Introduction
Materials and methods
Study participants
Statistical methods
Contribution of recently identified susceptibility loci to FRR
Contribution of BRCA1 and BRCA2 to the FRR
Results
Reported family history of breast cancer and pathology of index case tumours
Phenotype of index case tumour | Number of tumours (%)** | Number with affected relative (%)† | Number without affected relative (%)‡ | Comparison group for case-only analysis | OR§ | 95%CI | P-valuee |
---|---|---|---|---|---|---|---|
ER-positive | 3659 (81) | 599 (82) | 3060 (81) | ER-negative | 1.04 | 0.85-1.28 | 0.70 |
PR-positive | 1709 (69) | 267 (69) | 1442 (69) | PR-negative | 1.01 | 0.79-1.27 | 0.96 |
HER2-positive | 228 (12) | 38 (13) | 190 (12) | HER2-negative | 1.15 | 0.79-1.68 | 0.78 |
ER+PR+ | 1581 (65) | 247 (64) | 1334 (65) | ER-PR- | 1.00 | 0.75-1.31 | 0.95 |
ER-PR+ | 110 (4.5) | 18 (5) | 92 (5) | ||||
ER+PR- | 261 (11) | 43 (11) | 218 (11) | ||||
ER or PR+ (luminal) | 3787 (83) | 619 (84) | 3168 (83) | ||||
ER or PR+ HER2+ (luminal HER2+) | 138 (7) | 23 (8) | 115 (7) | luminal HER2- | 1.17 | 0.73-1.88 | 0.51 |
ER or PR+ HER2- (luminal HER2-) | 1404 (75) | 209 (74) | 1195 (75) | ||||
ER-PR-HER2+ (non-luminal HER2+) | 76 (5) | 11 (4) | 65 (5) | TN | 1.02 | 0.48-2.16 | 0.96 |
ER-PR-HER2- (TN) | 218 (13) | 30 (12) | 188 (13) |
Familial relative risks by pathological subtype
OBS | EXP | FRR | 95%CI | |
---|---|---|---|---|
Mothers | ||||
All cases | 663 | 398.81 | 1.66 | 1.53 - 1.79 |
ER-negative | 84 | 45.09 | 1.86 | 1.46 - 2.27 |
ER-positive | 332 | 199.36 | 1.67 | 1.49 - 1.85 |
Sisters | ||||
All cases | 416 | 207.25 | 2.01 | 1.81 - 2.21 |
ER-negative | 37 | 22.97 | 1.61 | 1.05 - 2.17 |
ER-positive | 226 | 106.81 | 2.12 | 1.83 - 2.41 |
All relatives | ||||
All cases | 1079 | 606.06 | 1.78 | 1.68 - 1.89 |
ER-negative | 121 | 68.06 | 1.78 | 1.44 - 2.11 |
ER-positive | 558 | 306.17 | 1.82 | 1.67 - 1.98 |
Age of relative (years) † | ER-negative | ER-positive | All cases | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
OBS | EXP | FRR | 95%CI | OBS | EXP | FRR | 95%CI | OBS | EXP | FRR | 95%CI | |
Index case <50*
| ||||||||||||
<50† | 26 | 7.65 | 3.40 | 2.04-4.75 | 60 | 22.21 | 2.70 | 2.01-3.39 | 129 | 50.62 | 2.55 | 2.09-3.01 |
50 to 84 | 21 | 14.77 | 1.42 | 0.81-2.03 | 84 | 50.3 | 1.67 | 1.32-2.02 | 186 | 113.76 | 1.64 | 1.33-1.95 |
0 to 84 | 47 | 22.43 | 2.10 | 1.48-2.71 | 144 | 72.51 | 1.99 | 1.65-2.32 | 315 | 164.37 | 1.92 | 1.70-2.13 |
Index case >= 50
| ||||||||||||
<50 | 22 | 8.59 | 2.56 | 1.31-3.81 | 75 | 43.57 | 1.72 | 1.33-2.11 | 160 | 82.16 | 1.95 | 1.63-2.56 |
50 to 84 | 52 | 37.04 | 1.40 | 1.01-1.80 | 339 | 190.09 | 1.78 | 1.59-1.98 | 604 | 359.53 | 1.68 | 1.54-1.82 |
0 to 84 | 74 | 45.63 | 1.62 | 1.22-2.02 | 414 | 233.66 | 1.77 | 1.59-1.95 | 764 | 441.69 | 1.73 | 1.60-1.86 |
Index case any age
| ||||||||||||
<50 | 48 | 16.24 | 2.96 | 2.04-3.87 | 135 | 65.78 | 2.05 | 1.70-2.40 | 289 | 132.78 | 2.18 | 1.92-2.44 |
50 to 84 | 73 | 51.82 | 1.41 | 1.08-1.74 | 423 | 240.39 | 1.76 | 1.59-1.93 | 790 | 473.28 | 1.67 | 1.54-1.80 |
0 to 84 | 121 | 68.06 | 1.78 | 1.44-2.11 | 558 | 306.17 | 1.82 | 1.67-1.98 | 1079 | 606.06 | 1.78 | 1.68-1.89 |
Phenotype | Age of relative (years)* | OBS | EXP | FRR | 95%CI |
---|---|---|---|---|---|
PR-positive | |||||
<50 | 60 | 29.46 | 2.04 | 1.52 to 2.55 | |
50 to 84 | 187 | 102.77 | 1.82 | 1.55 to 2.10 | |
0 to 84 | 247 | 132.23 | 1.87 | 1.63 to 2.11 | |
PR-negative
| |||||
<50 | 46 | 13.39 | 3.44 | 2.37 to 4.50 | |
50 to 84 | 65 | 46.00 | 1.41 | 1.06 to 1.76 | |
0 to 84 | 111 | 59.39 | 1.87 | 1.55 to 2.24 | |
HER2-positive
| |||||
<50 | 11 | 4.17 | 2.64 | 1.08 to 4.20 | |
50 to 84 | 25 | 13.70 | 1.83 | 1.08 to 2.57 | |
0 to 84 | 36 | 17.86 | 2.02 | 1.34 to 2.69 | |
HER2-negative
| |||||
<50 | 65 | 28.50 | 2.28 | 1.73 to 2.86 | |
50 to 84 | 154 | 100.77 | 1.53 | 1.28 to 1.77 | |
0 to 84 | 219 | 129.27 | 1.69 | 1.46 to 1.92 | |
ER+PR+
| |||||
<50 | 55 | 27.20 | 2.02 | 1.49 to 2.56 | |
50 to 84 | 173 | 95.89 | 1.80 | 1.52 to 2.08 | |
0 to 84 | 228 | 123.10 | 1.85 | 1.60 to 2.10 | |
ER-PR+
| |||||
<50 | 5 | 1.91 | 2.62 | 0.33 to 4.91 | |
50 to 84 | 12 | 5.74 | 2.09 | 0.84 to 3.35 | |
0 to 84 | 17 | 7.64 | 2.22 | 1.16 to 3.32 | |
ER+PR-
| |||||
<50 | 15 | 4.13 | 3.63 | 1.85 to 5.41 | |
50 to 84 | 24 | 16.31 | 1.47 | 0.88 to 2.06 | |
0 to 84 | 39 | 20.44 | 1.91 | 1.31 to 2.51 | |
ER or PR+ (luminal)
| |||||
<50 | 140 | 68.04 | 2.06 | 1.71 to 2.40 | |
50 to 84 | 437 | 247.27 | 1.77 | 1.61 to 1.94 | |
0 to 84 | 577 | 315.30 | 1.83 | 1.68 to 1.98 | |
ER or PR+ HER2+ (luminal HER2+)
| |||||
<50 | 6 | 2.68 | 2.24 | 0.48 to 4.00 | |
50 to 84 | 16 | 8.35 | 1.92 | 0.94 to 2.90 | |
0 to 84 | 22 | 11.03 | 2.00 | 1.15 to 2.84 | |
ER or PR+ HER2- (luminal HER2-)
| |||||
<50 | 53 | 23.49 | 2.26 | 1.65 to 2.87 | |
50 to 84 | 136 | 85.67 | 1.59 | 1.32 to 1.86 | |
0 to 84 | 189 | 109.15 | 1.73 | 1.48 to 2.00 | |
ER-PR- (non-luminal)
| |||||
<50 | 31 | 9.17 | 3.38 | 2.05 to 4.72 | |
50 to 84 | 41 | 29.10 | 1.41 | 0.97 to 1.85 | |
0 to 84 | 72 | 38.26 | 1.88 | 1.41 to 2.35 | |
ER-PR-HER2+ (non-luminal HER2+)
| |||||
<50 | 4 | 1.25 | 3.20 | 1.20 to 8.85 | |
50 to 84 | 6 | 4.52 | 1.33 | 0.35 to 2.29 | |
0 to 84 | 10 | 5.77 | 1.73 | 0.61 to 2.86 | |
ER-PR-HER2- (TN)
| |||||
<50 | 9 | 4.12 | 2.18 | 0.77 to 3.59 | |
50 to 84 | 15 | 12.55 | 1.20 | 0.60 to 1.79 | |
0 to 84 | 24 | 16.67 | 1.44 | 0.85 to 2.03 |
Contribution of BRCA1 and BRCA2 mutations to FRR
Contribution of recently identified susceptibility loci to FRR
Locus | Ref | Genes in/near region | Variant | MAF | ER-negative | ER-positive | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Hom- GRR | Het- GRR | FRR* | %FRR† | Hom- GRR | Het- GRR | FRR* | %FRR‡ | |||||
10q26 | [8] |
FGFR2
| rs2981582 | 0.38 | 1.18 | 1.08 | 1.0016 | 0.28 | 1.74 | 1.28 | 1.0186 | 3.08 |
16q12 | [8] |
TNRC9/TOX3
| rs3803662 | 0.25 | 1.28 | 1.16 | 1.0036 | 0.63 | 1.48 | 1.25 | 1.0089 | 1.48 |
5q11 | [8] |
MAP3KI
| rs889312 | 0.28 | 1.20 | 1.03 | 1.0009 | 0.16 | 1.26 | 1.12 | 1.0028 | 0.46 |
8q24 | [8] |
FAM84B/c-MYC
| rs13281615 | 0.40 | 1.09 | 0.99 | 1.0003 | 0.05 | 1.29 | 1.11 | 1.0038 | 0.63 |
11p15 | [8] |
LSP1
| rs3817198 | 0.30 | 1.13 | 1.01 | 1.0004 | 0.07 | 1.19 | 1.04 | 1.0010 | 0.17 |
3p24 | [6] |
NEK10/SLC4A7
| rs4973768 | 0.46 | 1.12 | 1.06 | 1.0008 | 0.15 | 1.25 | 1.12 | 1.0031 | 0.52 |
17q22 | [6] |
COX11
| rs6504950 | 0.27 | 1.06 | 1.03 | 1.0002 | 0.03 | 0.88 | 0.94 | 1.0008 | 0.13 |
10p14 | [32] |
CASP8 (D302H)
| rs1045485 | 0.13 | 0.82 | 0.95 | 1.0004 | 0.07 | 0.83 | 0.89 | 1.0013 | 0.21 |
2q35 | [62] |
TNP1/IGFBP5/IGFBP2/TNS1
| rs13387042 | 0.52 | 1.18 | 1.05 | 1.0018 | 0.31 | 1.29 | 1.08 | 1.0043 | 0.72 |
1p11.2 | [11] |
NOTCH2/FCGR1B
| rs1124933 | 0.40 | 1.07 | 1.03 | 1.0003 | 0.05 | 1.42 | 1.22 | 1.0078 | 1.30 |
14q24.1 | [11] |
RAD51L1
| rs999737 | 0.24 | 0.76 | 1.01 | 1.0005 | 0.09 | 0.69 | 0.93 | 1.0024 | 0.40 |
5p12 | [11] |
MRPS30/FGFR10
| rs10941679 | 0.26 | 1.01 | 1.03 | 1.0001 | 0.01 | 1.18 | 1.17 | 1.0027 | 0.46 |
Total
| 1.90 | 9.56 |