Background
Methods
Study subjects for survival and pathology analyses
Non-carriers | p.I157T carriers | c.1100delC carriers |
p value (I157T/nc) |
p value (I157T/1100delC) |
p value (1100delC/nc) | ||
---|---|---|---|---|---|---|---|
ER | Negative | 4595 | 85 | 26 | 0.00046 | 0.61 | 0.0015 |
20.2 %
|
15.5 %
|
11.2 %
| |||||
Positive | 18,179 | 462 | 207 | ||||
79.8 %
|
84.5 %
|
88.8 %
| |||||
Missing | 3166 | 43 | 38 | ||||
12.2 %
|
7.3 %
|
14.0 %
| |||||
PR | Negative | 6397 | 147 | 44 | 0.0034 | 0.90 | 0.0045 |
32.7 %
|
28.5 %
|
23.3 %
| |||||
Positive | 13,173 | 368 | 145 | ||||
67.3 %
|
71.5 %
|
76.7 %
| |||||
Missing | 6370 | 75 | 82 | ||||
24.6 %
|
12.7 %
|
30.3 %
| |||||
Her2 | Negative | 8220 | 231 | 95 | 0.68 | 0.10 | 0.24 |
84.7 %
|
83.7 %
|
81.9 %
| |||||
Positive | 1483 | 45 | 21 | ||||
15.3 %
|
16.3 %
|
18.1 %
| |||||
Missing | 16,237 | 314 | 155 | ||||
62.6 %
|
53.2 %
|
57.2 %
| |||||
EGFR | Negative | 3841 | 122 | 62 | 0.21 | 0.26 | 0.034 |
89.6 %
|
90.4 %
|
96.9 %
| |||||
Positive | 448 | 13 | 2 | ||||
10.4 %
|
9.6 %
|
3.1 %
| |||||
Missing | 21,651 | 455 | 207 | ||||
83.5 %
|
77.1 %
|
76.4 %
| |||||
CK5/6 | Negative | 4734 | 143 | 80 | 0.30 | 0.29 | 0.19 |
87.9 %
|
88.3 %
|
92.0 %
| |||||
Positive | 652 | 19 | 7 | ||||
12.1 %
|
11.7 %
|
8.0 %
| |||||
Missing | 20,554 | 428 | 184 | ||||
79.2 %
|
72.5 %
|
67.9 %
| |||||
TP53 | Negative | 3755 | 144 | 88 | 0.00048 | 0.21 | 0.16 |
81.6 %
|
90.6 %
|
86.3 %
| |||||
Positive | 847 | 15 | 14 | ||||
18.4 %
|
9.4 %
|
13.7 %
| |||||
Missing | 21,338 | 431 | 169 | ||||
82.3 %
|
73.1 %
|
62.4 %
| |||||
Tumor size (ordinal) | <20 mm | 14,949 | 340 | 149 | 0.29 | 0.33 | 0.83 |
65.6 %
|
65.6 %
|
62.6 %
| |||||
20–50 mm | 6953 | 162 | 82 | ||||
30.5 %
|
31.3 %
|
34.5 %
| |||||
>50 mm | 876 | 16 | 7 | ||||
3.8 %
|
3.1 %
|
2.9 %
| |||||
Missing | 3162 | 72 | 33 | ||||
12.2 %
|
12.2 %
|
12.2 %
| |||||
Lymph node status | Negative | 13,144 | 320 | 125 | 0.94 | 0.91 | 0.64 |
62.0 %
|
60.4 %
|
57.6 %
| |||||
Positive | 8070 | 210 | 92 | ||||
38.0 %
|
39.6 %
|
42.4 %
| |||||
Missing | 4726 | 60 | 54 | ||||
18.2 %
|
10.2 %
|
19.9 %
| |||||
Grade (ordinal) | 1 | 4916 | 132 | 38 | 0.00023 | 0.0030 | 0.38 |
22.5 %
|
26.7 %
|
17.4 %
| |||||
2 | 10,817 | 266 | 127 | ||||
49.6 %
|
53.7 %
|
58.0 %
| |||||
3 | 6089 | 97 | 54 | ||||
27.9 %
|
19.6 %
|
24.7 %
| |||||
Missing | 4118 | 95 | 52 | ||||
15.9 %
|
16.1 %
|
19.2 %
| |||||
Histological type | Ductal | 14,133 | 273 | 193 | 0.0044*
| 0.0010#
| 0.67#
|
72.7 %
|
60.0 %
|
76.9 %
| |||||
Lobular | 2966 | 100 | 36 | ||||
15.3 %
|
22.0 %
|
14.3 %
| |||||
Mixed (ductal and lobular)
| 455 | 26 | 4 | ||||
2.5 %
|
6.0 %
|
1.7 %
| |||||
Tubular | 271 | 17 | 2 | ||||
1.5 % | 4.0 % |
0.7 %
| |||||
Medullary | 177 | 4 | 3 | ||||
1.0 %
|
0.9 %
|
1.7 %
| |||||
Mucinous | 213 | 9 | 3 | ||||
1.2 %
|
2.1 %
|
1.4 %
| |||||
Papillary | 55 | 1 | 1 | ||||
0.3 %
|
0.2 %
|
1.8 %
| |||||
Missing† | 7670 | 160 | 29 | ||||
29.6 %
|
27.1 %
|
10.7 %
| |||||
Subtype‡ | LumA (ER+, PR+, Her2-) | 5415 | 164 | 72 | 0.00089 | 0.46 | 0.0087 |
58.9 % | 63.6 % | 65.5 % | |||||
LumB (ER+, PR-, Her2- or ER+, Her2+) | 1939 | 62 | 30 | ||||
21.1 % | 24.0 % | 27.3 % | |||||
Basal (ER-, PR-, Her2-) | 1306 | 16 | 4 | ||||
14.2 % | 6.2 % | 3.6 % | |||||
Her2-positive (ER-, PR-, Her2+) | 536 | 16 | 4 | ||||
5.8 % | 6.2 % | 3.6 % | |||||
Missing | 16,744 | 332 | 161 | ||||
64.5 % | 56.3 % | 59.4 % | |||||
AGE cat (ordinal) | 50 or younger | 6932 | 162 | 101 | 0.99 | 0.0037 | 0.0029 |
27.0 %
|
27.8 %
|
37.3 %
| |||||
Older than 50 and not more than 70 | 16,083 | 344 | 151 | ||||
62.6 %
|
59.0 %
|
55.7 %
| |||||
Older than 70 | 2674 | 77 | 19 | ||||
10.4 %
|
13.2 %
|
7.0 %
| |||||
Missing | 251 | 7 | 0 | ||||
1.0 %
|
1.2 %
|
0.0 %
| |||||
AGE | Mean | 57.1 | 57.9 | 54.3 | 0.41 | 0.028 | 0.024 |
St.dev. | 10.8 | 11.1 | 11.0 | ||||
Total | 25,940 | 590 | 271 |
Genotyping
Pathology analysis
Survival analysis
Study subjects for gene expression analysis
Gene expression analysis
Results and discussion
Association of p.I157T with clinico-pathological markers
Breast cancer subtypes
Intrinsic subtype PAM50 | IHC subtype St Gallen 2013 criteria | Histological type | |
---|---|---|---|
HEL_045 | Normal | LumA | Lobular |
HEL_055 | LumB | LumB | Ductal |
HEL_086 | LumA | LumA | Lobular |
HEL_126 | LumA | Basal | Ductal |
HEL_128 | LumA | LumB | Ductal |
HEL_131 | Basal | Her2pos | In situ |
HEL_144 | Normal | LumB | Lobular |
HEL_150 | Basal | LumB | Ductal |
HEL_163 | LumB | LumB | Ductal |
HEL_174 | Normal | LumA | Lobular |
Patient survival
(a) All breast cancer patients | Univariate analysis | Adjusted analysis | ||||
I157T/nc | I157T/1100delC | 1100delc/nc | I157T/nc | I157T/1100delC | 1100delC/nc | |
Early death | 0.85 [0.68 - 1.07] | 0.74 [0.50 - 1.09] | 1.28 [1.00 - 1.64] | 0.80 [0.60 - 1.07] | 0.51 [0.29 - 0.90] | 1.32 [0.94 - 1.86] |
0.16
|
0.12
|
0.054
|
0.13
|
0.0190
|
0.11
| |
Breast cancer-specific death | 0.85 [0.60 - 1.20] | 0.64 [0.37 - 1.12] | 1.44 [1.04 - 2.00] | 0.93 [0.62 - 1.40] | 0.46 [0.21 - 1.03] | 1.25 [0.78 - 2.00] |
0.36
|
0.12
|
0.030
|
0.73
|
0.058
|
0.36
| |
Distant metastasis relapse | 1.04 [0.79 - 1.37] | 0.66 [0.38 - 1.14] | 1.38 [0.90 - 2.11] | 1.05 [0.75 - 1.47] | 0.62 [0.31 - 1.23] | 1.37 [0.83 - 2.26] |
0.79
|
0.13
|
0.14
|
0.76
|
0.17
|
0.22
| |
Locoregional relapse | 1.43 [0.92 - 2.23] | 0.81 [0.58 - 1.13] | 2.07 [1.16 - 3.69] | 1.62 [0.99 - 2.66] | 0.91 [0.33 - 2.52] | 1.26 [0.59 - 2.70] |
0.11
|
0.21
|
0.014
|
0.056
|
0.85
|
0.55
| |
Second breast cancer | 1.54 [0.85 - 2.78] | 0.69 [0.47 - 1.03] | 2.88 [1.68 - 4.98] | 2.03 [1.05 - 3.92] | 0.69 [0.42 - 1.13] | 3.62 [1.82 - 7.21] |
0.15
|
0.070
|
0.00015
|
0.035
|
0.14
|
0.00026
| |
(b) Patients with ER+ breast cancer | Univariate analysis | Adjusted analysis | ||||
I157T/nc | I157T/1100delC | 1100delc/nc | I157T/nc | I157T/1100delC | 1100delC/nc | |
Early death | 0.81 [0.61 - 1.07] | 0.62 [0.39 - 0.99] | 1.32 [0.98 - 1.78] | 0.77 [0.55 - 1.07] | 0.46 [0.25 - 0.85] | 1.52 [1.06 - 2.17] |
0.14
|
0.044
|
0.067
|
0.12
|
0.013
|
0.022
| |
Breast cancer-specific death | 0.80 [0.51 - 1.23] | 0.47 [0.23 - 0.96] | 1.46 [0.96 - 2.22] | 0.80 [0.49 - 1.32] | 0.33 [0.13 - 0.84] | 1.50 [0.92 - 2.45] |
0.30
|
0.038
|
0.074
|
0.39
|
0.019
|
0.10
| |
Distant metastasis relapse | 1.00 [0.71 - 1.40] | 0.55 [0.29 - 1.02] | 1.58 [0.99 - 2.54] | 1.03 [0.70 - 1.51] | 0.56 [0.26 -1.19] | 1.61 [0.94 - 2.77] |
0.98
|
0.057
|
0.056
|
0.88
|
0.13
|
0.083
| |
Locoregional relapse | 1.46 [0.86 - 2.47] | 0.77 [0.52 - 1.14] | 2.33 [1.19 - 4.57] | 1.58 [0.90 - 2.79] | 0.93 [0.29 - 2.98] | 1.08 [0.44 - 2.66] |
0.16
|
0.19
|
0.014
|
0.11
|
0.90
|
0.87
| |
Second breast cancer | 1.33 [0.64 - 2.75] | 0.58 [0.37 - 0.92] | 4.09 [2.31 - 7.26] | 1.81 [0.82 - 3.96] | 0.61 [0.36 - 1.04] | 4.39 [2.17 - 8.87] |
0.44
|
0.019
|
1.4E-06
|
0.14
|
0.067
|
3.8E-05
| |
(c) Patients with lobular breast cancer | Univariate analysis | |||||
I157T/nc | ||||||
Early death | 0.67 [0.39 - 1.15] | |||||
0.14
| ||||||
Breast cancer-specific death | 0.91 [0.46 - 1.80] | |||||
0.79
| ||||||
Distant metastasis relapse | 0.87 [0.48 - 1.57] | |||||
0.64
| ||||||
Locoregional relapse | 2.45 [0.95 - 6.34] | |||||
0.065
| ||||||
Second breast cancer | 1.92 [0.57 - 6.49] | |||||
0.29
|
P.I157T associated differentially expressed genes
Gene ID | Symbol | Description | logFC |
p value |
---|---|---|---|---|
11283 | CYP4F8 | Cytochrome P450, family 4, subfamily F, polypeptide 8 | 1.10 | 0.00026 |
1289 | COL5A1 | Collagen, type V, alpha 1 | 1.24 | 0.00049 |
1292 | COL6A2 | Collagen, type VI, alpha 2 | 0.90 | 0.00056 |
56265 | CPXM1 | Carboxypeptidase X (M14 family), member 1 | 1.04 | 0.00063 |
1277 | COL1A1 | Collagen, type I, alpha 1 | 1.25 | 0.0011 |
23452 | ANGPTL2 | Angiopoietin-like 2 | 0.85 | 0.0020 |
5118 | PCOLCE | Procollagen C-endopeptidase enhancer | 0.90 | 0.0021 |
284297 | SSC5D | Scavenger receptor cysteine rich family, 5 domains | 0.84 | 0.0025 |
25903 | OLFML2B | Olfactomedin-like 2B | 0.88 | 0.0026 |
27239 | GPR162 | G protein-coupled receptor 162 | 0.73 | 0.0026 |
5654 | HTRA1 | HtrA serine peptidase 1 | 0.96 | 0.0027 |
9315 | NREP | Neuronal regeneration-related protein | 0.78 | 0.0028 |
1278 | COL1A2 | Collagen, type I, alpha 2 | 1.02 | 0.0046 |
8510 | MMP23B | Matrix metallopeptidase 23B | 0.73 | 0.0055 |
114902 | C1QTNF5 | C1q and tumor necrosis factor-related protein 5 | 0.77 | 0.0057 |
6678 | SPARC | Secreted protein, acidic, cysteine-rich (osteonectin) | 0.88 | 0.0073 |
9622 | KLK4 | Kallikrein-related peptidase 4 | 1.03 | 0.0082 |
1291 | COL6A1 | Collagen, type VI, alpha 1 | 0.92 | 0.0084 |
1307 | COL16A1 | Collagen, type XVI, alpha 1 | 0.73 | 0.0090 |
1290 | COL5A2 | Collagen, type V, alpha 2 | 0.93 | 0.0095 |
7070 | THY1 | Thy-1 cell surface antigen | 0.88 | 0.0098 |