Prognostic value and clinicopathological significance of proliferating cell nuclear antigen expression in gastric cancer: a systematic review and meta-analysis

Figures & data

Figure 1 Flowchart of the study selection process.

Table 1 Characteristics of studies included in the meta-analysis

Study	Year	Country	Cases	Mean age	Gender (M/F)	PCNA assay	Cutoff value (%)	Survival	NOS score
Li et al^Citation21	2015	People’s Republic of China	69	55	51/18	IHC	≥50.0	OS, DFS	8
Poteca et al^Citation32	2014	Romania	32	68	23/9	IHC	>50.0	–	5
Liu et al^Citation23	2013	People’s Republic of China	133	60	110/23	IHC	>50.0	OS, DFS	8
Kuang et al^Citation33	2013	People’s Republic of China	50	–	26/24	IHC	>75.0	–	5
Yang et al^Citation24	2012	People’s Republic of China	264	66	157/107	IHC	>50.0	OS, DFS	8
Ye (FGCa) et al^Citation34	2011	People’s Republic of China	81	–	43/38	IHC	>50.0	OS	6
Ye (SGCb) et al^Citation34	2011	People’s Republic of China	81	–	46/35	IHC	>50.0	OS	6
Czyzewska et al^Citation26	2009	Poland	100	63	67/33	IHC	>50.0	OS	6
Kanaji et al^Citation35	2006	Japan	160	61	89/71	IHC	≥55.2	OS	8
Wu et al^Citation36	2004	People’s Republic of China	59	–	35/24	IHC	≥33.0	–	5
Lee et al^Citation27	2003	Korea	841	56	568/273	IHC	≥50.0	OS	7
Noda et al^Citation37	2002	Japan	133	–	87/46	IHC	≥31.2	OS	8
Konno et al^Citation25	2001	Japan	116	60	66/50	IHC	≥50.0	OS	8
Elpek et al^Citation38	2000	Spain	74	–	42/32	IHC	≥49.0	OS	8
Danesi et al^Citation39	2000	Italy	137	66	77/60	IHC	≥34.0	–	7
Kinugasa et al^Citation40	1998	Japan	50	58	25/25	IHC	≥23.8	OS	7
Maeda et al^Citation41	1995	Japan	108	59	25/25	IHC	≥42.0	OS	8
Mangham et al^Citation42	1994	England	90	68	58/32	IHC	>50.0	OS	6
Kakeji et al^Citation43	1994	Japan	181	–	100/81	IHC	≥36.5	OS	6
Jain et al^Citation44	1991	England	93	64	58/35	IHC	>50.0	OS	8

Notes:

a Study investigated the prognostic effect of PCNA in FGC.

b Study investigated the prognostic effect of PCNA in SGC.

Abbreviations: DFS, disease-free survival; FGC, familial gastric cancer; IHC, immunohistochemistry; M, male; F, female; NOS, Newcastle–Ottawa Scale; OS, overall survival; PCNA, proliferating cell nuclear antigen; SGC, sporadic gastric cancer.

Figure 2 Forest plot of HR for the association between proliferating cell nuclear antigen expression and overall survival in gastric cancer patients.

Note: Weights are from random-effects analysis.
Abbreviations: CI, confidence interval; HR, hazard ratio.

Table 2 Stratified analysis of PCNA expression with overall survival in gastric cancer patients

Subgroup	No of studies	Pooled HR (95% CI)		Meta-regression P-value	Heterogeneity
		Fixed	Random		I^2 (%)	P-value
Location
Asia	12	1.41 (1.23, 1.62)	1.69 (1.28, 2.23)	0.865	70.4	<0.001
Europe	4	1.52 (1.11, 2.08)	1.56 (1.07, 2.29)		28.7	0.240
Year
>2005	7	1.77 (1.43, 2.19)	1.77 (1.43, 2.19)	0.507	0	0.655
<2005	9	1.27 (1.09, 1.49)	1.60 (1.12, 2.28)		74.5	<0.001
Cutoff value
≥50%	11	1.29 (1.11, 1.49)	1.51 (1.15, 1.97)	0.162	65.3	0.001
<50%	5	1.93 (1.50, 2.48)	2.04 (1.48, 2.83)		25.1	0.254

Abbreviations: CI, confidence interval; HR, hazard ratio; PCNA, proliferating cell nuclear antigen.

Figure 3 Forest plot of HR for the association between proliferating cell nuclear antigen expression and disease-free survival in gastric cancer patients.

Abbreviations: CI, confidence interval; HR, hazard ratio.

Table 3 Meta-analysis of PCNA high expression and clinicopathological features in gastric cancer

Clinicopathological parameters	No of studies	Heterogeneity		Effect model	Pooled OR (95% CI)	P-value
		I^2 (%)	P-value
Depth of invasion (T3T4 vs T1T2)	8	32.1	0.172	Fixed	2.37 (1.71, 3.27)	<0.001
Lymph node metastasis (+ vs −)	9	37.8	0.117	Fixed	2.49 (1.85, 3.35)	<0.001
Vascular invasion (+ vs −)	6	64.3	0.016	Random	1.32 (0.70, 2.48)	0.398
TNM stage (III–IV vs I–II)	6	37.3	0.157	Fixed	1.89 (1.36, 2.63)	<0.001
Histological grade (G3/G4 vs G1/G2)	11	58.0	0.008	Random	1.04 (0.72, 1.50)	0.836
Lauren classification (intestinal vs diffuse)	7	50.4	0.06	Random	1.14 (0.70, 1.86)	0.597

Abbreviations: CI, confidence interval; OR, odds ratio; PCNA, proliferating cell nuclear antigen.

Figure 4 Sensitivity analysis of proliferating cell nuclear antigen expression on overall survival.

Abbreviation: CI, confidence interval.

Figure 5 Funnel plots with trim-and-fill analysis for (A) overall survival and (B) Lauren classification.

Abbreviation: SE, standard error.

LiNDengWMaJPrognostic evaluation of Nanog, Oct4, Sox2, PCNA, Ki67 and E-cadherin expression in gastric cancerMed Oncol201532143325491144

 PubMed Web of Science ®Google Scholar

PotecaTPotecaASajinMComanescuMBiological prognostic parameters in gastric carcinomasChirurgia (Bucur)2014109334735424956340

 PubMedGoogle Scholar

LiuMLiJSTianDPHuangBRosqvistSSuMMCM2 expression levels predict diagnosis and prognosis in gastric cardiac cancerHistol Histopathol201328448149223329420

 PubMed Web of Science ®Google Scholar

KuangRGWuHXHaoGXWangJWZhouCJExpression and significance of IGF-2, PCNA, MMP-7, and alpha-actin in gastric carcinoma with Lauren classificationTurk J Gastroenterol20132429910823934455

 PubMedGoogle Scholar

YangCWenYLiHOverexpression of minichromosome maintenance 2 predicts poor prognosis in patients with gastric cancerOncol Rep201227113514221947329

 PubMed Web of Science ®Google Scholar

YeYWDongRZZhouYPrognostic analysis of familial gastric cancer in Chinese populationJ Surg Oncol20111041768221400534

 PubMedGoogle Scholar

CzyzewskaJGuzinska-UstymowiczKPryczyniczAKemonaABandurskiRImmunohistochemical evaluation of Ki-67, PCNA and MCM2 proteins proliferation index (PI) in advanced gastric cancerFolia Histochem Cytobiol200947228929619995716

 PubMed Web of Science ®Google Scholar

KanajiSSaitoHTsujitaniSExpression of polo-like kinase 1 (PLK1) protein predicts the survival of patients with gastric carcinomaOncology200670212613316645325

 PubMed Web of Science ®Google Scholar

WuKZhaoLLiYShanYJWuLJEffects of vitamin E succinate on the expression of Fas and PCNA proteins in human gastric carcinoma cells and its clinical significanceWorld J Gastroenterol200410794594915052671

 PubMedGoogle Scholar

LeeKELeeHJKimYHPrognostic significance of p53, nm23, PCNA and c-erbB-2 in gastric cancerJpn J Clin Oncol200333417317912810831

 PubMed Web of Science ®Google Scholar

NodaHMaeharaYIrieKKakejiYYonemuraTSugimachiKIncreased proliferative activity caused by loss of p21(WAF1/CIP1) expression and its clinical significance in patients with early-stage gastric carcinomaCancer20029472107211211932915

 PubMedGoogle Scholar

KonnoSTakebayashiYAibaMAkiyamaSOgawaKClinicopathological and prognostic significance of thymidine phosphorylase and proliferating cell nuclear antigen in gastric carcinomaCancer Lett2001166110311111295293

 PubMedGoogle Scholar

ElpekGOGelenTAksoyNHKarpuzogluTKelesNMicrovessel count, proliferating cell nuclear antigen and Ki-67 indices in gastric adenocarcinomaPathol Oncol Res200061596410749590

 PubMedGoogle Scholar

DanesiDTSpanoMFabianoAFlow cytometric DNA ploidy, p53, PCNA, and c-erbB-2 protein expressions as predictors of survival in surgically resected gastric cancer patientsCytometry2000421273410679740

 PubMedGoogle Scholar

KinugasaSAbeSTachibanaMOverexpression of transforming growth factor-beta1 in scirrhous carcinoma of the stomach correlates with decreased survivalOncology19985565825879778627

 PubMedGoogle Scholar

MaedaKChungYSTakatsukaSTumour angiogenesis and tumour cell proliferation as prognostic indicators in gastric carcinomaBr J Cancer19957223193237543771

 PubMed Web of Science ®Google Scholar

ManghamDCRowlandsDCNewboldKMReynoldsGMFieldingJWHallisseyMTExpression of proliferating cell nuclear antigen (PCNA) in gastric carcinoma: no evidence for prognostic valueJ Clin Pathol19944754734747913101

 PubMedGoogle Scholar

KakejiYMaeharaYAdachiYProliferative activity as a prognostic factor in Borrmann type 4 gastric carcinomaBr J Cancer19946947497537908217

 PubMedGoogle Scholar

JainSFilipeMIHallPAWaseemNLaneDPLevisonDAPrognostic value of proliferating cell nuclear antigen in gastric carcinomaJ Clin Pathol19914486556591679766

 PubMedGoogle Scholar