Accuracy of early detection of colorectal tumours by stool methylation markers: A meta-analysis

doi:10.3748/wjg.v20.i38.14040

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Meta-Analysis

World J Gastroenterol. Oct 14, 2014; 20(38): 14040-14050
Published online Oct 14, 2014. doi: 10.3748/wjg.v20.i38.14040

Table 1 Characteristics of the included studies in the meta-analysis and quality assessment of studies of diagnostic accuracy scores

Ref.	Country/region	Methylation of genes	n	CRC		Adenoma		Normal		Blind design	Detection method	QUADAS score
Ref.	Country/region	Methylation of genes	n	+	-	+	-	+	-	Blind design	Detection method	QUADAS score
Ahlquist et al[10] 2012	Ireland	Vimentin/NDRG4/BMP3/TFPI2	98	26	4	18	4	5	41	Yes	QuARTS	11
Bosch et al[11] 2011	The Netherlands	PHACTR3	185	40	25	6	13	4	97	Unclear	qMSP	10
		GATA4	160	29	11	3	16	6	95
		OSMR	185	25	40	4	15	7	94
Ahlquist et al[12] 2011	Ireland	PHACTR3	639	214	38	51	43	29	264	Yes	QuARTS	11
Azuara et al[13] 2010	Spain	RARB2/P16/MGMT/APC	98	25	13	20	20	0	20	Yes	MS-MCA	10
		RARB2	85	11	23	7	31	0	13
		P16	77	9	21	6	28	0	13
		MGMT	80	9	19	3	34	0	15
		APC	77	9	19	9	25	0	15
Tang et al[14] 2011	China	SFRP2	262	142	27	29	34	2	28	Yes	MSP	9
Baek et al[15] 2009	South Korea	Vimentin/MGMT/MLH1	149	45	15	31	21	5	32	Yes	MSP	9
		MLH1	149	18	42	6	46	0	37
		Vimentin	149	23	37	8	44	0	37
		MGMT	149	31	29	19	33	5	32
Li et al[16] 2009	United States	Vimentin	80	9	13	9	11	2	36	Unclear	Methyl-BEAMing	5
Melotte et al[17] 2009	The Netherlands	NDRG4	150	42	33	NR	NR	3	72	Yes	qMSP	11
Ausch et al[18] 2009	United States	IGTA4	37	NR	NR	7	2	6	22	Unclear	qMSP	4
Hellebrekers et al[19] 2009	The Netherlands	GATA4	150	44	31	NR	NR	9	66	Yes	qMSP	10
Mayor et al[20] 2009	Spain	EN1	60	8	22	NR	NR	1	29	Unclear	MS-MCA	7
Kim et al[21] 2009	United States	OSMR/SFRP1	42	12	8	6	11	0	5	Yes	qMSP	9
		OSMR	201	35	54	2	14	4	92
		SFRP1	52	11	9	5	12	0	15
Nagasaka et al[22] 2009	Japan	SFRP2	253	53	31	18	38	9	104	Unclear	COBRA	10
Nagasaka et al[22] 2009	Japan	RASSF2	253	38	46	7	49	6	107	Unclear	COBRA	10
Glöckner et al[23] 2009	United States	TFPI2	129	44	14	7	19	2	43	Yes	qMSP	12
Wang et al[24] 2008	China	SFRP2	133	60	9	21	13	2	28	Yes	MethyLight	8
Oberwalder et al[25] 2008	Australia	SFRP2	19	NR	NR	6	7	0	6	Yes	MethyLight	9
Itzkowitz et al[26] 2008	United States	Vimentin	80	9	13	9	11	2	36	Yes	MSP	13
Huang et al[27] 2007	China	SFRP2/HPP1/MGMT	97	50	2	15	6	1	23	Yes	MSP	8
		SFRP2	97	49	3	11	10	1	23
		HPP1	97	37	15	12	9	0	24
		MGMT	97	25	27	6	15	0	24
Itzkowitz et al[28] 2007	United States	Vimentin/HLTF	162	31	9	NR	NR	19	103	Yes	MSP	13
		HLTF	162	15	25	NR	NR	9	113
		Vimentin	162	29	11	NR	NR	16	106
Abbaszadegan et al[29] 2007	Hong kong	p16	45	5	20	NR	NR	0	20	Unclear	MSP	8
Zhang et al[30] 2007	Germany	SFRP1	44	16	4	7	0	2	15	Yes	MSP	9
Leung et al[31] 2007	Hong kong	SFRP2/MGMT/MLH1/HLTF/ATM/APC	75	16	4	18	7	3	27	Yes	MSP	13
		SFRP2	75	6	14	3	22	2	28
		MGMT	75	4	16	3	22	0	30
		MLH1	75	4	16	3	22	0	30
		HLTF	75	5	15	5	20	1	29
		ATM	75	5	15	5	20	0	30
		APC	75	4	16	4	21	0	30
Petko et al[32] 2005	United States	MGMT/CDKN2A/MLH1	48	NR	NR	16	13	7	12	Yes	MSP	9
		CDKN2A	48	NR	NR	9	20	3	16
		MGMT	48	NR	NR	14	15	5	14
		MLH1	48	NR	NR	0	29	2	17
Lenhard et al[33] 2005	Germany	HIC1	71	11	15	4	9	0	32	Yes	MSP	11
Chen et al[34] 2005	United States	Vimentin	263	43	51	6	44	8	111	Yes	MSP	11
Müller et al[35] 2004	Australia	SFRP2/SFRP5	39	20	3	NR	NR	8	8	Unclear	MethyLight	5
		SFRP2	39	19	4	NR	NR	4	12
		SFRP5	39	18	5	NR	NR	5	11
Xu et al[36] 2012	China	SFRP2	90	20	10	15	15	1	29	Unclear	MSP	5
Kang et al[37] 2011	China	MGMT/MAL/CDKN2A	119	64	5	17	7	2	24	Unclear	MSP	7
		MAL	119	54	15	14	10	1	25
		CDKN2A	119	36	33	10	14	0	26
		MGMT	119	38	31	9	15	1	25
Zhang et al[38] 2011	China	Vimentin/OSMR/TFPI2	107	52	8	13	4	4	26	Unclear	MSP	9
		Vimentin	107	32	28	5	12	0	30
		OSMR	107	41	19	7	10	0	30
		TFPI2	107	45	15	11	6	4	26
Fu et al[39] 2010	China	Vimentin	22	5	9	NR	NR	0	8	Unclear	MSP	5
Ling et al[40] 2009	China	P16	108	47	14	16	11	1	19	Unclear	MSP	7
Cheng et al[41] 2007	China	SFRP2	97	49	3	11	10	1	23	Unclear	MSP	5
Zhao et al[42]	China	NDRG4	114	64	20	NR	NR	3	27	Unclear	MSP	6
2009	China	NDRG4	114	64	20	NR	NR	3	27	Unclear	MSP	6
Chang et al[43] 2010	South Korea	IGTA4/SFRP2/P16	86	21	9	18	7	1	30	Yes	MSP	8
		IGTA4	86	11	19	4	21	0	31
		SFRP2	86	18	12	11	14	0	31
		P16	86	12	18	6	19	1	30
Zhang et al[44] 2013	China	SPG20	126	77	19	NR	NR	0	30	Unclear	MSP	7
Carmona et al[45] 2013	Spain	AGTR1/WNT2/SLIT2	102	50	14	NR	NR	4	34	Unclear	Pyrosequencing	10
		AGTR1	107	14	54	NR	NR	2	37
		WNT2	91	21	31	NR	NR	1	38
		SLIT2	108	37	34	NR	NR	2	35
		9-Sep	61	7	28	NR	NR	0	26
		Vimentin	55	18	15	NR	NR	3	19
Guo et al[46] 2013	China	FBN1	105	54	21	NR	NR	2	28		MSP	6

+: Represents the number of individuals when the DNA methylation test was positive; -: Represents the number of individuals when the DNA methylation test was negative; MSP: Methylation-specific PCR; NR: Not reported; n: Total number.

Table 2 Methylation of pooled genes for the diagnosis of colorectal cancer

Wnt pathway	DNA damage repair pathway	Other pathways	SE (95%CI)	SP (95%CI)	DOR (95%CI)	AUC
Wnt pathway	DNA damage repair pathway	Other pathways	73% (71%-75%)	92% (90%-93%)	31.49 (23.25-42.64)	0.928
Wnt pathway	-	-	72% (68%-75%)	93% (90%-96%)	33.99 (17.99-60.50)	0.931
-	DNA damage repair pathway	-	42% (36%-47%)	97% (94%-99%)	12.87 (5.98-27.72)	0.730
-	-	Other pathways	57% (55%-59%)	94% (93%-95%)	20.17 (15.18-26.80)	0.921
SFRP2	-	-	79% (75%-82%)	93% (90%-96%)	47.57 (20.08-112.72)	0.957
-	MGMT	-	47% (40%-53%)	95% (90%-98%)	11.67 (5.10-26.67)	0.709
-	MLH	-	28% (18%-39%)	100% (95%-100%)	23.68 (3.02-185.44)	0.500
-	-	Vimentin	49% (43%-54%)	93% (90%-95%)	13.81 (8.57-22.27)	0.847
-	-	OSMR	47% (40%-54%)	95% (91%-98%)	14.66 (5.06-42.47)	0.225
-	-	P16	50% (42%-58%)	98% (92%-100%)	24.39 (7.26-81.96)	0.975
SFRP2	MGMT	-	69% (66%-72%)	94% (91%-96%)	33.24 (16.76-65.93)	0.946
SFRP2	MLH	-	72% (68%-75%)	94% (92%-96%)	43.03 (20.15-91.87)	0.953
SFRP2	MLH	Vimentin	64% (60%-67%)	93% (92%-95%)	24.93 (15.34-40.50)	0.928
SFRP2	MLH	OSMR	65% (62%-69%)	95% (93%-96%)	33.10 (17.12-63.98)	0.951
SFRP2	MLH	P16	68% (64%-71%)	95% (93%-97%)	38.86 (20.11-67.54)	0.952

SE: Sensitivity; SP: Specificity; DOR: Diagnostic odds ratios; AUC: The area under the curve; CI: Confidence interval; MLH: MutL Homologue; MGMT: O-6-Methylguanine-DNA Methyltransferase.

Table 3 Methylation of pooled genes for the diagnosis of colorectal adenomas

Wnt pathway	DNA damage repair pathway	Other pathways	SE(95%CI)	SP(95%CI)	DOR(95%CI)	AUC
Wnt pathway	DNA damage repair pathway	Other pathways	51% (47%-54%)	92% (90%-93%)	12.61 (8.66-18.37)	0.883
Wnt pathway	-	-	40% (35%-46%)	95% (92%-97%)	10.81 (6.43-18.16)	0.932
-	DNA damage repair pathway	-	21% (17%-27%)	95% (91%-97%)	4.23 (2.01-8.88)	0.672
-	-	Other pathways	32% (28%-35%)	94% (93%-95%)	7.78 (5.48-11.05)	0.873
SFRP2	-	-	43% (38%-49%)	94% (91%-97%)	11.06 (5.77-21.18)	0.956
-	MGMT	-	29% (22%-36%)	93% (87%-96%)	4.42 (2.18-8.95)	0.614
-	MLH	-	8% (4%-16%)	98% (92%-100%)	2.35 (0.14-40.83)	-
-	-	Vimentin	23% (17%-31%)	95% (92%-98%)	8.30 (2.60-26.55)	0.898
-	-	OSMR	25% (14%-39%)	95% (91%-98%)	5.20 (1.44-18.82)	0.817
-	-	P16	33% (23%-44%)	97% (89%-100%)	13.27 (3.40-51.83)	0.97
SFRP2	MLH	-	34% (29%-39%)	95% (92%-97%)	9.62 (4.64-19.93)	0.947
SFRP2	MGMT	-	38% (33%-42%)	94% (91%-96%)	7.85 (4.79-12.87)	0.753
SFRP2	-	OSMR	41% (35%-46%)	95% (92%-96%)	9.25 (5.13-16.69)	0.948
SFRP2	-	Vimentin	36% (32%-41%)	95% (93%-96%)	9.88 (5.55-17.57)	0.946
SFRP2	-	P16	41% (36%-46%)	95% (92%-97%)	10.37 (6.21-17.31)	0.948
SFRP2	MGMT	Vimentin	34% (30%-38%)	94% (92%-96%)	7.81 (4.96-12.29)	0.804
SFRP2	MGMT	OSMR	36% (32%-41%)	94% (92%-96%)	7.25 (4.61-11.39)	0.775
SFRP2	MGMT	P16	37% (33%-41%)	94% (92%-96%)	7.92 (5.14-12.21)	0.772
SFRP2	MLH	Vimentin	31% (27%-35%)	95% (93%-97%)	8.99 (4.95-16.31)	0.944
SFRP2	MLH	OSMR	33% (29%-38%)	95% (93%-97%)	8.37 (4.50-15.59)	0.941
SFRP2	MLH	P16	34% (30%-38%)	95% (93%-97%)	9.98 (5.45-18.27)	0.947

SE: Sensitivity; SP: Specificity; DOR: Diagnostic odds ratios; AUC: The area under the curve; MLH: MutL Homologue; MGMT: O-6-Methylguanine-DNA Methyltransferase.

Table 4 Weighted meta-regression on the diagnostic accuracy of the methylation of genes assays

Covariates	Coefficient	SE	P value	RDOR	95%CI
QUADAS score¹	0.062	0.413	0.881	1.06	(0.46-2.47)
Detection method²	-0.146	0.401	0.719	0.86	(0.38-1.96)
Blinded design³	-0.166	0.364	0.651	0.85	(0.40-1.78)
Methylation genes⁴	-0.036	0.444	0.936	0.96	(0.39-2.39)

¹QUADAS score, which was divided into studies with higher quality (QUADAS score ≥ 10) and those with lower quality (QUADAS score < 10);

²Detection method, which was divided into qualitative and quantitative assay methods;

³Blinded design: the study was included with or without blinded design;

⁴Methylation genes, which were divided into single gene and combination genes.

Citation: Zhang H, Qi J, Wu YQ, Zhang P, Jiang J, Wang QX, Zhu YQ. Accuracy of early detection of colorectal tumours by stool methylation markers: A meta-analysis. World J Gastroenterol 2014; 20(38): 14040-14050
URL: https://www.wjgnet.com/1007-9327/full/v20/i38/14040.htm
DOI: https://dx.doi.org/10.3748/wjg.v20.i38.14040