0.99 (0.35–2.85)Ue	0.24
Farhadieh, 2004^Citation41	IHC	>10% of tumor cells stained	15	42	0.52 (0.27–1.01)M	0.053	0.4 (0.2–0.8)M	0.009
Goncharuk, 2004^Citation42	IHC	Median	77	27	0.47 (0.23–0.97)Ue	0.034	NM	NM
Su, 2004^Citation50	IHC	>50% of tumor cells stained	54	33	NM	NM	0.255 (0.111–0.588)M	0.0013
Hashida, 2003^Citation18	IHC	Scores ≥120 (range of 0–300)	63	83	0.903 (0.297–2.747)M	0.858	1.054 (0.431–2.577)M	0.909
Imai, 2002^Citation43	qRT-PCR	NM	25	18	0.51 (0.06–4.38)Ue	NM	NM	NM
Schindl, 2001^Citation44	IHC	Scores ≥4 (range of 3–7)	48	59	0.45 (0.22–0.92)M	0.0282	0.3 (0.09–0.93)M	0.0372
Miyazaki, 2000^Citation45	IHC	>10% of tumor cells stained	36	19	0.41 (0.17–1.00)Ue	0.024	NM	NM
Yang, 2000^Citation46	IHC	>5% of tumor cells stained	36	36	0.72 (0.20–2.61)Ue	NM	NM	NM
Sho, 1998^Citation47	IHC	>50% of tumor cells stained	15	25	1.16 (0.29–4.64)Ue	0.018	NM	NM
Huang, 1998^Citation48	IHC	HSCORE >50	44	65	0.442 (0.109–1.789)M	0.2528	0.360 (0.149–0.870)M	0.0234
Higashiyama, 1997^Citation35	IHC	>50% of tumor cells stained	65	135	0.700 (0.502–0.976)M	0.037	f	f
Adachi, 1996^Citation49	qRT-PCR	Gene conservation rate value >1.2	35	116	0.416 (0.175–0.986)M	0.046	NM	NM

Notes: The source of HR and 95% CI was extracted from survival curves or article reports.

a,b Data extracted from one study due to different assay method (IHC and qRT-PCR).

c,d Data extracted from one study due to different follow-up time (120 and 60 months).

e HR calculated from survival curves.

f Excluded due to its heterogeneity and publication bias.

Abbreviations: IHC, immunohistochemistry; qRT-PCR, quantitative reverse transcription-polymerase chain reaction; WB, western-blot; NM, not mentioned; IRS, immunoreactivity score; HSCORE, the intensity and respective percentage cells that stain at each intensity were multiplied to reach a HSCORE that ranged from 0 to 300; OS, overall survival; DFS, disease-free survival; RFS, recurrence-free survival; PFS, progression-free survival; SC, survival curve; HR, hazard ratio; CI, confidence interval; U, univariate analysis; M, multivariate analysis.

Figure 2 Forest plots of combined analyses associated with CD82 expression.

Notes: (A) OS and (B) DFS/RFS/PFS. Weights are from random effects analysis.
Abbreviations: DFS, disease-free survival; HR, hazard ratio; ID, identifier; OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival.

Figure 3 Forest plots of stratified analysis of the OS.

Notes: (A) Stratified by ethnic subgroup, (B) stratified by tumor subgroup, (C) stratified by pathological subgroup, and (D) stratified by assay method subgroup. Weights are from random effects analysis.
Abbreviations: AdenoCa, adenocarcinoma; HR, hazard ratio; ID, identifier; IHC, immunohistochemistry; LSCC, laryngeal squamous cell carcinoma; NSCLC, non-small-cell lung cancer; OS, overall survival; qRT-PCR, quantitative reverse transcription-polymerase chain reaction; SqCa, squamous carcinoma.

Figure 4 Forest plots of stratified analysis of the DFS/RFS/PFS.

Notes: (A) Stratified by ethnic subgroup and (B) stratified by pathological subgroup. Weights are from random effects analysis.
Abbreviations: AdenoCa, adenocarcinoma; DFS, disease-free survival; HR, hazard ratio; ID, identifier; OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival; SqCa, squamous carcinoma.

Figure 5 Sensitivity analysis under specific model and Begg’s funnel plots of publication bias test.

Notes: (A) Effect of individual studies on the combined HR for OS, (B) effect of individual studies on the combined HR for DFS/RFS/PFS, (C) Begg’s funnel plots of OS, and (D) Begg’s funnel plots of DFS/RFS/PFS.
Abbreviations: DFS, disease-free survival; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival.

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