Introduction
Materials and methods
Subjects
Country Group | BRCA1 | BRCA2 | Unaffected | Breast Cancer | ER- | ER+ | PR- | PR+ |
---|---|---|---|---|---|---|---|---|
Austria1 | 465 | 179 | 318 | 326 | 76 | 51 | 76 | 44 |
Australia2 | 660 | 552 | 541 | 671 | 235 | 200 | 297 | 121 |
Canada3 | 443 | 358 | 386 | 415 | 107 | 70 | 89 | 68 |
Denmark4 | 507 | 319 | 463 | 363 | 98 | 93 | 79 | 45 |
France-Belgium-Spain5 | 1,673 | 1,256 | 1,217 | 1,712 | 140 | 165 | 1,661 | 127 |
Finland6 | 103 | 105 | 91 | 117 | 59 | 54 | 74 | 39 |
Germany7 | 1,231 | 589 | 648 | 1,172 | 443 | 336 | 457 | 311 |
Iceland8 | 0 | 135 | 24 | 111 | 21 | 57 | 18 | 57 |
Italy9 | 994 | 666 | 686 | 974 | 203 | 251 | 231 | 216 |
Latvia-Lithuania-Russia10 | 190 | 0 | 79 | 111 | 21 | 6 | 18 | 7 |
Sweden11 | 537 | 177 | 396 | 318 | 86 | 54 | 89 | 50 |
Netherlands12 | 804 | 319 | 611 | 512 | 72 | 41 | 69 | 29 |
UK-Eire13 | 1,107 | 866 | 1,008 | 965 | 268 | 239 | 175 | 104 |
USA14 | 2,707 | 1559 | 2,118 | 2048 | 482 | 366 | 512 | 297 |
Total | 11,421 | 7,080 | 8,686 | 9,815 | 2,311 | 1,983 | 2,345 | 1,515 |
Tumour pathology data collection
Genotyping
Statistical analysis
Predicted breast cancer risks by ER status
Results
Associations with ER status - BRCA1 mutation carriers
Genotype | Unaffected, | Affected by subtype, N (%) | ER- | ER+ | P-het | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
N (%) | ER- | ER+ | Unknown | HR | 95% CI |
P-trend
| HR | 95% CI |
P-trend
| ||
FGFR2 rs2981582
| |||||||||||
GG | 1301 (36.2) | 447 (40.0) | 104 (29.6) | 869 (35.1) |
1.00
|
1.00
| |||||
GA | 1,721 (47.9) | 516 (46.2) | 166 (47.3) | 1190 (48.1) |
0.93
|
0.83 to 1.03
|
1.24
|
0.98 to 1.57
| |||
AA | 573 (15.9) | 154 (13.8) | 81 (23.1) | 416 (16.8) |
0.82
|
0.70 to 0.96
|
1.85
|
1.40 to 2.44
| |||
Per-allele |
0.91
|
0.85 to 0.98
|
0.01
|
1.35
|
1.17 to 1.56
|
4 × 10
-5
|
6.5 ×10
-6
| ||||
TOX3/TNRC9 rs3803662
| |||||||||||
CC | 1,811 (52.0) | 545 (49.5) | 154 (45.7) | 1195 (50.2) | 1.00 |
1.00
| |||||
CT | 1,405 (40.3) | 461 (41.8) | 143 (42.4) | 987 (41.5) | 1.06 | 0.96 to 1.18 |
1.20
|
0.97 to 1.50
| |||
TT | 269 (7.7) | 96 (8.7) | 40 (11.9) | 199 (8.4) | 1.09 | 0.90 to 1.31 |
1.61
|
1.14 to 2.27
| |||
Per-allele | 1.05 | 0.97 to 1.13 | 0.21 |
1.25
|
1.06 to 1.46
|
0.0062
| 0.07 | ||||
MAP3K1 rs889312 | |||||||||||
AA | 1,858 (49.6) | 569 (49.7) | 186 (52.1) | 1319 (51.6) | 1.00 | 1.00 | |||||
AC | 1,552 (41.4) | 480 (41.9) | 136 (38.1) | 987 (38.6) | 0.97 | 0.87 to 1.07 | 0.86 | 0.69 to 1.06 | |||
CC | 336 (9.0) | 97 (8.5) | 35 (9.8) | 250 (9.8) | 0.97 | 0.81 to 1.16 | 0.97 | 0.69 to 1.35 | |||
Per-allele | 0.98 | 0.91 to 1.06 | 0.56 | 0.97 | 0.83 to 1.13 | 0.69 | 0.92 | ||||
LSP1 rs3817198 | |||||||||||
TT | 1,894 (47.4) | 652 (45.4) | 195 (44.5) | 1205 (43.7) | 1.00 | 1.00 | |||||
TC | 1,680 (42.0) | 629 (43.8) | 197 (45.0) | 1239 (44.9) | 1.09 | 0.99 to 1.20 | 1.11 | 0.92 to 1.35 | |||
CC | 422 (10.6) | 154 (10.7) | 46 (10.5) | 315 (11.4) | 1.13 | 0.97 to 1.33 | 1.10 | 0.80 to 1.50 | |||
Per-allele |
1.07
|
1.00 to 1.15
|
0.047
| 1.07 | 0.93 to 1.22 | 0.33 | 0.98 | ||||
2q35 rs13387042 | |||||||||||
GG | 924 (24.0) | 301 (22.1) | 93 (22.2) | 576 (21.4) | 1.00 | 1.00 | |||||
GA | 1,855 (48.3) | 723 (53.1) | 194 (46.3) | 1370 (50.9) |
1.17
|
1.04 to 1.32
| 1.02 | 0.81 to 1.30 | |||
AA | 1,064 (27.7) | 338 (24.8) | 132 (31.5) | 745 (27.7) | 0.96 | 0.84 to 1.11 | 1.25 | 0.97 to 1.62 | |||
Per-allele | 0.98 | 0.91 to 1.04 | 0.48 | 1.13 | 0.99 to 1.28 | 0.075 | 0.065 | ||||
8q24 rs13281615 | |||||||||||
AA | 1,319 (32.8) | 502 (35.9) | 143 (33.7) | 897 (32.5) | 1.00 | 1.0 | |||||
AG | 2,008 (50.0) | 657 (47.0) | 198 (46.7) | 1,364 (49.5) | 0.98 | 0.88 to 1.08 | 0.97 | 0.79 to 1.19 | |||
GG | 691 (17.9) | 238 (17.0) | 83 (19.6) | 496 (18.0) | 1.00 | 0.87 to 1.16 | 1.17 | 0.89 to 1.53 | |||
Per-allele | 1.00 | 0.93 to 1.07 | 0.93 | 1.06 | 0.93 to 1.22 | 0.38 | 0.43 | ||||
SLC4A7/NEK10 rs4973768 | |||||||||||
CC | 1,148 (26.2) | 406 (27.2) | 103 (22.2) | 691 (24.7) | 1.00 | 1.00 | |||||
CT | 2,205 (50.4) | 736 (49.3) | 235 (50.5) | 1,399 (50.1) | 0.98 | 0.88 to 1.08 | 1.20 | 0.96 to 1.51 | |||
TT | 1,024 (23.4) | 350 (23.5) | 127 (27.3) | 703 (25.2) | 0.99 | 0.87 to 1.12 |
1.38
|
1.07 to 1.77
| |||
Per-allele | 0.99 | 0.93 to 1.06 | 0.83 |
1.17
|
1.03 to 1.33
|
0.013
|
0.027
| ||||
STXBP4/COX11 rs6504950 | |||||||||||
GG | 2,346 (53.1) | 814 (53.2) | 252 (52.9) | 1,502 (53.1)) | 1.00 | 1.00 | |||||
GA | 1,737 (39.3) | 593 (37.8) | 191 (40.1) | 1,127 (39.8) | 1.00 | 0.91 to 1.10 | 1.03 | 0.86 to 1.24 | |||
AA | 333 (7.5) | 122 (8.0) | 33 (6.9) | 200 (7.1) | 1.04 | 0.88 to 1.23 | 0.94 | 0.65 to 1.34 | |||
Per-allele | 1.01 | 0.94 to 1.09 | 0.77 | 1.00 | 0.87 to 1.15 | 0.97 | 0.87 | ||||
5p12 rs10941679 | |||||||||||
AA | 2,211 (55.8) | 815 (57.3) | 271 (61.0) | 1,529 (56.5) | 1.00 | 1.00 | |||||
AG | 1,472 (37.1) | 517 (36.4) | 145 (32.7) | 1,001 (37.0) | 0.99 | 0.90 to 1.09 | 0.84 | 0.69 to 1.02 | |||
GG | 280 (7.1) | 90 (6.3) | 28 (6.3) | 177 (6.5) | 0.89 | 0.73 to 1.08 | 0.84 | 0.58 to 1.20 | |||
Per-allele | 0.97 | 0.90 to 1.04 | 0.39 | 0.88 | 0.75 to 1.02 | 0.08 | 0.26 | ||||
6q25.1 - rs2046210 | |||||||||||
CC | 1,886 (43.3) | 567 (38.2) | 158 (36.0) | 1,007 (37.0) |
1.00
|
1.00
| |||||
TC | 1,919 (44.1) | 718 (48.3) | 232 (52.9) | 1,305 (48.0) |
1.21
|
1.10 to 1.33
|
1.37
|
1.13 to 1.67
| |||
TT | 547 (12.6) | 201 (13.5) | 49 (11.2) | 409 (15.0) |
1.39
|
1.21 to 1.59
|
1.11
|
0.81 to 1.53
| |||
Per-allele |
1.19
|
1.11 to 1.27
|
2.4 × 10
-7
|
1.14
|
1.01 to 1.30
|
0.043
| 0.60 | ||||
1p11.2 - rs11249433 | |||||||||||
TT | 1,491 (34.1) | 506 (33.7) | 144 (32.4) | 973 (35.1) | 1.00 | 1.00 | |||||
CT | 2,133 (48.7) | 745 (49.7) | 245 (55.2) | 1,342 (48.5) | 0.97 | 0.88 to 1.07 | 1.10 | 0.90 to 1.34 | |||
CC | 752 (17.2) | 248 (16.5) | 55 (12.4) | 455 (16.4) | 0.99 | 0.87 to 1.13 | 0.76 | 0.56 to 1.03 | |||
Per-allele | 0.99 | 0.93 to 1.06 | 0.79 | 0.92 | 0.81 to 1.05 | 0.22 | 0.35 | ||||
RAD51L1
- rs999737/rs10483813
| |||||||||||
CC/TT | 2,335 (61.5) | 760 (64.1) | 212 (62.5) | 1,551 (62.5) | 1.00 | 1.00 | |||||
TC/AT | 1,294 (34.1) | 370 (31.2) | 113 (33.3) | 819 (33.0) | 0.92 | 0.83 to 1.03 | 1.00 | 0.80 to 1.24 | |||
TT/AA | 170 (4.5) | 56 (4.7) | 14 (4.1) | 110 (4.4) | 1.02 | 0.81 to 1.28 | 0.93 | 0.56 to 1.56 | |||
per allele | 0.96 | 0.88 to 1.04 | 0.34 | 0.98 | 0.82 to 1.18 | 0.87 | 0.81 |
Associations with ER status - BRCA2 mutation carriers
Genotype | Unaffected, | Affected by subtype, N (%) | ER- | ER+ | P-het | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
N (%) | ER- | ER+ | Unknown | HR | 95%CI |
P-trend
| HR | 95% CI |
P-trend
| ||
FGFR2 rs2981582
| |||||||||||
GG | 794 (37.8) | 86 (32.7) | 248 (29.5) | 457 (29.8) | 1.00 |
1.00
| |||||
GA | 987 (47.0) | 137 (52.1) | 419 (49.8) | 755 (49.3) | 1.28 | 0.99 to 1.67 |
1.35
|
1.17 to 1.55
| |||
AA | 321 (15.3) | 40 (15.2) | 174 (20.7) | 320 (20.9) | 1.23 | 0.85 to 1.78 |
1.81
|
1.51 to 2.18
| |||
Per-allele | 1.14 | 0.97 to 1.35 | 0.12 |
1.35
|
1.23 to 1.48
|
1.4 × 10
-10
| 0.097 | ||||
TOX3/TNRC9 rs3803662
| |||||||||||
CC | 1,088 (53.4) | 136 (53.3) | 377 (46.3) | 702 (48.2) | 1.00 |
1.00
| |||||
CT | 792 (38.9) | 96 (37.7) | 361 (44.3) | 604 (41.5) | 0.98 | 0.75 to 1.27 |
1.33
|
1.17 to 1.53
| |||
TT | 157 (7.7) | 23 (9.0) | 77 (9.5) | 150 (10.3) | 1.27 | 0.83 to 1.93 |
1.54
|
1.22 to 1.95
| |||
Per-allele | 1.06 | 0.88 to 1.29 | 0.53 |
1.28
|
1.16 to 1.41
|
1.5 × 10
-6
| 0.11 | ||||
MAP3K1 rs889312 | |||||||||||
AA | 1,107 (51.1) | 121 (45.7) | 430 (50.3) | 746 (47.7) | 1.00 | 1.00 | |||||
AC | 888 (41.0) | 120 (45.3) | 349 (40.8) | 646 (41.3) | 1.23 | 0.96 to 1.59 | 1.03 | 0.90 to 1.17 | |||
CC | 170 (7.9) | 24 (9.1) | 76 (8.9) | 172 (11.0) | 1.42 | 0.93 to 2.16 |
1.29
|
1.03 to 1.62
| |||
Per-allele |
1.21
|
1.01 to 1.45
|
0.039
| 1.09 | 0.99 to 1.21 | 0.08 | 0.35 | ||||
LSP1 rs3817198 | |||||||||||
TT | 1,075 (46.1) | 142 (44.4) | 429 (42.0) | 718 (42.7) | 1.00 |
1.00
| |||||
TC | 1,005 (43.1) | 146 (45.6) | 466 (45.6) | 759 (45.2) | 1.08 | 0.86 to 1.36 |
1.14
|
1.01 to 1.29
| |||
CC | 252 (10.8) | 32 (10.0) | 127 (12.4) | 203 (12.1) | 1.02 | 0.68 to 1.51 |
1.39
|
1.14 to 1.70
| |||
Per-allele | 1.03 | 0.87 to 1.22 | 0.70 |
1.17
|
1.07 to 1.28
|
5.5 × 10
-4
| 0.20 | ||||
2q35 rs13387042 | |||||||||||
GG | 571 (25.3) | 71 (23.0) | 216 (22.0) | 382 (23.1) | 1.00 | 1.00 | |||||
GA | 1,080 (47.8) | 156 (50.5) | 500 (50.8) | 809 (48.8) | 1.12 | 0.85 to 1.47 |
1.18
|
1.01 to 1.36
| |||
AA | 608 (26.9) | 82 (26.5) | 268 (27.2) | 466 (28.1) | 1.06 | 0.78 to 1.45 | 1.13 | 0.95 to 1.34 | |||
Per-allele | 1.03 | 0.87 to 1.19 | 0.71 | 1.06 | 0.97 to 1.15 | 0.20 | 0.75 | ||||
8q24 rs13281615 | |||||||||||
AA | 794 (34.1) | 99 (31.6) | 317 (31.7) | 524 (31.3) | 1.00 | 1.00 | |||||
AG | 1,156 (49.6) | 165 (52.7) | 511 (51.1) | 837 (49.9) | 1.08 | 0.85 to 1.38 | 1.05 | 0.92 to 1.21 | |||
GG | 382 (16.4) | 49 (15.7) | 172 (17.2) | 315 (18.8) | 1.05 | 0.75 to 1.46 | 1.13 | 0.94 to 1.35 | |||
Per-allele | 1.04 | 0.89 to 1.21 | 0.66 | 1.06 | 0.97 to 1.16 | 0.19 | 0.80 | ||||
SLC4A7/NEK10 rs4973768 | |||||||||||
CC | 669 (26.5) | 82 (24.9) | 251 (22.6) | 401 (23.5) | 1.00 |
1.00
| |||||
CT | 1,241 (49.1) | 164 (49.9) | 546 (49.4) | 829 (48.7) | 1.05 | 0.81 to 1.36 |
1.14
|
0.99 to 1.31
| |||
TT | 618 (24.5) | 83 (25.2) | 311 (28.0) | 474 (27.8) | 1.04 | 0.77 to 1.41 |
1.27
|
1.08 to 1.50
| |||
Per-allele | 1.02 | 0.88 to 1.19 | 0.78 |
1.13
|
1.04 to 1.22
|
0.0043
| 0.25 | ||||
STXBP4/COX11 rs6504950 | |||||||||||
GG | 1,420 (55.6) | 171 (51.0) | 601 (53.1) | 896 (52.5) | 1.00 | 1.00 | |||||
GA | 951 (37.2) | 145 (43.3) | 444 (39.3) | 684 (40.1) |
1.27
|
1.03 to 1.58
| 1.09 | 0.97 to 1.23 | |||
AA | 184 (7.2) | 19 (5.7) | 86 (7.6) | 127 (7.4) | 0.84 | 0.54 to 1.30 | 1.08 | 0.87 to 1.34 | |||
Per-allele | 1.07 | 0.92 to 1.25 | 0.36 | 1.06 | 0.97 to 1.16 | 0.19 | 0.91 | ||||
5p12 rs10941679 | |||||||||||
AA | 1,372 (58.6) | 176 (54.8) | 584 (54.8) | 924 (56.3) | 1.00 | 1.00 | |||||
AG | 824 (35.2) | 122 (38.0) | 425 (39.9) | 622 (37.9) | 1.08 | 0.86 to 1.37 |
1.15
|
1.01 to 1.30
| |||
GG | 146 (6.2) | 23 (7.2) | 57 (5.4) | 94 (5.7) | 1.25 | 0.82 to 1.91 | 0.94 | 0.73 to 1.22 | |||
Per-allele | 1.10 | 0.92 to 1.31 | 0.28 | 1.06 | 0.96 to 1.17 | 0.23 | 0.70 | ||||
6q25.1 - rs2046210 | |||||||||||
CC | 985 (39.8) | 121 (39.2) | 466 (42.1) | 634 (37.7) |
1.00
| 1.00 | |||||
TC | 1,165 (47.1) | 132 (42.7) | 499 (45.1) | 802 (47.7) |
0.99
|
0.78 to 1.12
| 0.96 | 0.85 to 1.08 | |||
TT | 324 (13.1) | 56 (18.1) | 141 (12.8) | 247 (14.7) |
1.47
|
1.08 to 2.01
| 0.94 | 0.78 to 1.12 | |||
Per-allele | 1.17 | 0.99 to 1.38 | 0.059 | 0.97 | 0.89 to 1.05 | 0.41 |
0.045
| ||||
1p11.2 - rs11249433 | |||||||||||
TT | 895 (35.9) | 107 (33.6) | 345 (31.4) | 599 (34.7) | 1.00 |
1.00
| |||||
CT | 1,226 (49.2) | 160 (50.3) | 553 (50.3) | 843 (48.9) | 1.00 | 0.79 to 1.28 |
1.08
|
0.96 to 1.23
| |||
CC | 371 (14.9) | 51 (16.0) | 202 (18.4) | 282 (16.4) | 1.00 | 0.73 to 1.40 |
1.27
|
1.08 to 1.50
| |||
Per-allele | 1.00 | 0.86 to 1.17 | 0.98 |
1.12
|
1.03 to 1.22
|
0.0065
| 0.23 | ||||
RAD51L1
- rs999737/rs10483813
| |||||||||||
BRCA1
| CC/TT | 1,368 (59.5) | 167 (59.0) | 589 (61.4) | 1,000 (62.0) | 1.00 | 1.00 | ||||
TC/AT | 789 (34.3) | 104 (36.8) | 323 (33.6) | 534 (33.1) | 1.06 | 0.84 to 1.35 | 0.94 | 0.83 to 1.07 | |||
TT/AA | 141 (6.1) | 12 (4.2) | 48 (5.0) | 80 (4.9) | 0.74 | 0.42 to 1.32 | 0.87 | 0.67 to 1.14 | |||
Per-allele | 0.97 | 0.80 to 1.17 | 0.73 | 0.94 | 0.85 to 1.03 | 0.20 | 0.77 |