Running Head: MMP and TIMP Polymorphisms in Breast Cancer

Running head: MMP and TIMP polymorphisms in breast cancer

Original report

Promoter polymorphisms in matrix metalloproteinases and their inhibitors: few associations with breast cancer susceptibility and progression

Haixin Lei1, Kari Hemminki1,2, Andrea Altieri1, Robert Johansson3, Kerstin Enquist4, Göran Hallmans4, Per Lenner3 and Asta Försti1,2

1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

2 Center for Family Medicine, Karolinska Institute, Alfred Nobels allé 12, Huddinge, Sweden

3 Department of Oncology, Norrlands University Hospital, Umeå, Sweden

4 Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, Umeå, Sweden

Correspondence: Asta Försti, German Cancer Research Center (DKFZ), Division of Molecular Genetic Epidemiology, Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany, Tel: +49-6221-421803, Fax: +49-6221-421810, E-mail:

Supplementary material

Supplementary table 1. Association of the MMP1 -1607 1G/2G genotypes with breast cancer susceptibility and tumor characteristics.

MMP1 -1607 1G/2Ga,b
1G/1G / 1G/2G / 2G/2G
Controls / 269 (28.5) / 443 (46.7) / 235 (24.8)
Cases / 255 (26.8) / 483 (50.6) / 216 (22.6)
OR (95% CI) / 1.00 / 1.15 (0.93-1.43) / 0.97 (0.75-1.25)
Distant metastases
Negative / 200 (26.6) / 384 (51.2) / 167 (22.2)
Positive / 2 (18.2) / 6 (54.6) / 3 (27.2)
OR (95% CI) / 1.00 / 1.56 (0.31-7.81) / 1.80 (0.29-10.87)
Regional lymph node metastasis
Negative / 143 (25.6) / 292 (52.2) / 124 (22.2)
Positive / 70 (30.0) / 111 (47.6) / 52 (22.4)
OR (95% CI) / 1.00 / 0.78 (0.54-1.11) / 0.86 (0.56-1.32)
Stage
O + I / 106 (25.2) / 222 (52.7) / 93 (22.1)
II – IV / 98 (28.5) / 168 (48.8) / 78 (22.7)
OR (95% CI) / 1.00 / 0.82 (0.58-1.15) / 0.91 (0.60-1.36)
Histologic grade
Grade 1 / 34 (24.5) / 73 (52.5) / 32 (23.0)
Grade 2-3 / 154 (27.5) / 283 (50.5) / 123 (22.0)
OR (95% CI) / 1.00 / 0.86 (0.54-1.34) / 0.85 (0.50-1.45)
Estrogen receptors
Positive / 97 (27.7) / 163 (46.6) / 90 (25.7)
Negative / 31 (21.8) / 86 (60.6) / 25 (17.6)
OR (95% CI) / 1.00 / 1.65 (1.02-2.67) / 0.87 (0.48-1.58)
Progesterone receptors
Positive / 71 (26.6) / 126 (47.2) / 70 (26.2)
Negative / 42 (25.8) / 92 (56.4) / 29 (17.8)
OR (95% CI) / 1.00 / 1.23 (0.77-1.97) / 0.70 (0.39-1.25)
Tumor size (mm)
<=20 / 135 (26.2) / 268 (52.0) / 112 (21.8)
>20 / 61 (26.3) / 114 (49.1) / 57 (24.6)
OR (95% CI) / 1.00 / 0.94 (0.65-1.36) / 1.12 (0.72-1.74)

a The number of cases may vary because of some missing data

b HWE: p=0.05

Supplementary table 2. Association of the MMP3 -1171 6A/5A genotypes with breast cancer susceptibility and tumor characteristics.

MMP3 -1171 6A/5Aa,b
6A/6A / 6A/5A / 5A/5A
Controls / 262 (27.7) / 478 (50.5) / 206 (21.8)
Cases / 273 (28.6) / 478 (50.1) / 203 (21.3)
OR (95% CI) / 1.00 / 0.96 (0.78-1.19) / 0.95 (0.73-1.22)
Distant metastases
Negative / 217 (28.9) / 379 (50.5) / 155 (20.6)
Positive / 2 (18.1) / 6 (54.6) / 3 (27.3)
OR (95% CI) / 1.00 / 1.71 (0.34-8.57) / 2.10 (0.35-12.74)
Regional lymph node metastasis
Negative / 154 (27.5) / 284 (50.6) / 123 (21.9)
Positive / 72 (31.1) / 120 (51.7) / 40 (17.2)
OR (95% CI) / 1.00 / 0.90 (0.63-1.28) / 0.70 (0.44-1.10)
Stage
O + I / 120 (28.5) / 214 (51.0) / 86 (20.5)
II – IV / 99 (28.7) / 173 (50.1) / 73 (21.2)
OR (95% CI) / 1.00 / 0.98 (0.70-1.36) / 1.03 (0.68-1.56)
Histologic grade
Grade 1 / 42 (30.4) / 72 (52.2) / 24 (17.4)
Grade 2-3 / 156 (27.8) / 283 (50.4) / 122 (21.8)
OR (95% CI) / 1.00 / 1.05 (0.69-1.61) / 1.36 (0.78-2.36)
Estrogen receptors
Positive / 106 (30.1) / 178 (50.6) / 68 (19.3)
Negative / 41 (28.9) / 73 (51.4) / 28 (19.7)
OR (95% CI) / 1.00 / 1.06 (0.67-1.67) / 1.06 (0.68-1.66)
Progesterone receptors
Positive / 78 (29.0) / 139 (51.7) / 52 (19.3)
Negative / 47 (28.8) / 82 (50.3) / 34 (20.9)
OR (95% CI) / 1.00 / 0.97 (0.62-1.54) / 1.08 (0.62-1.90)
Tumor size (mm)
<=20 / 150 (29.2) / 260 (50.6) / 104 (20.2)
>20 / 68 (29.0) / 116 (49.6) / 50 (21.4)
OR (95% CI) / 1.00 / 0.98 (0.68-1.41) / 1.06 (0.68-1.66)

a The number of cases may vary because of some missing data

b HWE: P=0.66

Supplementary table 3. Association of the MMP13 -105 A/G genotypes with breast cancer susceptibility and tumor characteristics.

MMP13 -105 A/Ga,b
A/A / A/G / G/G
Controls / 449 (47.3) / 417 (43.9) / 84 (8.8)
Cases / 443 (46.4) / 408 (42.8) / 103 (10.8)
OR (95% CI) / 1.00 / 0.99 (0.82-1.19) / 1.24 (0.90-1.71)
Distant metastases
Negative / 350 (46.6) / 401 (53.4)
Positive / 7 (63.6) / 4 (36.4)
OR (95% CI) / 1.00 / 2.00 (0.58-6.91)
Regional lymph node metastasis
Negative / 263 (47.3) / 237 (42.3) / 58 (10.4)
Positive / 97 (41.5) / 109 (46.5) / 28 (12.0)
OR (95% CI) / 1.00 / 1.25 (0.90-1.73) / 1.31 (0.79-2.17)
Stage
O + I / 199 (47.4) / 180 (43.0) / 40 (9.6)
II – IV / 159 (46.0) / 147 (42.4) / 40 (11.6)
OR (95% CI) / 1.00 / 1.02 (0.76-1.38) / 1.25 (0.78-2.03)
Histologic grade
Grade 1 / 67 (48.6) / 54 (39.1) / 17 (12.3)
Grade 2-3 / 263 (46.8) / 240 (42.7) / 59 (10.5)
OR (95% CI) / 1.00 / 1.13 (0.76-1.69) / 0.88 (0.48-1.61)
Estrogen receptors
Positive / 156 (44.2) / 160 (45.3) / 37 (10.5)
Negative / 73 (52.1) / 53 (37.9) / 14 (10.0)
OR (95% CI) / 1.00 / 0.71 (0.47-1.1) / 0.81 (0.41-1.59)
Progesterone receptors
Positive / 125 (46.3) / 120 (44.4) / 25 (9.3)
Negative / 79 (49.4) / 63 (39.4) / 18 (11.2)
OR (95% CI) / 1.00 / 0.83 (0.55-1.26) / 1.14 (0.58-2.22)
Tumor size (mm)
<=20 / 238 (46.4) / 224 (43.7) / 51 (9.9)
>20 / 112 (47.9) / 93 (39.7) / 29 (12.4)
OR (95% CI) / 1.00 / 0.88 (0.63-1.23) / 1.21 (0.73-2.01)

a The number of cases may vary because of some missing data

b HWE: p=0.36

Supplementary table 4. Association of the RECK -402 T/C genotypes with breast cancer susceptibility and tumor characteristics.

RECK -402 T/Ca,b
T/T / T/C / C/C
Controls / 793 (83.7) / 150 (15.8) / 5 (0.5)
Cases / 793 (83.2) / 150 (15.7) / 10 (1.1)
OR (95% CI) / 1.00 / 1.00 (0.78-1.28) / 2.00 (0.68-5.88)
Distant metastases
Negative / 632 (84.0) / 112 (14.9) / 8 (1.1)
Positive / 10 (90.9) / 1 (9.1) / -
OR (95% CI) / 1.00 / 0.53 (0.07-4.15) / -
Regional lymph node metastasis
Negative / 469 (84.0) / 84 (15.1) / 5 (0.9)
Positive / 194 (82.9) / 36 (15.4) / 4 (1.7)
OR (95% CI) / 1.00 / 1.04 (0.68-1.58) / 1.93 (0.51-7.27)
Stage
O + I / 350 (83.3) / 67 (16.0) / 3 (0.7)
II – IV / 295 (85.2) / 46 (13.3) / 5 (1.5)
OR (95% CI) / 1.00 / 0.81 (0.54-1.22) / 1.97 (0.47-8.34)
Histologic grade
Grade 1 / 111 (79.9) / 26 (18.7) / 2 (1.4)
Grade 2-3 / 478 (85.1) / 78 (13.9) / 6 (1.0)
OR (95% CI) / 1.00 / 0.70 (0.14-3.50) / 0.70 (0.42-1.14)
Estrogen receptors
Positive / 298 (84.9) / 547 (13.4) / 6 (1.71)
Negative / 119 (83.8) / 22 (15.5) / 1 (0.7)
OR (95% CI) / 1.00 / 1.17 (0.68-2.03) / 0.42 (0.05-3.50)
Progesterone receptors
Positive / 227 (84.7) / 37 (13.8) / 4 (1.5)
Negative / 137 (84.1) / 23 (14.1) / 3 (1.8)
OR (95% CI) / 1.00 / 1.02 (0.59-1.80) / 1.24 (0.27-5.6)
Tumor size (mm)
<=20 / 428 (83.2) / 82 (16.0) / 4 (0.8)
>20 / 199 (85.0) / 31 (13.3) / 4 (1.7)
OR (95% CI) / 1.00 / 0.81 (0.52-1.27) / 2.15 (0.53-8.68)

a The number of cases may vary because of some missing data

b HWE: p=0.46

Supplementary table 5. Association of the genotype combination MMP9 -1562 CC and TIMP3 TT with breast cancer susceptibility and tumor characteristics.

MMP9(-1562) and TIMP(-1296) a
All other combinations / CC and TT
Controls / 598 (62.8) / 354 (37.2)
Cases / 647 (67.5) / 312 (32.5)
OR (95% CI) / 1.00 / 0.81 (0.68-0.98)
Distant metastases
Negative / 507 (67.4) / 245 (32.6)
Positive / 9 (81.8) / 2 (18.2)
OR (95% CI) / 1.00 / 0.47 (0.10-2.18)
Regional lymph node metastasis
Negative / 377 (67.4) / 182 (32.6)
Positive / 160 (68.4) / 74 (31.6)
OR (95% CI) / 1.00 / 0.95 (0.68-1.32)
Stage
O + I / 286 (68.3) / 133 (31.7)
II – IV / 233 (67.2) / 114 (32.8)
OR (95% CI) / 1.00 / 1.04 (0.77-1.42)
Histologic grade
Grade 1 / 97 (69.8) / 42 (30.2)
Grade 2-3 / 377 (66.7) / 188 (33.3)
OR (95% CI) / 1.00 / 1.12 (0.75-1.69)
Estrogen receptors
Positive / 247 (69.8) / 107 (30.2)
Negative / 95 (66.9) / 47 (33.1)
OR (95% CI) / 1.00 / 1.17 (0.77-1.77)
Progesterone receptors
Positive / 189 (70.0) / 81 (30.0)
Negative / 102 (62.6) / 61 (37.4)
OR (95% CI) / 1.00 / 1.43 (0.95-2.16)
Tumor size (mm)
<=20 / 349 (68.0) / 164 (32.0)
>20 / 157 (66.8) / 78 (33.2)
OR (95% CI) / 1.00 / 1.06 (0.76-1.48)

a The number of cases may vary because of some missing data

Supplementary table 6. Association of the genotype combination MMP9 -1562 CC and RECK -585 TT with breast cancer susceptibility and tumor characteristics.

MMP9(-1562) and RECK(-585) a
All other combinations / CC and TT
Controls / 797 (83.7) / 155 (16.3)
Cases / 793 (82.7) / 166 (17.3)
OR (95% CI) / 1.00 / 1.08 (0.85-1.37)
Distant metastases
Negative / 630 (83.8) / 122 (16.2)
Positive / 11 (100.0) / 0
OR (95% CI) / - / -
Regional lymph node metastasis
Negative / 469 (83.9) / 90 (16.1)
Positive / 198 (84.6) / 36 (15.4)
OR (95% CI) / 1.00 / 0.94 (0.61-1.43)
Stage
O + I / 348 (83.1) / 71 (16.9)
II – IV / 296 (85.3) / 51 (14.7)
OR (95% CI) / 1.00 / 0.84 (0.56-1.24)
Histologic grade
Grade 1 / 122 (87.8) / 17 (12.2)
Grade 2-3 / 471 (83.4) / 94 (16.6)
OR (95% CI) / 1.00 / 1.38 (0.79-2.42)
Estrogen receptors
Positive / 296 (83.6) / 58 (16.4)
Negative / 121 (85.2) / 21 (14.8)
OR (95% CI) / 1.00 / 0.88 (0.51-1.52)
Progesterone receptors
Positive / 229 (84.8) / 41 (15.2)
Negative / 133 (81.6) / 30 (18.4)
OR (95% CI) / 1.00 / 1.29 (0.77-2.17)
Tumor size (mm)
<=20 / 426 (83.0) / 87 (17.0)
>20 / 203 (86.4) / 32 (13.6)
OR (95% CI) / 1.00 / 0.77 (0.50-1.19)

a The number of cases may vary because of some missing data