Single-nucleotide polymorphisms of matrix metalloproteinases and their inhibitors in gastrointestinal cancer

Table 1 Effects of matrix metalloproteinases single nucleotide polymorphisms on promoter activity

MMP	SNP	Effect of mutation	Influence on promoter activity in vitro	Reference
MMP-1	-1607 1G/2G	Extra Guanine (2G) creates a binding site for transcription factor Ets-1	Increased in 2G allele (4-fold)	Rutter et al[18]
MMP-2	-1306 C/T	C to T substitution disrupts Sp-1 binding site	Decreased in T-allele	Price et al[22]
MMP-2	-735 C/T	C to T substitution influences Sp-1 binding site	Decreased in T-allele	Yu et al[15]
MMP-2	-790 T/G	Three transcription factors1 bind to T (but not G) allele sequence	Decreased in G allele2	Vasku et al[28]
MMP-2	-955 A/C	Unknown	Effect unclear	Price et al[22]
MMP-2	-1575 G/A	G to T substitution decreases estrogen receptor α binding	Decreased in A allele	Harendza et al[27]
MMP-3	-1171 5A/6A3	Transcription suppressor binds with higher affinity to 6A allele	Decreased in 6A allele (2-fold)	Ye et al[19]
MMP-3	Lys45Glu	Lys to Glu substitution in exon 2 of gene	Effect unclear	Ouyang et al[16]
MMP-7	-181 A/G	Nuclear proteins bind with higher affinity to G allele	Increased in G allele4 (2- to 3- fold)	Jormsjö et al[17]
MMP-7	-153 C/T	T allele binds additional nuclear proteins compared with C allele	Increased in T allele4 (2- to 3- fold)	Jormsjö et al[17]
		affinity for proteins that bind to both alleles higher in C allele
MMP-8	-799 C/T	Influences binding of transcription factor?	Increased in T allele5	Wang et al[23]
MMP-8	17 C/G	Influences binding of transcription factor?	Increased in G allele5	Wang et al[23]
MMP-9	-90 CA(n)	Number of repeats influences strength of nuclear binding	Increased in n = 21 vs n = 14, n = 18	Shimajiri et al[12]
MMP-9	-1562 C/T	C to T substitution disrupts nuclear protein binding site	Increased in T allele	Zhang et al[20]
MMP-9	R279Q	Arg to Gln substitution in fibronectin type II domains	Effect unclear6	Wu et al[13]
MMP-9	P574R	Pro to Arg substitution in hemopexin domain	Effect unclear6	Wu et al[13]
MMP-9	R668Q	Arg to Gln substitution in hemopexin domain	Effect unclear6	Wu et al[13]
MMP-12	-82 A/G	A to G substitution results in decreased affinity for transcription factor AP-1	Decreased in G allele	Jormsjö et al[21]
MMP-12	1082 A/G	Asn to Ser substitution at coding region of hemopexin domain	Effect unclear	Joos et al[25]
MMP-13	-77 A/G	A to G substitution results in decreased affinity for transcription factor AP-1	Decreased in G allele (2-fold)	Yoon et al[24]
MMP-21	C572T	Ala to Val substitution in enzymes catalytic domain	Effect unclear	Shagisultanova et al[29]
TIMP-1	372 C/T	Unknown, located in exon 5, no effect on transcription or amino-acid sequence	Effect unclear	Hinterseher et al[26]
TIMP-2	-418 G/C	G to C substitution results in disruption of Sp-1 binding site	Decreased in C allele2	Hirano et al[30]
TIMP-2	303C/T	Unknown, located in exon 3, no effect on transcription or amino-acid sequence	Effect unclear	Kubben et al[14]

¹The three transcription factors are: GKLF (Gut-enriched Krueppel-like factor), S8 and Evi1 (ectopic viral integration site 1 encoded factor);

²Not confirmed;

³Formerly known as -1612 5A/6A;

⁴Only in combination MMP-7 -181G/-153T;

⁵Only in combination MMP-8 -799T/-381G/+17G, in cells resembling chorion cytotrophoblasts;

⁶Probably influences substrate binding and inhibitor binding. MMP: Matrix metalloproteinase; SNP: Single-nucleotide polymorphisms; TIMP: Tissue inhibitor of metalloproteinase.

Table 2 Polymorphisms of tissue inhibitor of matrix metalloproteinases in esophageal cancer

Gene	SNP	Reference	Cancer type	Ethnicity	Case/control	Outcome parameter	Results	Parameter OR	OR	95% CI	P value
MMP-1	-1607 1G/2G	Bradbury[33]	EA	Caucasian	313/455	Cancer risk	Increased cancer risk in 1G/2G and 2G/2G	2G/2G vs 1G/1G	1.83	1.2-2.8	0.005
						Overall survival	No difference in overall survival
		Fruh[32]	EA	Caucasian	101/101	Cancer risk	No difference in cancer risk
		Jin[42]	ESCC	Chinese	234/350	Cancer risk	No difference in cancer risk
						LN metastases	No difference in LN metastases
MMP-2	-735 C/T	Li[39]	ESCC	Chinese	335/624	Cancer risk	No difference in cancer risk
		Yu[15]	ESCC	Chinese	527/777	Cancer risk	Increased cancer risk in CC (trend)	CC vs CT+TT	1.30	1.04-1.63	0.056
		Sun[31]	ESCC	Chinese	335/624	Cancer risk	No difference in cancer risk
		Chen[40]	ESCC	Mongolian	188/324	Cancer risk	Increased cancer risk in TT	TT vs CC	4.82	1.59-14.60
MMP-2	-1306 C/T	Fruh[32]	EA	Caucasian	101/101	Cancer risk	No difference in cancer risk
						Cancer risk and HP	HP infection protects against EA in CC	CC vs CT+TT	0.29	0.1-0.7
		Chen[40]	ESCC	Mongolian	188/324	Cancer risk	No difference in cancer risk
		Li[39]	ESCC	Chinese	335/624	Cancer risk	Increased cancer risk in CC	CC vs CT+TT	1.57	1.10-2.23	0.010
		Yu[15]	ESCC	Chinese	527/777	Cancer risk	Increased cancer risk in CC	CC vs CT+TT	1.52	1.17-1.96	0.001
		Sun[31]	ESCC	Chinese	335/624	Cancer risk	Increased cancer risk in CC	CC vs CT+TT	1.57	1.10-2.23
MMP-3	-1171 6A/5A	Bradbury[33]	EA	Caucasian	313/455	Cancer risk	Increased cancer risk in 6A/5A and 5A/5A	5A/5A vs 6A/6A	1.61	1.0-2.5	0.030
						Overall survival	No difference in overall survival
		Fruh[32]	EA	Caucasian	101/101	Cancer risk	No difference in cancer risk
						Cancer risk and HP	HP infection protects against EA in 6A/6A	6A/6A vs 5A/5A + 5A/6A	0.04	0.002-0.9	0.040
		Zhang[44]	ESCC	Chinese	234/350	Cancer risk	No difference in cancer risk
						Cancer in smoker	Increased cancer risk in 5A allele in smokers	5A/5A + 5A/6A vs 6A/6A	1.95	1.08-3.53
						LN metastases	Increased risk of LN metastases in 5A allele	5A/5A vs 6A/6A	2.24	1.07-4.69	0.030
						Infiltration depth	No difference in infiltration depth
MMP-3	Lys45Glu	Ouyang [16]	ESCC	Chinese	227/378	Cancer risk	No difference in cancer risk
MMP-7	-181 A/G	Zhang et al[45]	ESCC	Chinese	258/350	Cancer risk	Increased cancer risk in AG and GG	AG+GG vs AA	1.83	1.12-2.99
						LN metastases	No difference in LN metastases
MMP-9	R279Q	Wu [13]	ESCC	Chinese	132/132	Cancer risk	No difference in cancer risk
MMP-9	P574R	Wu et al[13]	ESCC	Chinese	132/132	Cancer risk	Increased cancer risk in RR	RR vs PP	4.08	1.58-10.52	0.000
MMP-9	R668Q	Wu et al[13]	ESCC	Chinese	132/132	Cancer risk	No difference in cancer risk
MMP-9	-1562 C/T	Xia et al[43]	ESCC	Chinese		Cancer risk	No difference in cancer risk
MMP-12	-82 A/G	Bradbury et al[33]	EA	Caucasian	313/455	Cancer risk	No difference in cancer risk
						Overall survival	No difference in overall survival
		Fruh et al[32]	EA	Caucasian	101/101	Cancer risk	No difference in cancer risk
						Cancer risk and HP	HP infection protects against EA in AA	AA vs AG/GG	0.44	0.2-0.8	0.020
MMP-12	1082 A/G	Bradbury et al[33]	EA	Caucasian	313/455	Cancer risk	No difference in cancer risk
						Overall survival	No difference in overall survival
MMP-12	-82 A/G	Li et al[39]	ESCC	Chinese	335/624	Cancer risk	No difference in cancer risk
						Cancer risk	No difference in cancer risk
MMP-13	-77 A/G	Zhang et al[41]	ESCC	Chinese	316/609	Cancer risk	No difference in cancer risk

SNP: Single nucleotide polymorphism; EA: Esophageal adenocarcinoma; ESCC: Esophageal squamous cell carcinoma; LN: Lymph node; HP: Helicobacter pylori; OR: Odds Ratio; 95% CI: 95% confidence interval.

Table 3 Polymorphisms of matrix metalloproteinases in hepatocellular carcinoma

Gene	SNP	Reference	Cancer type	Ethnicity	Case/control	Outcome parameter	Results	Parameter OR	OR	95% CI	P value
MMP-1	-1607 1G/2G	Matsumura[65]	Gastric	Japanese	215/166	Cancer risk	No difference in cancer risk
						Clinicopathol. par.	No correlation with any clinicopath. par.
		Jin[42]	GCA	Chinese	183/350	Cancer risk	No difference in cancer risk
						LN metastases	No difference in LN metastases
MMP-2	-1306 C/T	Zhang[53]	Gastric	Chinese	228/774	Cancer risk	Increased cancer risk in CC	CC vs CT/TT	1.67	1.17-2.38
		Wu[55]	Gastric	Taiwanese	240/283	Cancer risk	No difference in cancer risk
						LN metastases	Increased risk of lymphatic invasion in CC	CC vs CT+TT	2.77	1.27-6.04	0.01
						Venous invasion	Increased risk of venous invasion in CC	CC vs CT+TT	2.93	1.27-6.78	0.012
						Survival	No difference in survival
		Kubben[14]	Gastric	Caucasian	79/169	Cancer risk	No difference in cancer risk
						Tumor-related survival	No difference in tumor-related survival
		Alakus[56]	Gastric	Caucasian	135/58	Cancer risk	No difference in cancer risk
						MMP-2 protein expression	No correlation with protein expression
						Overall survival	No difference in overall survival
		Li[39]	GCA	Chinese	257/624	Cancer risk	No difference in cancer risk
		Miao[54]	GCA	Chinese	356/789	Cancer risk	Increased cancer risk in CC	CC vs CT+TT	3.36	2.34-4.97
						Distant metastases	No difference in metastases
MMP-2	-735 C/T	Li[39]	GCA	Chinese	257/624	Cancer risk	Trend towards increased cancer risk in CC	CC vs CT+TT	1.36	0.99-1.87	0.06
						Cancer risk in non-smoker	Increased cancer risk in CC in non-smoker	CC vs CT+TT	1.7	1.07-2.68	0.02
MMP-3	-1171 6A/5A	Zhang[44]	GCA	Chinese	183/350	Cancer risk	No difference in cancer risk
						Cancer risk in smoker	No difference in cancer risk in smoker
						LN metastases	No difference in LN metastases
						Infiltration depth	No difference in infiltration depth
MMP-8	-799 C/T	Kubben[14]	Gastric	Caucasian	79/169	Cancer risk	No difference in cancer risk
						Tumor-related survival	No difference in tumor-related survival
MMP-7	-181 A/G	Sugimoto[63]	Gastric	Japanese	160/434	Cancer risk	Increased cancer risk in G-allele carriers	AG+GG vs AA	2.32	1.24-4.35	0.009
						Cancer stage	Increased cancer stage in G allele carriers	AG+GG vs AA	3.66	1.54-8.73	0.003
		Kubben[14]	Gastric	Caucasian	79/169	Cancer risk	More AA and less AG in cancer group	AG+GG vs AA	0.50	0.28-0.87	< 0.04
						Tumor-related survival	No difference in tumor-related survival
		Li[64]	Gastric	Chinese	338/380	Cancer risk	Increased cancer risk in G allele carriers	AG+GG vs AA	1.95	1.24-3.05	0.004
						LN metastases	Increased risk of LN metastases in G allele	AG+GG vs AA			0.040
						Cancer stage	More advanced cancer stage in G allele	AG+GG vs AA			0.007
		Alakus[56]	Gastric	Caucasian	135/58	Cancer risk	No difference in cancer risk	AG+GG vs AA	1.06	0.69-1.64	0.79
						Overall survival	No difference in overall survival
		Zhang[45]	GCA	Chinese	201/350	Cancer risk	Increased cancer risk in G allele carriers	AG+GG vs AA	1.96	1.17-3.29
						LN metastases	No difference in LN metastases
MMP-7	-153 C/T	Kubben[14]	Gastric	Caucasian	79/169	Cancer risk	No difference in cancer risk
						Tumor-related survival	No difference in tumor-related survival
MMP-8	17 C/G	Kubben[14]	Gastric	Caucasian	79/169	Cancer risk	No difference in cancer risk
						Tumor-related survival	No difference in tumor-related survival
MMP-9	R279Q	Tang[59]	Gastric	Chinese	74/100	Cancer risk	No difference in cancer risk
						LN metastases	Increased risk of LN metastases in RR	RR vs QQ+RQ	5.74	1.59-13.43
MMP-9	P574R	Tang[59]	Gastric	Chinese	74/100	Cancer risk	No difference in cancer risk
						LN metastases	Increased risk of LN metastases in PP	PP vs RR+PR	4.17	1.39-11.78
MMP-9	-1562 C/T	Kubben[14]	Gastric	Caucasian	79/169	Cancer risk	No difference in cancer risk
						Tumor-related survival	No difference in tumor-related survival
		Matsumura[57]	Gastric	Japanese	177/224	Cancer risk	No difference in cancer risk
						Infiltration depth	Deeper submucosal infiltration in T allele	CT+TT vs CC	2.61	1.07-6.34	0.034
						Lymphatic invasion	Increased lymphatic invasion in T allele	CT+TT vs CC	2.27	1.09-4.74	0.028
						TNM classification	More advanced stage cancer in T allele	CT+TT vs CC	2.26	1.12-4.55	0.022
						Venous invasion	No difference in venous invasion	CT+TT vs CC	1.98	0.99-3.97	0.053
		Zhang[53]	Gastric	Chinese	228/774	Cancer risk	No difference in cancer risk
		Wu[58]	Gastric	Taiwanese	263/354	Cancer risk	No difference in cancer risk
MMP-12	-82 A/G	Li[39]	GCA	Chinese	335/624	Cancer risk	No difference in cancer risk
						Cancer risk in smoker	No difference in cancer risk in smoker
MMP-13	-77 A/G	Li[39]	GCA	Chinese	257/624	Cancer risk	No difference in cancer risk
						Cancer risk in smoker	Decreased cancer risk in AG in smoker	AG vs AA/AG	0.47	0.28-0.8	0.01
		Zhang[41]	GCA	Chinese	243/609	Cancer risk	No difference in cancer risk
						Cancer risk in smoker	Decreased cancer risk in AG in smoker
TIMP-1	372 C/T	Kubben[14]	Gastric	Caucasian	79/169	Cancer risk	No difference in cancer risk
						Tumor-related survival	No difference in tumor-related survival
TIMP-2	-418 G/C	Kubben[14]	Gastric	Caucasian	79/169	Cancer risk	No difference in cancer risk
						Tumor-related survival	No difference in tumor-related survival
		Wu[55]	Gastric	Taiwanese	240/283	Cancer risk	No difference in cancer risk
						LN metastases	Increased risk of LN metastases in GG	GG vs CG+GG	2.87	1.22-6.76	0.16
						Venous invasion	Increased venous invasion in GG	GG vs CG+GG	2.65	1.08-6.49	0.033
						Survival	No difference in survival
		Yang[66]	Gastric	China	206/206	Cancer risk	More C-alleles in cancer patients	CC+CG vs GG	1.51	1.00-2.26	0.049
						Clinicopathol. par.	No correlation with any clinicopath. par.
TIMP-2	303 C/T	Kubben[14]	Gastric	Caucasian	79/169	Cancer risk	No difference in cancer risk
						Tumor-related survival	Better survival in CC patients	CC vs CT/TT	4.45	1.81-10.9	0.001
		Alakus[56]	Gastric	Caucasian	135/58	Cancer risk	No difference in cancer risk
						LN metastases	More LN metastases in CC				0.01
						Distant metastases	Increased risk of distant metastases in CC				0.022
						Survival	No difference in survival

SNP: Single nucleotide polymorphism; GCA: Gastric Cardia Adenocarcinoma; LN: Lymph node; OR: Odds ratio; 95% CI: 95% confidence interval; Clinicopath. par.: Clinicopathological parameters. ¹Except histological subtype.

Table 4 Polymorphisms of matrix metalloproteinases in hepatocellular carcinoma

Gene	SNP	Reference	Ethnicity	Case/control	Parameter	Results	Parameter OR	OR	95% CI	P value
MMP-1	-1607 1G/2G	Zhai[80]	Chinese	434/480	Cancer risk	No difference in cancer risk
		Okamoto[78]	Japanese	95/83	Cancer risk	Increased risk of HCC in 2G/2G				0.002
					Clinicopath. par.	No correlation with any clinicopath. par.
					Survival	No difference in survival
		Okamoto[79]	Japanese	92/170	Cancer risk	No difference in cancer risk
					Survival/clinicopath. par.	No difference in survival/clinicopath. par.
MMP-2	-735 C/T	Zhai[80]	Chinese	434/480	Cancer risk	No difference in cancer risk
					Cancer risk	No difference in cancer risk
MMP-2	-1306 C/T	Zhai[80]	Chinese	434/480	Cancer risk	No difference in cancer risk
		Wu[82]	Chinese	93/0	HCC recurrence after LTx	More CC in recurrence group	CT vs CC	0.42	0.18-0.99	< 0.05
MMP-3	-1171 5A/6A	Zhai[80]	Chinese	434/480	Cancer risk	No difference in cancer risk
		Okamoto[78]	Japanese	95/83	Cancer risk	No difference in cancer risk
					HCC diameter at diagnosis	Larger diameter in 5A allele carriers
					Survival	Decreased survival in 5A allele carriers
		Okamoto[79]	Japanese	92/170	Cancer risk	Increased cancer risk in 5A allele carriers
					Survival/clinicopath. par.	Decreased survival in 5A allele carriers				0.035
MMP-7	-181 A/G	Qiu[81]	Chinese	434/480	Cancer risk	No difference in cancer risk
MMP-8	-799 C/T	Qiu[81]	Chinese	434/480	Cancer risk	No difference in cancer risk
MMP-9	-1562 C/T	Zhai[80]	Chinese	434/480	Cancer risk	No difference in cancer risk
		Wu[82]	Chinese	93/0	HCC recurrence after LTx	No difference in HCC recurrence
		Okamoto[78]	Japanese	95/83	Cancer risk	No difference in cancer risk
					Differentiation grade	Differentiation worse in T allele carriers		0.03
					Survival	No difference in survival
		Okamoto[79]	Japanese	92/170	Cancer risk	No difference in cancer risk
					Survival/clinicopath. par.	No difference in survival/clinicopath. par.
MMP-12	-82 A/G	Zhai[80]	Chinese	434/480	Cancer risk	No difference in cancer risk
MMP-13	-77 A/G	Zhai[80]	Chinese	434/480	Cancer risk	No difference in cancer risk
MMP-21	C572T	Qiu[81]	Chinese	434/480	Cancer risk	No difference in cancer risk
TIMP-2	-418 G/C	Okamoto[83]	Japanese	92/70	Cancer risk HCC	No difference in cancer risk
					Survival	No difference in survival

SNP: Single nucleotide polymorphism; LN: Lymph node; Clinicopath. par.: Clinicopathological parameters; OR: Odds ratio; 95% CI: 95% confidence interval; HCC: Hepatocellular carcinoma; LTx: Liver transplantation.

Table 5 Polymorphisms of matrix metalloproteinases in colorectal cancer

Gene	SNP	Reference	Ethnicity	Case/control	Parameter	Results	Parameter OR	OR	95% CI	P value
MMP-1	-1607 1G/2G	Ghilardi[92]	Caucasian	60/164	Cancer risk	Increased cancer risk in 2G/2G	2G/2G vs 1G/1G + 1G/2G	2.21	1.17-4.16	0.014
					Distant metastases	Increased risk of metastases in 2G/2G	2G/2G vs 1G/1G + 1G/2G	4.73	1.46-15.26	0.008
		Zinzindohoue[99]	Caucasian	201/0	Survival	Overall survival worse in 2G/2G	2G/2G vs 1G/1G	5.4	2.0-14.7	0.001
		Hettiaratchi[96]	Australian	503/471	Cancer risk	No difference in cancer risk
					Survival	Increased survival in 2G/2G	2G/2G vs 1G/2G + 1G/1G	0.43	0.19-0.96	0.040
					Clinicopath. par.	No correlation with any clinicopath. par.
		Woo[89]	Korean	185/304	Cancer risk	Increased cancer risk in 2G/2G and G-allele	2G/2G in patients vs controls	1.8	1.23-2.64	0.044
					LN metastases	More often >10 LN in 2G/2G
		Fang[94]	Chinese	237/252	Cancer risk	No difference in cancer risk
		Xu[97]	Chinese	126/126	Cancer risk	No difference in cancer risk
					Clinicopath. par.	No correlation with any clinicopath. par.
		Przybylowska[98]	Caucasian	33/52	Cancer risk	No difference in cancer risk
		Hinoda[91]	Japanese	101/127	Cancer risk	Increased cancer risk in 2G/2G	2G/2G vs 1G/1G + 1G/2G	2.08	1.22-3.53	0.007
					Clinicopath. par.	No correlation with any clinicopath. par.
		Biondi[93]	Caucasian	63/164	Cancer risk	More 2G allele in cancer patients				< 0.08
		de Lima[95]	Brasilian	130/130	Cancer risk	No difference in cancer risk
					Distant metastases	Increased risk of metastases in 1G allele (trend)
					LN metastases	No difference in LN metastases
		Elander[90]	Caucasian	127/208	Cancer risk	Increased cancer risk in 2G allele carriers	2G allele vs 1G allele	1.41	1.02-1.96	0.037
					Clinicopath. par.	No correlation with any clinicopath. par.
		Kouhkan[88]	Iranian	150/100	Cancer risk	Increased cancer risk in 2G/2G and G-allele
					Distant metastases	Earlier metastases in 2G/2G
MMP-2	-1306 C/T	Xu[102]	Chinese	126/126	Cancer risk	Increased cancer risk in CC	CC vs CT+TT	1.96	1.06-3.64	< 0.05
					Infiltration depth	More serosa/adventitia involvement in CC	CC vs CT+TT			0.042
		Hettiaratchi[96]	Australian	503/471	Cancer risk	No difference in cancer risk
					Survival	No difference in survival
					Clinicopath. par.	No correlation with any clinicopath. par.
		Langers[105]	Caucasian	215/0	Survival	10 year survival worse in TT	CC/CT vs TT	1.4	1.02-1.91	0.038
		Ohtani[103]	Japanese	47/67	Cancer risk	No difference in cancer risk
		Elander[90]	Caucasian	127/208	Cancer risk	No difference in cancer risk
					Clinicopath. par.	No correlation with any clinicopath. par.
MMP-2	-790 T/G	Xu[104]	Chinese	126/126	Cancer risk	No difference in cancer risk
					Infiltration depth	No difference in infiltration depth
MMP-2	-955 A/C	Xu[104]	Chinese	126/126	Cancer risk	No difference in cancer risk
					Infiltration depth	No difference in infiltration depth
MMP-2	-1575 G/A	Xu[104]	Chinese	126/126	Cancer risk	Increased cancer risk in GG and G allele	GG vs GA+AA	1.96	1.06-3.64	0.04
					Infiltration depth	More serosa/adventitia infiltration in GG	GG vs GA+AA			< 0.05
MMP-3	-1171 5A/6A	Hinoda[91]	Japanese	101/127	Cancer risk	Increased cancer risk in 6A/6A	6A/6A vs 5A/5A + 5A/6A	2.11	1.17-3.82	0.01
					Clinicopath. par.	No correlation with any clinicopath. par.
		Biondi[93]	Caucasian	63/164	Cancer risk	No difference in cancer risk
		Ghilardi[92]	Caucasian	60/164	Cancer risk	No difference in cancer risk
					Distant metastases	No difference in metastases
		Woo[89]	Korean	185/304	Cancer risk	No difference in cancer risk
					LN metastases	No difference in LN metastases
		Ohtani[103]	Japanese	47/67	Cancer risk	No difference in cancer risk
		Elander[90]	Caucasian	127/208	Cancer risk	No difference in cancer risk
					Clinicopath var.	No correlation with any clinicopath. par.
		Zinzindohoue[99]	Caucasian	201/0	Survival	No difference in overall survival
		Hettiaratchi[96]	Australian	503/471	Cancer risk	No difference in cancer risk
					Survival	No difference in survival
					Clinicopath. par.	No correlation with any clinicopath. par.
		Xu[97]	Chinese	126/126	Cancer risk	No difference in cancer risk
					Clinicopath. par.	No correlation with any clinicopath. par.
MMP-7	-153 C/T	Ghilardi[111]	Caucasian	58/111	Cancer risk	Increased cancer risk in T allele carriers	T allele in patients vs controls	2.2	0.89-5.48	0.05
					Clinicopath. par.	No correlation with any clinicopath. par.
		Langers[110]	Caucasian	174/0	Survival	Better survival in CC patients	CC vs CT+TT (LR)	14		0.001
MMP-7	-181 A/G	Woo[89]	Korean	185/304	Cancer risk	No difference in cancer risk
					LN metastases	No difference in LN metastases
		Fang[94]	Chinese	237/252	Cancer risk	No difference in cancer risk
		Ghilardi[111]	Caucasian	58/111	Cancer risk	Increased cancer risk in GG	GG in patients vs controls	2.41	0.98-5.89	0.03
					Distant metastases	GG more often distant metastases	G in M+ vs M-	7.5	2.07-27.19	0.001
					LN metastases	GG more frequent LN metastases
		Ohtani[103]	Japanese	47/67	Cancer risk	No difference in cancer risk
		Langers[110]	Caucasian	174/0	Survival	No difference in survival
		de Lima[95]	Brasilian	130/130	Cancer risk	No difference in cancer risk
					Distant metastases	No difference in metastases
					LN metastases	No difference in LN metastases
MMP-9	R279Q	Woo[89]	Korean	185/304	Cancer risk	No difference in cancer risk
					LN metastases	No difference in LN metastases
		Xing[106]	Chinese	137/199	Cancer risk	No difference in cancer risk
					LN metastases	No difference in LN metastases
		Fang[94]	Chinese	237/252	Cancer incidence	Increased cancer risk in RR	RR vs QQ	2.21	1.25-3.93	0.006
MMP-9	-90(CA)n	Woo[89]	Korean	185/304	Cancer risk	No difference in cancer risk
					LN metastases	No difference in LN metastases
MMP-9	-1562 C/T	Xu[107]	Chinese	126/126	Cancer risk	No difference in cancer risk
					Infiltration depth	No difference in infiltration depth
		Woo[89]	Korean	185/304	Cancer risk	Increased cancer risk in CC patients	GG in patients vs controls	1.7	1.04-2.66	0.03
					LN metastases	No difference in LN metastases
		Xing[106]	Chinese	137/199	Cancer risk	No difference in cancer risk
					LN metastases	Increased risk of LN metastases in CT+TT	CT+TT vs CC			0.02
		Langers[105]	Caucasian	215/0	Survival	No difference in survival
		Ohtani[103]	Japanese	47/67	Cancer risk	No difference in cancer risk
		Elander[90]	Caucasian	127/208	Cancer risk	No difference in cancer risk
					Clinicopath. par.	No relationschip with clinicopath. par.
MMP-12	-82A/G	Woo[89]	Korean	185/304	Cancer risk	No difference in cancer risk
					LN metastases	No difference in LN metastases

SNP: Single nucleotide polymorphism; LN: Lymph node; Clinicopath. par.: Clinicopathological parameters; OR: Odds ratio; aOR: Adjusted odds ratio; 95% CI: 95% confidence interval.