MTHFR C677T polymorphism and breast, ovarian cancer risk: a meta-analysis of 19,260 patients and 26,364 controls

Figures & data

Figure 1 Flow diagram of literature search.

Table 1 Characteristics of the studies included in this meta-analysis

First author	Year	Nationality	Ethnicity	Cancer type	Patient/control	Control			Patient			P for HWE	Score	Control type
						CC	TC	TT	CC	TC	TT
Sharp^Citation50	2002	England	Caucasians	BC	54/57	25	21	11	30	19	5	0.10	7	PB
Campbell^Citation38	2002	England	Caucasians	BC	335/233	118	92	23	140	162	33	0.42	8	HB
Ergul^Citation51	2003	Turkey	Mixed	BC	118/193	94	87	12	60	41	17	0.16	7	HB
Semenza^Citation41	2003	USA	Caucasians	BC	105/247	112	111	24	42	58	5	0.64	7	HB
Langsenlehner^Citation37	2003	Austrian	Caucasians	BC	494/495	215	215	65	208	222	64	0.33	8	PB
Grieu^Citation39	2004	Australia	Caucasians	BC	307/551	242	259	50	166	141	27	0.10	8	PB
Forsti^Citation40	2004	Finland	Caucasians	BC	223/298	181	104	13	134	81	8	0.69	7	Not stated
Lee^Citation52	2004	Korea	Asians	BC	186/147	50	80	17	58	96	32	0.08	7	HB
Qi^Citation34	2004	China	Asians	BC	217/218	59	105	54	42	104	71	0.59	7	HB
Lin^Citation53	2004	China	Asians	BC	88/342	173	145	24	43	38	7	0.39	8	PB
Shrubsole^Citation54	2004	China	Asians	BC	1,112/1,160	387	577	196	374	555	183	0.44	8	PB
Justenhoven^Citation55	2005	Germany	Caucasians	BC	584/633	261	279	93	249	274	61	0.19	8	PB
Kalemi^Citation56	2005	Greece	Caucasians	BC	42/51	23	20	8	19	16	7	0.31	7	Not stated
Deligezer^Citation57	2005	Turkey	Mixed	BC	189/223	128	83	12	98	68	23	0.76	7	Not stated
Chou^Citation58	2006	China	Asians	BC	142/285	132	120	33	73	51	18	0.47	7	HB
Reljic^Citation59	2007	Croatia	Caucasians	BC	93/65	27	34	4	40	44	9	0.11	7	PB
Hekim^Citation60	2007	Turkey	Mixed	BC	40/68	38	26	4	22	16	2	0.87	7	Not stated
Xu^Citation61	2007	USA	Mixed	BC	1,063/1,104	440	509	155	398	476	189	0.69	7	PB
Macis^Citation62	2007	Italy	Caucasians	BC	46/80	28	41	11	14	20	12	0.51	7	PB
Yu^Citation63	2007	China	Asians	BC	119/420	225	170	25	56	54	9	0.34	7	PB
Kotsopoulos^Citation64	2008	Canada	Caucasians	BC	944/680	252	341	87	383	421	140	0.09	7	HB
Langsenlehner^Citation65	2008	Austrian	Caucasians	BC	105/105	40	48	17	51	43	11	0.68	7	Not stated
Cheng^Citation66	2008	China	Asians	BC	349/530	268	221	41	185	133	31	0.62	7	HB
Inoue^Citation67	2008	Singapore	Asians	BC	380/662	393	226	43	239	120	21	0.18	8	PB
Suzuki^Citation68	2008	Japan	Asians	BC	454/909	338	425	146	150	220	84	0.52	7	HB
Cam^Citation69	2009	Turkey	Mixed	BC	110/95	47	42	6	48	49	13	0.4	7	Not stated
Henriquez-Hernandez^Citation70	2009	Spain	Caucasians	BC	135/292	107	138	47	52	65	18	0.82	7	PB
Platek^Citation71	2009	USA	Caucasians	BC	994/1,802	788	795	219	429	446	119	0.40	7	PB
Ericson^Citation72	2009	Sweden	Caucasians	BC	540/1,074	531	452	91	255	235	50	0.71	8	PB
Maruti^Citation73	2009	USA	Mixed	BC	318/647	301	284	62	133	139	46	0.67	7	PB
Ma^Citation74	2009	Brazil	Mixed	BC	458/458	222	187	49	225	188	45	0.31	7	HB
Li^Citation42	2009	China	Asians	BC	65/143	90	50	3	38	17	10	0.19	7	PB
Jin^Citation43	2009	China	Asians	BC	41/100	49	41	10	18	20	3	0.74	7	Not stated
Yuan^Citation35	2009	China	Asians	BC	80/80	32	35	13	16	35	29	0.52	7	HB
Gao^Citation36	2009	China	Asians	BC	624/624	235	301	88	202	305	117	0.59	7	PB
Ma^Citation75	2009	Japan	Asians	BC	388/387	115	188	84	124	183	81	0.66	7	HB
Bentley^Citation76	2010	USA	Caucasians	BC	939/1,226	429	592	205	346	402	191	0.97	7	HB
Prasad^Citation47	2011	India	Asians	BC	130/125	116	8	1	124	5	1	0.06	7	Not stated
Wu^Citation77	2012	China	Asians	BC	75/75	37	32	6	32	30	13	0.80	7	HB
Akilzhanova^Citation78	2013	Kazakhstan	Asians	BC	315/604	287	269	48	181	109	25	0.17	7	HB
Lu^Citation33	2015	China	Asians	BC	560/560	226	250	84	170	288	102	0.28	8	HB
Pooja^Citation44	2015	India	Asians	BC	588/508	386	111	11	437	134	17	0.37	8	HB
Awwad^Citation79	2015	Jordan	Caucasians	BC	150/146	79	51	16	66	69	15	0.09	7	HB
Wu^Citation46	2007	China	Asians	OC	81/80	32	35	13	17	40	24	0.52	7	HB
Terry1^Citation48	2010	USA	Caucasians	OC	1,059/1,125	499	488	138	427	492	140	0.27	7	HB
Terry2^Citation48	2010	USA	Caucasians	OC	158/496	210	217	55	71	72	10	0.93	7	HB
Terry3^Citation48	2010	USA	Caucasians	OC	364/412	193	168	51	164	167	33	0.13	7	HB
Webb^Citation80	2011	Australian	Mixed	OC	1,638/1,278	571	568	139	744	709	185	0.90	7	PB
Prasad^Citation47	2011	India	Asians	OC	80/125	116	8	1	72	3	5	0.06	7	Not stated
Pawlik^Citation81	2011	Poland	Caucasians	OC	136/160	63	79	18	67	55	13	0.36	7	PB
Jakubowska^Citation31	2012	Poland	Caucasians	OC	985/3,350	1,447	1,481	422	423	446	116	0.16	8	HB
Zhang^Citation82	2012	China	Asians	OC	215/218	115	92	11	102	94	19	0.17	7	HB
Gao^Citation45	2012	China	Asians	OC	224/432	232	178	22	97	100	27	0.10	7	HB

Abbreviations: HWE, Hardy–Weinberg equilibrium; OC, ovarian cancer; BC, breast cancer; HB, hospital-based control; PB, population-based control; Mixed, mixed population.

Figure 2 Forest plot of homozygous comparison (CC vs TT) for breast cancer and/or ovarian cancer (cancer type).

Note: Weights are from random effects analysis.
Abbreviations: OR, odds ratio; CI, confidence interval; BC, breast cancer; OC, ovarian cancer.

Figure 3 Forest plot of homozygous comparison (CC vs TT) for breast cancer and/or ovarian cancer (ethnicity).

Note: Weights are from random effects analysis.
Abbreviations: OR, odds ratio; CI, confidence interval.

Table 2 Results of meta-analysis for the association of MTHFR C677T polymorphism with breast cancer and/or ovarian cancer risk (ethnicity and source of control)

MTHFR C677T	C vs T		CC vs TT		CC vs (CT+TT)		(CC+CT) vs TT		CC vs CT		Heterogeneity
	OR/95% CI	P-value	OR/95% CI	P-value	OR/95% CI	P-value	OR/95% CI	P-value	OR/95% CI	P-value	I^2 (%)	P-value
Total	1.07 (1.04–1.10)	<0.05	1.16 (1.10–1.23)	<0.05	1.06 (1.02–1.10)	0.003	1.15 (1.08–1.21)	<0.05	1.13 (1.06–1.20)	<0.05	51.4	0.000
BC	1.19 (1.12–1.28)	<0.05	1.20 (1.12–1.28)	<0.05	1.19 (1.79–1.95)	<0.05	1.19 (1.11–1.27)	<0.05	1.02 (0.98–1.07)	0.34	44.2	0.001
OC	1.03 (0.98–1.09)	0.26	1.05 (0.93–1.18)	0.45	1.05 (0.97–1.13)	0.21	1.02 (0.92–1.15)	0.68	1.05 (0.97–1.13)	0.24	71.1	0.000
Asians	1.19 (1.13–1.25)	<0.05	1.43 (1.30–1.59)	<0.05	1.20 (1.12–1.28)	<0.05	1.35 (1.23–1.48)	<0.05	1.13 (1.05–1.21)	<0.05	57.8	0.000
Caucasians	1.01 (0.97–1.05)	0.61	1.01 (0.93–1.18)	0.77	1.02 (0.96–1.07)	0.53	1.00 (0.93–1.09)	0.93	1.02 (0.96–1.08)	0.52	10.2	0.324
HB	1.15 (1.10–1.21)	<0.05	1.37 (1.24–1.52)	<0.05	1.13 (1.06–1.21)	<0.05	1.33 (1.20–1.46)	<0.05	1.07 (1.00–1.15)	<0.05	56.3	0.000
PB	1.07 (1.03–1.11)	<0.05	1.16 (1.06–1.27)	<0.05	1.07 (1.01–1.13)	<0.05	1.14 (1.05–1.24)	<0.05	1.04 (0.98–1.11)	0.15	52.20	0.004

Abbreviations: MTHFR, methylenetetrahydrofolate reductase; OC, ovarian cancer; BC, breast cancer; HB, hospital-based control; PB, population-based control; OR, odds ratio; CI, confidence interval.

Table 3 Results of subgroup analysis based on ethnicity and source of control

MTHFR C677T	Cancer type	C vs T		CC vs TT		CC vs (CT+TT)		(CC+CT) vs TT		CC vs CT
		OR/95% CI	P-value	OR/95% CI	P-value	OR/95% CI	P-value	OR/95% CI	P-value	OR/95% CI	P-value
Caucasians	BC	1.01 (0.96–1.06)	0.62	1.04 (0.93–1.16)	0.50	1.01 (0.94–1.08)	0.87	1.04 (0.94–1.15)	0.45	1.00 (0.93–1.07)	0.93
	OC	1.00 (0.94–1.07)	0.95	0.96 (0.82–1.11)	0.55	1.04 (0.95–1.14)	0.44	0.93 (0.80–1.07)	0.30	1.06 (0.96–1.17)	0.24
Asians	BC	1.12 (1.06–1.18)	<0.05	1.29 (1.16–1.44)	<0.05	1.10 (1.03–1.18)	<0.05	1.27 (1.15–1.40)	<0.05	1.05 (0.97–1.12)	0.23
	OC	1.52 (1.29–1.80)	<0.05	2.74 (1.85–4.06)	<0.05	1.49 (1.21–1.84)	<0.05	2.46 (1.68–3.59)	<0.05	1.30 (1.04–1.63)	<0.05
HB	BC	1.06 (1.01–1.11)	<0.05	1.18 (1.07–1.31)	<0.05	1.02 (0.96–1.10)	0.48	1.19 (1.08–1.31)	<0.05	0.98 (0.91–1.05)	0.57
	OC	1.06 (1.00–1.14)	0.06	1.09 (0.94–1.25)	0.25	1.11 (1.01–1.21)	<0.05	1.03 (0.90–1.18)	0.67	1.11 (1.02–1.22)	<0.05
PB	BC	1.10 (1.05–1.15)	<0.05	1.22 (1.11–1.34)	<0.05	1.11 (1.04–1.18)	<0.05	1.17 (1.07–1.29)	<0.05	1.08 (1.01–1.15)	<0.05
	OC	0.97 (0.87–1.08)	0.55	0.99 (0.78–1.25)	0.91	0.94 (0.81–1.08)	0.35	1.03 (0.82–1.28)	0.82	0.92 (0.80–1.07)	0.29

Abbreviations: MTHFR, methylenetetrahydrofolate reductase; OC, ovarian cancer; BC, breast cancer; HB, hospital-based control; PB, population-based control; OR, odds ratio; CI, confidence interval.

Figure 4 Funnel plot of homozygous comparison (CC vs TT) for breast cancer and/or ovarian cancer.

Abbreviations: OR, odds ratio; SE, standard error.

Figure 5 Funnel plot of homozygous comparison (CC vs TT) for breast cancer.

Abbreviations: OR, odds ratio; SE, standard error.

Figure 6 Funnel plot of homozygous comparison (CC vs TT) for ovarian cancer.

Abbreviations: OR, odds ratio; SE, standard error.

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