Effects of four single nucleotide polymorphisms of EZH2 on cancer risk: a systematic review and meta-analysis

Figures & data

Figure 1 EZH2 polymorphism affects transcription of downstream targets.

Abbreviation: SNP, single nucleotide polymorphism.

Table 1 Characteristics of studies included in the meta-analysis

First author	Years	Cancer type	Region	Ethnicity	Methods	Controls	Case	Control	Polymorphism site	HWE	NOS
Bachmann et al^Citation19	2005	Prostate cancer	Germany	Caucasian	SNaPshot	PB	287	96	rs2302427	Yes	8
Breyer et al^Citation20	2009	Prostate cancer	America	Caucasian	Illumina	PB	523	523	rs2302427	Yes	8
Yoon et al^Citation21	2010	Lung cancer	Korea	Asian	Illumina	PB	335	335	rs887569, rs2302427, rs3757441, rs41277434	Yes	8
Zhou et al^Citation22	2014	Gastric cancer	China	Asian	Sequenom	PB	311	425	rs3757441	Yes	8
Yu et al^Citation23	2013	Hepatocellular carcinoma	Taiwan	Asian	TaqMan	HB	220	552	rs2302427, rs3757441, rs41277434	Yes	7
Wang et al^Citation24	2014	Colorectal cancer	China	Asian	PCR-RFLP	HB	512	576	rs887569, rs3757441, rs41277434	Yes	7
Yu et al^Citation25	2014	Urothelial cell carcinoma	Taiwan	Asian	TaqMan	HB	233	552	rs2302427, rs3757441, rs41277434	Yes	7
Ma et al^Citation26	2014	Esophageal squamous cell carcinoma	China	Asian	PCR-RFLP	HB	476	492	rs887569, rs3757441, rs41277434	Yes	7
Huang et al^Citation27	2015	Colorectal cancer	China	Asian	PCR-RFLP	PB	96	100	rs887569	Yes	8
Su et al^Citation28	2015	Oral squamous cell cancer	Taiwan	Asian	TaqMan	HB	576	552	rs2302427, rs3757441, rs41277434	Yes	7
Tao et al^Citation29	2015	Breast cancer	China	Asian	SNaPshot	PB	234	300	rs2302427, rs3757441	Yes	8
Chang et al^Citation30	2016	Bladder cancer	Taiwan	Asian	PCR-RFLP	PB	375	375	rs887569, rs3757441, rs41277434	Yes	8

Abbreviations: HB, hospital-based controls; HWE, Hardy–Weinberg equilibrium; Illumina, Illumina GoldenGate platform; NOS, Newcastle–Ottawa Quality Assessment Scale; PB, population-based controls; PCR-RFPL, polymerase chain reaction-restriction fragment length polymorphism; Sequenom, Sequenom MassARRAY iPLEX platform; SNaPshot, multiplex-PCR SNaPshot assay; TaqMan, TaqMan Real-Time PCR Assays.

Figure 2 Studies identified with criteria of inclusion and exclusion.

Abbreviation: SNP, single nucleotide polymorphism.

Table 2 Analysis of associations between SNPs of EZH2 and cancer risk

Comparisons	Study	Na	Cases/controls	WM vs WWb	P-valuec	I^2, %	MM vs WWb	P-valuec	I^2, %	WM + MM vs WWb	P-valuec	I^2, %	MM vs WM + WWb	P-valuec	I^2, %
				OR (95% CI)			OR (95% CI)			OR (95% CI)			OR (95% CI)
rs887569 C>T	Overall (Asian)	5	1,794/1,878	0.889 (0.771 to 1.026)	0.466	0.0	0.738 (0.520 to 1.047)	0.058	56.2	0.849 (0.740 to 0.973)	0.29	19.6	0.793 (0.654 to 0.962)	0.162	38.9
Cancer type	DSC	3	1,084/1,168	0.923 (0.764 to 1.115)	0.260	25.7	0.878 (0.533 to 1.445)	0.068	62.8	0.894 (0.746 to 1.071)	0.179	41.9	0.877 (0.696 to 1.104)	0.186	40.6
rs2302427 C>G	Overall	7	2,408/2,910	0.866 (0.696 to 1.077)	0.051	52.0	0.562 (0.400 to 0.792)	0.967	0.0	0.856 (0.748 to 0.980)	0.089	45.4	0.733 (0.571 to 0.940)	0.621	0.0
Ethnicity	Asian	5	1,598/2,291	0.937 (0.733 to 1.197)	0.093	49.8	0.550 (0.384 to 0.787)	0.881	0.0	0.911 (0.782 to 1.061)	0.098	49.0	0.731 (0.566 to 0.944)	0.356	0.0
	Caucasian	2	810/619	0.686 (0.511 to 0.921)	0.601	0.0	0.723 (0.226 to 2.313)	0.914	0.0	0.688 (0.515 to 0.917)	0.627	0.0	0.768 (0.240 to 2.456)	0.898	0.0
Cancer type	DSC	2	796/1,104	1.132 (0.925 to 1.385)	0.958	0.0	0.618 (0.394 to 0.970)	0.558	0.0	1.045 (0.862 to 1.267)	0.927	0.0	0.593 (0.380 to 0.925)	0.547	0.0
	USC	3	1,033/1,362	0.684 (0.546 to 0.857)	0.872	0.0	0.484 (0.248 to 0.943)	0.733	0.0	0.664 (0.534 to 0.826)	0.837	0.0	0.533 (0.274 to 1.035)	0.769	0.0
rs3757441 T>C	Overall (Asian)	9	3,272/4,159	0.938 (0.849 to 1.036)	0.202	27.2	0.827 (0.555 to 1.231)	0.000	81.3	0.915 (0.774 to 1.081)	0.002	67.0	0.846 (0.599 to 1.193)	0.000	77.6
Cancer type	DSC	5	2,905/2,579	0.947 (0.806 to 1.177)	0.068	54.2	0.947 (0.513 to 1.748)	0.000	87.7	0.976 (0.743 to 1.282)	0.001	80.0	0.946 (0.562 to 1.592)	0.000	85.0
	USC	2	608/927	0.937 (0.751 to 1.169)	0.538	0.0	0.811 (0.563 to 1.170)	0.881	0.0	0.912 (0.739 to 1.125)	0.625	0.0	0.817 (0.575 to 1.160)	0.845	0.0
rs41277434 A>C	Overall (Asian)	7	2,727/3,403	1.050 (0.908 to 1.213)	0.990	0.0	1.044 (0.812 to 1.240)	0.986	0.0	1.037 (0.905 to 1.187)	0.988	0.0	0.957 (0.791 to 1.158)	0.948	0.0
Cancer type	DSC	4	1,784/2,172	1.041 (0.872 to 1.242)	0.855	0.0	0.971 (0.755 to 1.247)	0.928	0.0	1.017 (0.860 to 1.203)	0.881	0.0	0.920 (0.738 to 1.148)	0.827	0.0
	USC	2	608/927	1.045 (0776 to 1.408)	0.996	0.0	1.705 (0.717 to 1.595)	0.851	0.0	1.049 (0.807 to 1.365)	0.913	0.0	1.056 (0.718 to 1.554)	0.856	0.0

Notes:

a Number of comparisons;

b W, major allele; M, minor allele.

c P-value of Q-test of heterogeneity test. DSCs, including hepatocellular carcinoma, oral squamous cell cancer, colorectal cancer, esophageal squamous cell carcinoma, or gastric cancer; USCs, including urothelial cell carcinoma, prostate cancer, bladder cancer. Random-effects models were used if heterogeneity between articles was reported (P<0.10, I²>50%), otherwise fixed-effects models were applied. WM, WW, MM represent heterozygote, homozygote for major allele and homozygote for minor allele, respectively. Bold data is statistically significant.

Abbreviations: DSC, digestive system cancer; USC, urogenital system cancer.

Figure 3 Forest plot for the relationship between rs887569 and cancer risk: (A) CT/CC; (B) TT/CC; (C) CTTT/CC; (D) TT/CCCT.

Note: Weights are from random effects analysis.

Figure 4 Forest plot for the relationship between rs2302427 and cancer risk: (A) CG/CC; (B) GG/CC; (C) CGGG/CC; (D) GG/CCCG.

Note: Weights are from random effects analysis.

Table 3 Publication bias in meta-analysis for each inheritance model

SNPs	Inheritance model	Studies	Begg’s test		Egger’s test
			Z-value	P-value	95% CI	P-value
rs887569 C>T	Heterozygote genotype: CT/CC	5	0.73	0.462	(−0.54 to 5.08)	0.082
	Homozygote genotype: TT/CC	5	0.24	0.806	(−9.31 to 10.11)	0.904
	Dominant genetic model: CTTT/CC	5	0.73	0.462	(−1.75 to 6.47)	0.165
	Recessive genetic model: TT/CCCT	5	0.24	0.806	(−10.84 to 5.23)	0.328
rs2302427 C>G	Heterozygote genotype: CG/CC	7	0.60	0.548	(−5.94 to 1.95)	0.250
	Homozygote genotype: GG/CC	7	0.00	1.000	(−1.08 to 1.44)	0.729
	Dominant genetic model: CGGG/CC	7	1.20	0.230	(−5.41 to 2.10)	0.308
	Recessive genetic model: GG/CCCG	7	0.30	0.764	(−2.24 to 0.91)	0.328
rs3757441 T>C	Heterozygote genotype: CT/TT	9	1.98	0.048	(−11.99 to 3.87)	0.265
	Homozygote genotype: CC/TT	9	1.77	0.076	(−13.17 to −2.36)	0.012
	Dominant genetic model: CCCT/TT	9	1.77	0.076	(−17.25 to 5.26)	0.268
	Recessive genetic model: CC/CTTT	9	1.36	0.175	(−10.34 to −2.11)	0.009
rs41277434 A>C	Heterozygote genotype: AC/AA	7	0.90	0.368	(−1.66 to 0.47)	0.212
	Homozygote genotype: CC/AA	7	2.10	0.035	(−0.10 to 1.17)	0.083
	Dominant genetic model: ACCC/AA	7	1.20	0.230	(−1.56 to 0.54)	0.263
	Recessive genetic model: CC/AAAC	7	2.10	0.035	(−0.18 to 1.38)	0.106

Abbreviation: SNP, single nucleotide polymorphism.

Figure S1 Forest plot for the relationship between rs3757441 and cancer risk: (A) CT/TT; (B) CC/TT; (C) CCCT/TT; (D) CC/CTTT.

Note: Weights are from random effects analysis.

Figure S2 Forest plot for the relationship between rs41277434 and cancer risk: (A) AC/AA; (B) CC/AA; (C) ACCC/AA; (D) CC/AAAC.

Figure S3 Forest plot of sensitivity analysis for EZH2 SNPs.

Abbreviation: SNP, single nucleotide polymorphism.

Table S1 Characteristics of eligible studies for each SNP in the meta-analysis

Gene	Reference	Years	Cancer type	Region	Ethnicity	Controls	NOS	Genotype-case			Genotype-control			Method	HWE P-value
EZH2	Rs887569 C>T							CC	CT	TT	CC	CT	TT
	Huang et al^Citation9	2015	Colorectal cancer	China	Asian	PB	8	10	47	39	16	43	41	PCR-RFLP	0.41
	Wang et al^Citation6	2014	Colorectal cancer	China	Asian	HB	7	237	239	36	221	266	59	PCR-RFLP	0.11
	Ma et al^Citation8	2014	Esophageal squamous cell cancer	China	Asian	HB	7	126	253	97	129	264	99	PCR-RFLP	0.09
	Yoon et al^Citation3	2010	Lung cancer	Korea	Asian	PB	8	159	144	32	148	145	42	Illumina	0.49
	Chang et al^Citation12	2016	Bladder cancer	China	Asian	PB	8	180	171	24	150	182	43	PCR-RFLP	0.27
EZH2	Rs2302427 C>G							CC	CG	GG	CC	CG	GG
	Yu et al^Citation5	2013	Hepatocellular carcinoma	Taiwan	Asian	HB	7	135	75	10	346	171	35	TaqMan	0.03
	Yoon et al^Citation3	2010	Lung cancer	Korea	Asian	PB	8	284	49	2	282	50	3	Illumina	0.64
	Yu et al^Citation7	2014	Urothelial cell carcinoma	Taiwan	Asian	HB	7	169	57	7	346	171	35	TaqMan	0.03
	Su et al^Citation10	2015	Oral squamous cell cancer	Taiwan	Asian	HB	7	356	200	20	346	171	35	TaqMan	0.03
	Breyer et al^Citation2	2009	Prostate cancer	America	Caucasian	PB	8	450	69	4	420	98	5	Illumina	0.79
	Tao et al^Citation11	2015	Breast cancer	China	Asian	PB	8	11	80	143	7	105	188	SNaPshot	0.08
	Bachmann et al^Citation1	2005	Prostate cancer	Germany	Caucasian	PB	8	243	42	2	78	17	1	SNaPshot	0.95
EZH2	Rs3757441T>C							TT	TC	CC	TT	TC	CC
	Yu et al^Citation5	2013	Hepatocellular carcinoma	Taiwan	Asian	HB	7	131	80	9	271	223	58	TaqMan	0.23
	Wang et al^Citation6	2014	Colorectal cancer	China	Asian	HB	7	196	230	86	245	248	53	PCR-RFLP	0.39
	Yu et al^Citation7	2014	Urothelial cell carcinoma	Taiwan	Asian	HB	7	123	88	22	271	223	58	TaqMan	0.23
	Ma et al^Citation8	2014	Esophageal squamous cell cancer	China	Asian	HB	7	112	260	104	147	267	78	PCR-RFLP	0.43
	Su et al^Citation10	2015	Oral squamous cell cancer	Taiwan	Asian	HB	7	312	221	43	271	223	58	TaqMan	0.23
	Yoon et al^Citation3	2010	Lung cancer	Korea	Asian	PB	8	193	125	17	169	134	32	Illumina	0.47
	Zhou et al^Citation4	2012	Gastric cancer	China	Asian	PB	7	181	112	18	235	162	28	Sequenom	0.99
	Tao et al^Citation11	2015	Breast cancer	China	Asian	PB	8	127	91	16	144	129	27	SNaPshot	0.80
	Chang et al^Citation12	2016	Bladder cancer	China	Asian	PB	8	169	172	34	165	168	42	PCR-RFLP	0.94
EZH2	Rs41277434A>C							AA	AC	CC	AA	AC	CC
	Yu et al^Citation5	2013	Hepatocellular carcinoma	Taiwan	Asian	HB	7	209	11	0	517	34	1	TaqMan	0.58
	Wang et al^Citation6	2014	Colorectal cancer	China	Asian	HB	7	193	236	83	212	248	86	PCR-RFLP	0.34
	Yu et al^Citation7	2014	Urothelial cell carcinoma	Taiwan	Asian	HB	7	218	15	0	517	34	1	TaqMan	0.58
	Ma et al^Citation8	2014	Esophageal squamous cell cancer	China	Asian	HB	7	133	242	101	141	231	120	PCR-RFLP	0.19
	Su et al^Citation10	2015	Oral squamous cell cancer	Taiwan	Asian	HB	7	540	35	1	517	34	1	TaqMan	0.58
	Yoon et al^Citation3	2010	Lung cancer	Korea	Asian	PB	8	293	40	2	298	36	1	Illumina	0.94
	Chang et al^Citation12	2016	Bladder cancer	China	Asian	PB	8	215	98	62	220	96	59	PCR-RFLP	5.6E-13

Abbreviations: HB, hospital-based controls; HWE, Hardy–Weinberg equilibrium; Illumina, Illumina GoldenGate platform; NOS, Newcastle–Ottawa Quality Assessment Scale; PB, population-based controls; PCR-RFPL, polymerase chain reaction-restriction fragment length polymorphism; SNaPshot, multiplex-PCR SNaPshot assay; SNP, single nucleotide polymorphism; TaqMan, TaqMan Real-Time PCR Assays.

BachmannNHoegelJHaeuslerJMutation screen and association study of EZH2 as a susceptibility gene for aggressive prostate cancerProstate200565325225916015586

 PubMed Web of Science ®Google Scholar

BreyerJPMcReynoldsKMYaspanBLBradleyKMDupontWDSmithJRGenetic variants and prostate cancer risk: candidate replication and exploration of viral restriction genesCancer Epidemiol Biomarkers Prev20091872137214419567509

 PubMed Web of Science ®Google Scholar

YoonKAGilHJHanJParkJLeeJSGenetic polymorphisms in the polycomb group gene EZH2 and the risk of lung cancerJ Thorac Oncol201051101619901851

 PubMed Web of Science ®Google Scholar

ZhouYDuWDWuQEZH2 genetic variants affect risk of gastric cancer in the Chinese Han populationMol Carcinog201453858959722228224

 PubMed Web of Science ®Google Scholar

YuYLSuKJHsiehYHEffects of EZH2 polymorphisms on susceptibility to and pathological development of hepatocellular carcinomaPLoS One201389e7487024040354

 PubMed Web of Science ®Google Scholar

WangJMaZBLiKGuoGHAssociation between EZH2 polymorphisms and colorectal cancer risk in Han Chinese populationMed Oncol201431387424488618

 PubMed Web of Science ®Google Scholar

YuYLSuKJHsiehMJImpact of EZH2 polymorphisms on urothelial cell carcinoma susceptibility and clinicopathologic featuresPLoS One201494e9363524691023

 PubMed Web of Science ®Google Scholar

MaZBGuoGHNiuQShiNRole of EZH2 polymorphisms in esophageal squamous cell carcinoma risk in Han Chinese populationInt J Mol Sci2014157126881269725036033

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HuangYWangXZhangLCorrelations of single nucleotide polymorphisms of EZH2 gene with genetic susceptibility of colorectal cancerChin J Clin Lab Sci2015334262265

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SuKJLinCWChenMKYangSFYuYLEffects of EZH2 promoter polymorphisms and methylation status on oral squamous cell carcinoma susceptibility and pathologyAm J Cancer Res20155113475348426807327

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TaoRChenZWuPThe possible role of EZH2 and DNMT1 polymorphisms in sporadic triple-negative breast carcinoma in southern Chinese femalesTumour Biol201536129849985526162541

 PubMedGoogle Scholar

ChangWSLiaoCHTsaiCWAssociation of Enhancer of Zeste 2 (EZH2) Genotypes with Bladder Cancer Risk in TaiwanAnticancer Res20163694509451427630289

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HuangYWangXZhangLCorrelations of single nucleotide polymorphisms of EZH2 gene with genetic susceptibility of colorectal cancerChin J Clin Lab Sci2015334262265

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WangJMaZBLiKGuoGHAssociation between EZH2 polymorphisms and colorectal cancer risk in Han Chinese populationMed Oncol201431387424488618

 PubMed Web of Science ®Google Scholar

MaZBGuoGHNiuQShiNRole of EZH2 polymorphisms in esophageal squamous cell carcinoma risk in Han Chinese populationInt J Mol Sci2014157126881269725036033

 PubMed Web of Science ®Google Scholar

YoonKAGilHJHanJParkJLeeJSGenetic polymorphisms in the polycomb group gene EZH2 and the risk of lung cancerJ Thorac Oncol201051101619901851

 PubMed Web of Science ®Google Scholar

ChangWSLiaoCHTsaiCWAssociation of Enhancer of Zeste 2 (EZH2) Genotypes with Bladder Cancer Risk in TaiwanAnticancer Res20163694509451427630289

 PubMed Web of Science ®Google Scholar

YuYLSuKJHsiehYHEffects of EZH2 polymorphisms on susceptibility to and pathological development of hepatocellular carcinomaPLoS One201389e7487024040354

 PubMed Web of Science ®Google Scholar

YuYLSuKJHsiehMJImpact of EZH2 polymorphisms on urothelial cell carcinoma susceptibility and clinicopathologic featuresPLoS One201494e9363524691023

 PubMed Web of Science ®Google Scholar

SuKJLinCWChenMKYangSFYuYLEffects of EZH2 promoter polymorphisms and methylation status on oral squamous cell carcinoma susceptibility and pathologyAm J Cancer Res20155113475348426807327

 PubMed Web of Science ®Google Scholar

BreyerJPMcReynoldsKMYaspanBLBradleyKMDupontWDSmithJRGenetic variants and prostate cancer risk: candidate replication and exploration of viral restriction genesCancer Epidemiol Biomarkers Prev20091872137214419567509

 PubMed Web of Science ®Google Scholar

TaoRChenZWuPThe possible role of EZH2 and DNMT1 polymorphisms in sporadic triple-negative breast carcinoma in southern Chinese femalesTumour Biol201536129849985526162541

 PubMedGoogle Scholar

BachmannNHoegelJHaeuslerJMutation screen and association study of EZH2 as a susceptibility gene for aggressive prostate cancerProstate200565325225916015586

 PubMed Web of Science ®Google Scholar

ZhouYDuWDWuQEZH2 genetic variants affect risk of gastric cancer in the Chinese Han populationMol Carcinog201453858959722228224

 PubMed Web of Science ®Google Scholar