Background
Methods
Study sample
Loss of heterozygosity
Statistical Analysis
Results
Characteristics of TH versus SH1 and SH2 mutation carriers
BRCA1 mutation |
BRCA2 mutation |
N
| % | Breast cancer only | Ovarian cancer only | Breast + ovarian cancer | No cancer | Self-identified race/ethnicity | Country of ascertainment | ||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
HGVS: genomic level | HGVS: genomic level | ||||||||||||
n
| % |
n
| % |
n
| % |
n
| % | ||||||
c.-19-?_80 + ?dup | c.8633-?_8754 + ?amp* | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Jewish | Hungary |
c.68_69delAG | c.5946delT | 31 | 33.3 | 13 | 13.9 | 1 | 1.1 | 3 | 3.2 | 14 | 15.0 | Caucasian, Jewish, NR | USA, Hungary, Israel |
c.68_69delAG | c.5722_5723delCT | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Germany |
c.1016delA | c.7379_7382delACAA | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Asian | USA |
c.1390delA* | c.658_659delGT | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Hispanic | USA |
c.1504_1508del5 | c.2798_2799delCA | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Asian | Korea |
c.1504_1508del5 | c.462_463delAA | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | 0 | 0.0 | Caucasian | Germany |
c.1687C > T | c.6469C > T | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | 0 | 0.0 | Caucasian | Italy |
c.1793 T > ? | c.8537_8538delAG | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | 0 | 0.0 | Caucasian | USA |
c.181 T > G | c.1318_1319dupCT | 3 | 3.2 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 2 | 2.2 | Caucasian | Austria |
c.211A > G | c.4380_4381delTT | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | UK |
c.212 + 1G > A | c.739_740delAT* | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Spain |
c.213-12A > G | c.7180A > T | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Italy |
c.2389G > T | c.3068dupA | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Canada |
c.2405_2406delTG | c.4284dupT | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | 0 | 0.0 | Caucasian | Italy |
c.246delT | c.517-2A > G | 2 | 2.2 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | Caucasian | UK |
c.301 + 1G > A | c.5682C > G | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | USA |
c.3048_3052dup5 | c.2830A > T | 2 | 2.2 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | NR | Sweden |
c.3155delA | c.3160_ 3163delGATA | 2 | 2.2 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | Caucasian | Australia |
c.3196G > T* | c.658_659delGT | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Germany |
c.3228_3229delAG | c.3689delC | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | Caucasian | UK |
c.3228_3229delAG | c.9253dupA | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Italy |
c.3400G > T | c.2808_2811delACAA | 2 | 2.2 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | Caucasian | UK |
c.3477_3480 delAAAG | c.9401delG | 1 | 1.1 | 0 | 0.0 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | Caucasian | Italy |
c.3627dupA | c.6724_6725delGA | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Asian | Korea |
c.3700_3704del5 | c.681 + 1G > A | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Australia |
c.3700_3704del5 | c.1815dupA | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Germany |
c.3756_3759delGTCT | c.7757G > A | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | USA |
c.3759_3760delTA | c.9699_9702 delTATG | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | 0 | 0.0 | Hispanic | USA |
c.3770_3771delAG | c.5946delT | 2 | 2.2 | 1 | 1.1 | 0 | 0.0 | 1 | 1.1 | 0 | 0.0 | NR, Jewish | Australia, USA |
c.3839_3843 delinsAGGC | c.1636delT | 2 | 2.2 | 0 | 0.0 | 1 | 1.1 | 0 | 0.0 | 1 | 1.1 | NR | France |
c.390C > A | c.3018delA | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Asian | Korea |
3910delG | c.2830A > T | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Germany |
c.3916_3917delTT | c.5380delG* | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | 0 | 0.0 | Caucasian | Italy |
c.4035delA | c.658_659delGT | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | Caucasian | Australia |
c.4065_4068delTCAA | c.5350_5351delAA | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | USA |
c.4186-?_4357 + ?dup | c.2636_2637delCT | 2 | 2.2 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | Caucasian | UK |
c.427G > T | c.8730delT | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Denmark |
c.5030_5033 delCTAA | c.1399A > T | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Asian | Korea |
c.5123C > A | c.6275_6276delTT | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Germany |
c.5136G > A | c.4965delC | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Asian | USA |
c.5193 + 1delG | c.658_659delGT | 1 | 1.1 | 0 | 0.0 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | Caucasian | Germany |
c.5251C > T | c.6753_6754delTT | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Austria |
c.5266dupC | c.8364G > A | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Austria |
c.5266dupC | c.5946delT | 5 | 5.4 | 3 | 3.2 | 0 | 0.0 | 1 | 1.1 | 1 | 1.1 | Jewish | UK, Israel |
c.5266dupC | c.4478_4481delAAAG | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Germany |
c.5266dupC | c.5645C > A | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | 0 | 0.0 | Caucasian | Germany |
c.5406 + 664_*8273del | c.9748dupT | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Greece |
c.548-?_4185 + ?del | c.2269A > T* | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 1 | 1.1 | 0 | 0.0 | Caucasian | Germany |
c.962G > A | c.2231C > G | 1 | 1.1 | 1 | 1.1 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | Caucasian | Germany |
Total | 93 | 100 | 51 | 54.8 | 4 | 4.3 | 13 | 14.0 | 25 | 26.9 | |||
Mean age (range) | 39.9 (23–67) | 59.2 (57–62) | 41.9 (26–53) | 39.1 (20–68) |
Variable | Value |
BRCA1 + BRCA2 (TH)N(%)
|
BRCA1 (SH1)N(%)
|
P value* |
P value* |
BRCA1 + BRCA2 (TH) N(%)
|
BRCA2 (SH2)N(%)
|
P value** |
P value** |
---|---|---|---|---|---|---|---|---|---|
Total matched | 91 | 9316 | 89 | 3370 | |||||
Year of birth | <1940 1941–1950 1951–1960 1961–1970 >1970 | 5 (5.5) 20 (22.0) 21 (22.6) 27 (29.0) 18 (19.8) | 886 (9.5) 1628 (17.4) 2607 (28.0) 2409 (25.9) 1779 (19.0) | 0.424 | (ref) 0.112 0.474 0.153 0.245 | 5 (5.6) 19 (21.3) 19 (21.3) 27 (30.3) 19 (21.3) | 486 (14.4) 735 (21.8) 914 (27.1) 724 (21.5) 511 (15.2) |
0.025
| (ref) 0.060 0.156
0.005
0.007
|
Ethnicity | White African American Asian Hispanic Jewish Other | 47 (51.6) 0 (0) 6 (6.6) 1 (1.1) 30 (33.0) 7 (7.7) | 5736 (61.6) 20 (0.2) 82 (0.9) 143 (1.5) 1779 (19.1) 1556 (16.7) |
<0.001
| (ref) 1.00*
<0.001
1.00
0.002
-- | 45 (50.6) 0 (0) 6 (6.7) 2 (2.2) 29 (32.6) 7 (7.9) | 1686 (50.0) 15 (0.4) 66 (2.0) 57 (1.7) 936 (27.8) 610 (18.1) |
0.007
| (ref) 1.00*
0.004
0.667 0.573
--
|
Breast cancer | No Yes | 29 (31.9) 62 (68.1) | 4470 (48.0) 4846 (52.0) |
0.002
| 29 (32.6) 60 (67.4) | 1671 (49.6) 1699 (50.4) |
0.002
| ||
Age of breast cancer | Mean (range) | 40.4 (23–67) | 41.9 (18–82) | 0.231 | 40.5 (23–67) | 45.0 (19–82) |
<0.001
| ||
Ovarian cancer | No Yes | 74 (81.3) 17 (18.7) | 7766 (83.4) 1550 (16.6) | 0.603 | 74 (83.1) 15 (16.9) | 3056 (90.7) 314 (9.3) |
0.017
| ||
Age of ovarian cancer | Mean (range) | 54.1 (36–66) | 50.9 (20–85) | 0.154 | 54.7 (42–66) | 56.8 (26–89) | 0.421 | ||
Bilateral mastectomy | No Yes | 58 (63.7) 8 (9.0) | 4807 (51.6) 809 (8.7) | 0.599 | 58 (65.2) 8 (9.0) | 1856 (55.0) 305 (9.1) | 0.646 | ||
Prophylactic oophorectomy | No Yes | 45 (49.5) 24 (26.4)) | 3583 (38.4) 2476 (26.6) | 0.307 | 45 (50.6) 24 (27.0) | 1388 (41.2) 980 (29.1) | 0.272 | ||
Follow up age (if no cancer) | Mean (range) | 39.1 (20–68) | 40.5 (18–99) | 0.587 | 39.1 (20–68) | 44.1 (18–94) | 0.068 |
Trait | Value |
BRCA1 + BRCA2 (TH) N(%)
|
BRCA1 (SH1) N(%)
|
P value |
BRCA1 + BRCA2 (TH) N(%)
|
BRCA2 (SH2) N(%)
|
P value |
---|---|---|---|---|---|---|---|
N
| 62 | 4846 | 60 | 1699 | |||
HER2 | Negative | 14 (93.3) | 908 (88.7) | 1.00 | 15 (93.8) | 274 (86.2) | 0.706 |
Positive | 1 (7.7) | 116 (11.3) | 1 (6.3) | 44 (13.8) | |||
PR | Negative | 19 (59.4) | 1260 (80.0) |
0.013
| 19 (59.4) | 215 (37.2) |
0.012
|
Positive | 13 (40.6) | 356 (20.0) | 13 (40.6) | 363 (62.8) | |||
ER | Negative | 20 (57.1) | 1347 (76.0) |
0.010
| 20 (57.1) | 150 (23.5) |
<0.0001
|
Positive | 15 (42.9) | 424 (24.0) | 15 (42.9) | 487 (76.5) | |||
Nodal status | Negative | 20 (66.7) | 1197 (65.1) | 0.854 | 19 (65.5) | 399 (61.3) | 0.647 |
Positive | 10 (33.3) | 643 (35.0) | 10 (34.5) | 252 (38.7) | |||
Grade | Well differentiated | 2 (7.1) | 36 (2.3) | 0.161 | 2 (7.1) | 36 (6.4) | 0.690 |
Moderately differentiated | 8 (28.8) | 342 (22.1) | 8 (28.8) | 207 (36.6) | |||
Poorly/undifferentiated | 18 (64.3) | 1172 (75.6) | 18 (64.3) | 322 (57.0) | |||
Stage | 0 | 1 (4.8) | 34 (3.6) | 0.541 | 1 (4.6) | 48 (13.9) | 0.065 |
1 | 7 (33.3) | 399 (42.2) | 7 (31.8) | 123 (35.7) | |||
2 | 13 (61.9) | 440 (46.6) | 14 (63.6) | 124 (35.9) | |||
3 | 0 (0) | 65 (6.9) | 0 (0) | 36 (10.4) | |||
4 | 0 (0) | 7 (0.7) | 0 (0) | 14 (4.1) | |||
Morphology | Ductal | 26 (70.3) | 1544 (74.3) | 0.345 | 27 (73.0) | 629 (78.8) | 0.359 |
Lobular | 3 (8.1) | 61 (2.9) | 3 (8.1) | 70 (8.8) | |||
Medullary | 3 (8.1) | 173 (8.3) | 2 (5.4) | 13 (1.6) | |||
Other | 5 (13.5) | 301 (14.5) | 5 (13.5) | 86 (10.8) | |||
Number of positive nodes (SD) | 2 (6.1) | 1.2 (3.4) | 0.215 | 2.1 (6.2) | 1.7 (3.9) | 0.627 | |
Tumor size (SD) | 19.0 (14.9) | 18.3 (12.5) | 0.775 | 19.0 (14.9) | 19.2 (14.6) | 0.932 |
Trait | Value |
BRCA1 + BRCA2 (TH)N(%)
|
BRCA1 (SH1)N(%)
|
P value |
BRCA1 + BRCA2 (TH)N(%)
|
BRCA2 (SH2)N(%)
|
P value |
---|---|---|---|---|---|---|---|
N
| 17 | 1550 | 15 | 314 | |||
Grade | Well differentiated | 0 | 8 (2.8) | 0.930 | 0 | 4 (6.2) | 0.847 |
Moderately differentiated | 1 (25) | 60 (20.8) | 1 (25) | 12 (18.5) | |||
Poorly/undifferentiated | 3 (75) | 220 (76.4) | 3 (75) | 49 (75.4) | |||
Stage | 1 | 0 | 39 (17.4) | 0.600 | 0 | 6 (13.3) | 0.589 |
2 | 1 (33.3) | 31 (13.8) | 1 (33.3) | 5 (11.1) | |||
3 | 2 (66.7) | 120 (53.6) | 2 (66.7) | 28 (62.2) | |||
4 | 0 | 34 (15.2) | 0 | 6 (13.3) | |||
Morphology | Serous | 5 (83.3) | 292 (66.8) | 0.905 | 5 (83.3) | 71 (73.2) | 0.943 |
Mucinous | 0 | 4 (0.9) | 0 | 2 (2.0) | |||
Endometroid | 0 | 44 (10.1) | 0 | 7 (7.2) | |||
Clear cell | 0 | 6 (1.4) | 0 | 2 (2.0) | |||
Other | 1 (16.7) | 91 (20.8) | 1 (16.7) | 15 (15.5) | |||
Behavior | Invasive | 7 (100) | 449 (99.1) | 0.803 | 6 (100) | 89 (95.7) | 0.604 |
Borderline | 0 | 4 (0.9) | 0 | 4 (4.3) |
Loss of heterozygosity
LOH in breast tumor | LOH in ovarian tumor | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Case | Diagnosis | Tissue studied |
BRCA1 mutation |
BRCA2 mutation | Micro-satellite Data | Sequence data | Inference | Micro-satellite data | Sequence data | Inference |
1 | DCIS | DCIS | c.5136G > A | c.4965delC |
BRCA1, BRCA2
| No | No LOH | |||
2 | Breast | Inv Br | c.1793 T > A | c.8537_8538delAG |
BRCA2
|
BRCA1
| No LOH | |||
3 | Invasive breast | Inv Br | c.68_69delAG | c.5946delT |
BRCA1
| No | No LOH | |||
5 | Invasive breast | DCISb
| c.181 T > G | c.1318_1319dupCT | No |
BRCA2
| No LOH | |||
6 L | Bilateral breast | DCISb
| c.5251C > T | c.6753_6754delTT | No | No | No LOHd
| |||
6R | Bilateral breast | DCISb
| c.5251C > T | c.6753_6754delTT |
BRCA1
| No | No LOHd
| |||
7 | Invasive breast | DCISb
| c.5266dupC | c.8364G > A | No |
BRCA1
| No LOH | |||
8 | Invasive breast | DCISb
| c.3700_3704del5 | c.681 + 1G > A |
BRCA1, BRCA2
|
BRCA1
|
BRCA1 LOH | |||
9 | Invasive breast | DCISb
| c.68_69delAG | c.5946delT |
BRCA2
|
BRCA1, BRCA2
|
BRCA2 LOH | |||
10 | Invasive breast | Inv Br | c.68_69delAG | c.5946delT |
BRCA1, BRCA2
| Failed | Failedc
| |||
11a
| Invasive breast | Inv Br | c.3770_3771delAG | c.5946delT |
a
|
a
|
BRCA2 LOH | |||
12a
| Breast | Inv Br | c.68_69delAG | c.5946delT |
a
|
a
| No LOH | |||
2 | Ovary | Ov | c.1793 T > A | c.8537_8538delAG |
BRCA1
|
BRCA1
|
BRCA1 LOH | |||
4 | Ovary | Ov | c.68_69delAG | c.5946delT | No | No | No LOH | |||
12a
| Ovary | Ov | c.68_69delAG | c.5946delT |
a
|
a
| No |
a
|
a
| No LOH |
Discussion
Conclusions
Acknowledgments
Study
|
Funding
|
Acknowledgements
|
BCFR - all | This work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. | |
BCFR-AU | Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis. | |
BCFR-NY | We wish to thank members and participants in the New York site of the Breast Cancer Family Registry for their contributions to the study. | |
BCFR-ON | We wish to thank members and participants in the Ontario Familial Breast Cancer Registry for their contributions to the study. | |
BFBOCC-LT | BFBOCC is partly supported by: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015 | BFBOCC-LT acknowledge Vilius Rudaitis and Laimonas Griškevičius. BFBOCC-LV acknowledge Drs Janis Eglitis, Anna Krilova and Aivars Stengrevics. |
BIDMC | BIDMC is supported by the Breast Cancer Research Foundation | |
BMBSA | BRCA gene mutations and breast cancer in South African women (BMBSA) was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg | BMBSA wish to thank the families who contribute to the BMBSA study |
BRICOH | SLN was partially supported by the Morris and Horowitz Families Endowed Professorship. | We wish to thank Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management. |
CBCS | We thank Bent Ejlertsen Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of participants | |
CNIO | This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA) and SAF2010-20493 | We thank Alicia Barroso, Rosario Alonso and Guillermo Pita for their assistance. |
COH-CCGCRN | City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health | |
CONSIT TEAM | Funds from Italian citizens who allocated the 5×1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5×1000’) to SM. | Bernard Peissel, Jacopo Azzollini and Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Bernardo Bonanni, Monica Barile and Irene Feroce of the Istituto Europeo di Oncologia, Milan, Italy; Alessandra Viel and Riccardo Dolcetti of the CRO Aviano National Cancer Institute, Aviano (PN), Italy; Barbara Pasini and Francesca Vignolo-Lutati of the University of Turin, Turin, Italy; Laura Papi and Gabriele Capone of the University of Florence, Florence, Italy; Laura Ottini and Giuseppe Giannini of the “Sapienza” University, Rome, Italy; Liliana Varesco of the IRCCS AOU San Martino – IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; Maria Grazia Tibiletti of the Ospedale di Circolo-Università dell’Insubria, Varese, Italy; Antonella Savarese and Aline Martayan of the Istituto Nazionale Tumori Regina Elena, Rome, Italy; Stefania Tommasi of the Istituto Nazionale Tumori “Giovanni Paolo II” - Bari, Italy. |
CORE | The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861, C12292/A11174. ACA is a Cancer Research UK Senior Cancer Research Fellow. GCT is an NHMRC Senior Principal Research Fellow. | UK grants C12292/A20861. We wish to thank Sue Healey for her many contributions to CIMBA. |
DEMOKRITOS | This research has been co-financed by the European Union (European Social Fund – ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. | |
DKFZ | The DKFZ study was supported by the DKFZ. | |
EMBRACE | EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust | RE is supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust |
FCCC | The authors acknowledge support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. | We thank Ms. JoEllen Weaver and Dr. Betsy Bove for their technical support. |
GC-HBOC | The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 110837), Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC) | |
GEMO | The study was supported by the Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award; the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program and the French National Institute of Cancer (INCa). | Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study : National Cancer Genetics Network «UNICANCER Genetic Group», France. We wish to pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet initiated and coordinated GEMO until she sadly passed away on the 30th June 2014, and to thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, & Equipe «Génétique du cancer du sein», Centre de Recherche en Cancérologie de Lyon: Olga Sinilnikova†, Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Mélanie Léone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud; and Service de Génétique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Etienne Rouleau, Lisa Golmard, Agnès Collet, Virginie Moncoutier, Muriel Belotti, Antoine de Pauw, Camille Elan, Catherine Nogues, Emmanuelle Fourme, Anne-Marie Birot. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud-Bataille. Centre Jean Perrin, Clermont–Ferrand: Yves-Jean Bignon, Nancy Uhrhammer. Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona, Sandrine Handallou. Centre François Baclesse, Caen: Agnès Hardouin, Pascaline Berthet, Dominique Vaur, Laurent Castera. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, François Eisinger. CHU Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joëlle Fournier, Françoise Révillion, Philippe Vennin†, Claude Adenis. Centre Paul Strauss, Strasbourg: Danièle Muller, Jean-Pierre Fricker. Institut Bergonié, Bordeaux: Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU Grenoble: Dominique Leroux, Hélène Dreyfus, Christine Rebischung, Magalie Peysselon. CHU Dijon: Fanny Coron, Laurence Faivre. CHU St-Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz. Hôtel Dieu Centre Hospitalier, Chambéry: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frénay. CHU Limoges: Laurence Vénat-Bouvet. CHU Nantes: Capucine Delnatte. CHU Bretonneau, Tours: Isabelle Mortemousque. Groupe Hospitalier Pitié-Salpétrière, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy : Johanna Sokolowska, Myriam Bronner. CHU Besançon: Marie-Agnès Collonge-Rame, Alexandre Damette. Creighton University, Omaha, USA: Henry T. Lynch, Carrie L. Snyder. |
GEORGETOWN | CI received support from the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Familial Cancer Research, and Swing Fore the Cure. | |
HCSC | Was supported by a grant RD12/0036/0006 and 15/00059 from ISCIII (Spain), partially supported by European Regional Development FEDER funds | We acknowledge Alicia Tosar and Paula Diaque for their technical assistance |
HEBCS | The HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. | HEBCS would like to thank Dr. Kristiina Aittomäki, Taru A. Muranen, Drs. Carl Blomqvist and Kirsimari Aaltonen and RNs Irja Erkkilä and Virpi Palola for their help with the HEBCS data and samples. |
HEBON | The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grant 110005 and the BBMRI grant NWO 184.021.007/CP46. HEBON thanks the registration teams of the Comprehensive Cancer Centre Netherlands and Comprehensive Centre South (together the Netherlands Cancer Registry) and PALGA (Dutch Pathology Registry) for part of the data collection. | The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, J.L. de Lange, R. Wijnands; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C.J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center, NL: C.M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, NL: E.B. Gómez-Garcia, M.J. Blok; University Medical Center Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J.Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of IKNL and PALGA for part of the data collection. |
HRBCP | HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong | We wish to thank Hong Kong Sanatorium and Hospital for their continued support |
HUNBOCS | Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745, OTKA K-112228 and the Norwegian EEA Financial Mechanism Hu0115/NA/2008-3/OP-9 | We wish to thank the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Tibor Vaszko, Aniko Bozsik, Timea Pocza, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study. |
HVH | We wish to thank the Oncogenetics Group (VHIO) and the High Risk and Cancer Prevention Unit of the University Hospital Vall d’Hebron. Acknowledgements to the Cellex Foundation for providing research facilities and equipment. | |
ICO | ICO: Contract grant sponsor: Asociación Española Contra el Cáncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290 and 2014SGR364. | We wish to thank the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella. |
IHCC | The IHCC was supported by Grant PBZ_KBN_122/P05/2004 | |
INHERIT | This work was supported by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program, the Canadian Breast Cancer Research Alliance-grant #019511 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. | We would like to thank Dr Martine Dumont, Martine Tranchant for sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. J.S. and P.S. were part of the QC and Genotyping coordinating group of iCOGS (BCAC and CIMBA). |
IOCHBOCS | IOCHBOCS is supported by Ministero della Salute and “5×1000” Istituto Oncologico Veneto grant. | |
IPOBCS | This study was in part supported by Liga Portuguesa Contra o Cancro. | We wish to thank Drs. Ana Peixoto, Catarina Santos, Patrícia Rocha and Pedro Pinto for their skillful contribution to the study. |
KCONFAB | kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia; | We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. |
KOHBRA | KOHBRA is supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350). | |
MAYO | MAYO is supported by NIH grants CA116167, CA128978 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, and a generous gift from the David F. and Margaret T. Grohne Family Foundation. | |
MCGILL | Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade | |
MODSQUAD | MODSQUAD was supported by MH CZ - DRO (MMCI, 00209805) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague project UNCE204024 (MZ). | Modifier Study of Quantitative Effects on Disease (MODSQUAD): MODSQUAD acknowledges ModSQuaD members Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA); Lenka Foretova and Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic); and Michal Zikan, Petr Pohlreich and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic). |
MSKCC | MSKCC is supported by grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Research Fund. | Anne Lincoln, Lauren Jacobs |
NCI | The research of Drs. MH Greene and PL Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD. For CIMBA PRS paper: The research of Drs. MH Greene and JT Loud was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD. | |
NNPIO | This work has been supported by the Russian Federation for Basic Research (grants 14-04-93959 and 15-04-01744). | |
NRG Oncology | This study was supported by NRG Oncology Operations grant number U10 CA180868 as well as NRG SDMC grant U10 CA180822, Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank (CA 27469) and the GOG Statistical and Data Center (CA 37517). Drs. Greene, Mai and Savage were supported by funding from the Intramural Research Program, NCI. | We thank the investigators of the Australia New Zealand NRG Oncology group |
OCGN | We wish to thank members and participants in the Ontario Cancer Genetics Network for their contributions to the study. | |
OSU CCG | OSUCCG is supported by the Ohio State University Comprehensive Cancer Center. | Leigha Senter, Kevin Sweet, Caroline Craven, Julia Cooper, and Michelle O’Conor were instrumental in accrual of study participants, ascertainment of medical records and database management. |
PBCS | This work was supported by the ITT (Istituto Toscano Tumori) grants 2011-2013. | |
SEABASS | Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation | We would like to thank Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan and all the research nurses, research assistants and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection and sample preparation. In addition, we thank Philip Iau, Sng Jen-Hwei and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study respectively. The Malaysian Breast Cancer Genetic Study is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HIR/MOHE/06) and charitable funding from Cancer Research Initiatives Foundation. |
SMC | This project was partially funded through a grant by the Israel cancer association and the funding for the Israeli Inherited breast cancer consortium | SMC team wishes to acknowledge the assistance of the Meirav Comprehensive breast cancer center team at the Sheba Medical Center for assistance in this study. |
SWE-BRCA | SWE-BRCA collaborators are supported by the Swedish Cancer Society | Swedish scientists participating as SWE-BRCA collaborators are: from Lund University and University Hospital: Åke Borg, Håkan Olsson, Helena Jernström, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Öfverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Umeå University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellström Pigg, Richard Rosenquist; from Linköping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren |
UCHICAGO | UCHICAGO is supported by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women’s Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an ACS Clinical Research Professor. | We wish to thank Cecilia Zvocec, Qun Niu, physicians, genetic counselors, research nurses and staff of the Cancer Risk Clinic for their contributions to this resource, and the many families who contribute to our program. |
UCLA | Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation | We thank Joyce Seldon MSGC and Lorna Kwan, MPH for assembling the data for this study. |
UCSF | UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center | We would like to thank Dr. Robert Nussbaum and the following genetic counselors for participant recruitment: Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad. And thanks to Ms. Salina Chan for her data management. |
UKFOCR | UKFOCR was supported by a project grant from CRUK to Paul Pharoah. | We thank Simon Gayther, Carole Pye, Patricia Harrington and Eva Wozniak for their contributions towards the UKFOCR. |
UPENN | National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA | |
UPITT/MWH | Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program;Hackers for Hope Pittsburgh | |
VFCTG | Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation | Geoffrey Lindeman, Marion Harris, Martin Delatycki of the Victorian Familial Cancer Trials Group. We thank Sarah Sawyer and Rebecca Driessen for assembling this data and Ella Thompson for performing all DNA amplification. |
WCP | Dr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124 | |
Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund . |