Introduction
Reference | Type of study | Polymorphism | Study size | Population | Main effect on risk | Other results |
---|---|---|---|---|---|---|
Zuppan [1] | Linkage analysis | c.454-351A→G | 11 families | American late-onset familial cases | N/A | Nothing overall, linkage in one family |
Hill [46] | Tumor and normal samples | c.454-397C→T | 188 tumors, 53 reference samples | Not specified | N/A | c.454-397C→T C allele associated with ER- |
Parl [47] | Cases only | c.454-397C→T, c.454-351A→G | 59 cases | 56 'American-white', 3 African-American, 33–87 years | N/A | c.454-397C→T TT were younger at diagnosis (more often poorly differentiated) |
Yaich [13] | Cases only (case-control) | c.454-397C→T | 257/140 | American pre- and postmenopausal | None | c.454-397C→T TT were younger at diagnosis (slightly more often ER-) |
Andersen [41] | Case-control | c.454-397C→T | 360/672 | Norwegian Caucasian, pre- and postmenopausal (27–94 years) | c.454-351A→G: increased risk with G allele | c.454-351A→G G were older at diagnosis, P = 0.25 |
c.454-351A→G | c.454-397C→T: None | c.454-397C→T T more often PR- | ||||
Roodi [11] | Cases only | c.975C→G, c.729C→T | 118 ER+, 70 ER | American | N/A | c.975C→G G associated with family history of breast cancer, P = 0.0005 |
Iwase [43] | Cases only (case-control) | c.975C→G | 13 ER/PR+, 57/30 | British | Increased risk with c.975C→G G, P = 0.057 | |
Southey [49] | Case-control | c.975C→G | 388/294 | Australian early-onset (<40 years) | None | c.975C→G GG v. CC, OR 1.59 (95% CI 0.7–3.6) |
Schubert [48] | Familial cases, case-control | c.975C→G, c.729C→T | 31+139 familial, 105/151 | Caucasian-American and African-American | c.975C→G: No increased risk for familial disease | 28% G in relatives with breast cancer and 24% in unaffected relatives, P = 0.18 |
Curran [30] | Cross-sectional association | c.975C→G | 125/125 | Caucasian-Australian | None | 83% c.975C→G C in cases v. 77% in controls, P = 0.14 |
Vasconcelos [44] | Case-control | c.975C→G | 70/69 | Portuguese | Increased risk with c.975C→G G or GG, OR 2.3 (1.10–5.1) | Fewer lymph node metastases with c.975C→G G or GG, P = 0.038 |
Kang [57] | Case-control | c.975C→G | 110/45 | Korean | None | More often ER+, PR+ and p53 – with c.975C→G G allele |
Comings [50] | Case-control | c.454-351A→G | 67/145 | Mixed American | Did not contribute to breast cancer variance in a multi-gene model | |
Shin [42] | Case-control | c.454-397C→T, c.454-351A→G | 205/205 | Korean | Decreased risk with c.454-351A→G A allele 0.4 (0.3–0.6) | Association stronger among postmenopausal |
Cai [45] | Case-control | c.454-397C→T, c.454-351A→G | 1069/1166 | Shanghai Chinese | Increased risk with c.454-397C→T, TC OR 1.3 (1.0–1.7) and CC OR 1.4 (1.1–1.8) |
Methods
Parent study
Selection of present study population
Collection of biological samples
Genetic analyses
SNPs and microsatellite markers
Minisequencing assay with fluorescence polarisation detection
Molecular Beacon assay
Solid-phase minisequencing assay
Microsatellite assay
Statistical methods
Results
General
Association with breast cancer
Single loci
Genotypea
| 00 | 01 | 11 |
P
HWE
c
| ||||||
---|---|---|---|---|---|---|---|---|---|---|
Polymorphism | Cases/Controls | ORb
| 95% CI | Cases/Controls | ORb
| 95% CI | Cases/Controls | ORb
| 95% CI | |
Promoter TA
n
| ||||||||||
Ductal | 369/445 | 1 | Ref | 494/593 | 1.01 | 0.84–1.21 | 230/312 | 0.87 | 0.70–1.09 | <0.001, <0.0001d
|
Lobular | 52/445 | 1 | Ref | 81/593 | 1.30 | 0.88–1.91 | 33/212 | 0.92 | 0.57–1.49 | |
Intron 1 c.454-397C→T | ||||||||||
Ductal | 347/384 | 1 | Ref | 542/651 | 0.93 | 0.77–1.12 | 229/313 | 0.80 | 0.64–1.01 | 0.32 |
Lobular | 43/384 | 1 | Ref | 92/651 | 1.42 | 0.95–2.11 | 39/313 | 1.18 | 0.73–1.90 | |
Intron 1 c.454-351A→G | ||||||||||
Ductal | 522/577 | 1 | Ref | 471/610 | 0.86 | 0.72–1.02 | 124/161 | 0.86 | 0.66–1.12 | 0.88 |
Lobular | 66/577 | 1 | Ref | 89/610 | 1.36 | 0.96–1.92 | 19/161 | 1.05 | 0.60–1.84 | |
Exon 3 c.729C→T | ||||||||||
Ductal | 1037/1253 | 1 | Ref | 84/93 | 1.07 | 0.78–1.45 | 1/3 | 0.41 | 0.04–4.00 | 0.20 |
Lobular | 164/1253 | 1 | Ref | 10/93 | 0.92 | 0.46–1.83 | 0/3 | - | - | |
Exon 4 c.975C→G | ||||||||||
Ductal | 722/805 | 1 | Ref | 346/477 | 0.81 | 0.68–0.96 | 54/67 | 0.93 | 0.64–1.35 | 0.87 |
Lobular | 106/805 | 1 | Ref | 59/477 | 0.94 | 0.66–1.34 | 9/67 | 1.00 | 0.48–2.10 |
Haplotypes
|D| | ||||||
---|---|---|---|---|---|---|
r
2
| TA
n
a
| c.454-397C→T | c.454-351A→G | c.729C→T | c.975C→G | |
TA
n
a
| - | 0.784 | 0.727 | 0.122 | 0.161 | |
c.454-397C→T | 0.569 | - | 0.998 | 0.895 | 0.329 | |
c.454-351A→G | 0.337 | 0.587 | - | 0.872 | 0.242 | |
c.729C→T | 0.001 | 0.028 | 0.016 | - | 0.848 | |
c.975C→G | 0.006 | 0.029 | 0.009 | 0.097 | - |
Locus | Proportion | |||||
---|---|---|---|---|---|---|
c.454-397C→T | c.454-351A→G | c.729C→T | c.975C→G | Controls (n = 1511) | Ductal cases (n = 1148) | Lobular cases (n = 184) |
T | A | C | C | 0.369 | 0.404 | 0.373 |
C | G | C | C | 0.285 | 0.267 | 0.276 |
C | A | C | C | 0.114 | 0.117 | 0.125 |
T | A | C | G | 0.123 | 0.117 | 0.123 |
C | G | C | G | 0.058 | 0.049 | 0.076 |
T | A | T | G | 0.032 | 0.027 | 0.021 |
Proportion accounted for by the above most common haplotypes: | 0.981 | 0.981 | 0.994 |
SNP/haplotype tested
| Unadjusted | Adjusted for multiple testing | dfa
| |
---|---|---|---|---|
Control v. ductal | Control v. lobular | Control v. ductal | ||
Single loci | ||||
c.454-397C→T | 0.154 | 0.458 | 0.157 | 2 |
c.454-351A→G | 0.128 | 0.292 | 0.235 | 2 |
c.729C→T | 0.524 | 0.440 | -b
| 2 |
c.975C→G | 0.037 | 0.845 | 0.106 | 2 |
Two-locus haplotypes | ||||
c.454-397C→T and c.454-351A→G | 0.152 | 0.918 | 0.219 | 3 |
c.454-397C→T and c.975C→G | 0.019 | 0.921 | 0.071 | 3 |
c.454-351A→G and c.975C→G | 0.022 | 0.930 | 0.077 | 3 |
Three-locus haplotype | ||||
c.454-397C→T and c.454-351A→G and c.975C→G | 0.097 | 0.995 | 0.178 | 7 |
Factor | Number, cases/controls | c.454-351A→G c.975C→G AC haplotype | c.454-397C→T c.975C→G TC haplotype | ||
---|---|---|---|---|---|
Haplotype proportion, cases/controls | OR (95% CI)a, 1 v. 0 copiesb
| Haplotype proportion, cases/controls | OR (95% CI)a, 1 v. 0 copiesb
| ||
All ductal cancer cases | 1148/1511 | 0.531/0.484 | 1.19 (1.06–1.33) | 0.412/0.373 | 1.19 (1.06–1.34) |
BMI | |||||
<25 | 549/761 | 0.525/0.517 | 1.04 (0.89–1.23) | 0.404/0.388 | 1.08 (0.91–1.27) |
25-<28 | 299/429 | 0.531/0.458 | 1.32 (1.06–1.64) | 0.391/0.348 | 1.21 (0.97–1.51) |
≥ 28 | 300/321 | 0.541/0.456 | 1.41 (1.12–1.77) | 0.449/0.357 | 1.48 (1.17–1.88) |
Parity | |||||
0 | 158/134 | 0.495/0.472 | 1.14 (0.82–1.60) | 0.399/0.388 | 1.11 (0.80–1.54) |
1 | 248/258 | 0.535/0.439 | 1.43 (1.10–1.84) | 0.422/0.349 | 1.35 (1.04–1.74) |
2+ | 706/1043 | 0.535/0.496 | 1.17 (1.01–1.34) | 0.413/0.377 | 1.17 (1.02–1.35) |
Menopausal hormone treatment | |||||
<2 years | 861/1169 | 0.533/0.482 | 1.23 (1.08–1.40) | 0.416/0.374 | 1.21 (1.06–1.38) |
≥ 2 years | 251/266 | 0.515/0.490 | 1.08 (0.84–1.40) | 0.391/0.369 | 1.08 (0.84–1.40) |
Family history | |||||
No | 935/1246 | 0.528/0.486 | 1.18 (1.04–1.33) | 0.413/0.368 | 1.21 (1.07–1.30) |
Yes | 183/128 | 0.548/0.505 | 1.17 (0.84–1.63) | 0.403/0.425 | 0.93 (0.67–1.30) |
Age at menopause | |||||
≤ 49 years | 324/506 | 0.555/0.496 | 1.25 (1.02–1.54) | 0.431/0.385 | 1.25 (1.01–1.54) |
49.5–51.5 years | 445/503 | 0.511/0.470 | 1.19 (0.98–1.43) | 0.397/0.356 | 1.19 (0.98–1.45) |
≥ 52 years | 372/489 | 0.534/0.494 | 1.18 (0.97–1.44) | 0.411/0.372 | 1.17 (0.96–1.44) |