Background
Methods
Patients and samples
Microdissection and DNA extraction
Copy number profiling
Whole-exome sequencing
Statistical analysis
Results
Case | Age (years) | Lesion pairs | Same quadrant? | Size of invasive lesion (cm) | Number of mutations (shared/total)a
| Clonality test p values | Diagnosis | Shared mutationsb
| |||
---|---|---|---|---|---|---|---|---|---|---|---|
Tumor 1 | Tumor 2 | Mutationsa
| Copy number arraysc
|
CDH1
|
PIK3CA
d
| ||||||
LCIS-ILC | |||||||||||
13 | 50 | LCIS1-ILC | No | 1.6 | 16/3300 | 16/56 | <0.001 | 0.002 | Clonal | – | – |
24 | 57 | LCIS1-ILC | Yes | 2.1 | 25/36 | 25/34 | <0.001 | <0.001 | Clonal | √ | √ |
LCIS2-ILC | No | 2/29 | 2/34 | <0.001 | Clonal | – | – | ||||
28 | 60 | LCIS-ILC | Yes | 0.12 | 0.93 | Independent | |||||
31 | 69 | LCIS-ILC | Yes | 1.5 | 0.31 | Independent | |||||
33 | 65 | LCIS-ILC | Yes | 2.1 | 66/81 | 66/1015 | <0.001 | <0.001 | Clonal | – | – |
35 | 72 | LCIS-ILC | Yes | 4.7 | <0.001 | Clonal | |||||
38 | 73 | LCIS2-ILC | Yes | Missing | 23/527 | 23/615 | <0.001 | 0.54 | Clonal | – | – |
42 | 52 | LCIS-ILC | Yes | 2.3 | 56/119 | 56/109 | <0.001 | Clonal | √ | √ | |
LCIS2-ILC | Yes | 0.01 | Equivocal | ||||||||
43 | 41 | LCIS-ILC | Yes | 1.9 | 0.001 | Clonal | |||||
45 | 55 | LCIS-ILC | Yes | 12.2 | <0.001 | Clonal | |||||
46 | 51 | LCIS-ILC | Yes | 4.5 | 0/46 | 0/15 | 1.0 | Independent | |||
LCIS3-ILC | No | 0/37 | 0/15 | 1.0 | Independent | ||||||
47 | 51 | LCIS1-ILC | No | 1.5 | 7/29 | 7/25 | <0.001 | <0.001 | Clonal | √ | – |
LCIS2-ILC | No | 7/22 | 7/25 | <0.001 | 0.42 | Clonal | √ | – | |||
48 | 37 | LCIS1-ILC | Yes | 6.0 | 20/33 | 20/40 | <0.001 | <0.001 | Clonal | √ | – |
LCIS2-ILC | No | 1/22 | 1/40 | 0.03 | 0.10 | Equivocal | – | – | |||
52 | 50 | LCIS-ILC | Yes | 1.9 | 0.005 | Clonal | |||||
LCIS2-ILC | Yes | 0.05 | Independent | ||||||||
55 | 72 | LCIS-ILC | Yes | 1.3 | 6/31 | 6/36 | <0.001 | 0.002 | Clonal | – | √ |
68 | 48 | LCIS1-ILC | No | 1.4 | 0/44 | 0/33 | 1.0 | 0.58 | Independent | – | – |
69 | 56 | LCIS-ILC | Yes | 3.0 | 18/56 | 18/31 | <0.001 | 0.001 | Clonal | √ | √ |
73 | 44 | LCIS1-ILC | Yes | 0.5 | 0/26 | 0/42 | 1.0 | Independent | |||
75 | 58 | LCIS1-ILC | Yes | 3.5 | 15/46 | 15/39 | <0.001 | Clonal | √ | √ | |
LCIS-IDC | |||||||||||
26 | 54 | LCIS-IDC | No | 1.8 | 0/29 | 0/32 | 1.0 | Independent | |||
47 | 51 | LCIS1-IDC | No | 1.0 | 1/29 | 1/30 | 0.02 | 0.35 | Equivocal | – | – |
LCIS2-IDC | No | 1/22 | 1/30 | 0.03 | 0.48 | Equivocal | – | – | |||
53 | 41 | LCIS1-IDC | Yes | 3.7 | 2/20 | 2/23 | <0.001 | 0.40 | Clonal | – | – |
LCIS2-IDC | Yes | 1/15 | 1/23 | 0.02 | 0.62 | Equivocal | – | – | |||
74 | 61 | LCIS1-IDC | Yes | 0.75 | 0/32 | 0/34 | 1.0 | 0.50 | Independent | – | – |
LCIS2-IDC | No | 0/37 | 0/34 | 1.0 | 0.73 | Independent | – | – | |||
LCIS3-IDC | No | 3/42 | 3/34 | <0.001 | Clonal | – | – | ||||
75 | 58 | LCIS2-IDC | Yes | 1.8 | 0/22 | 0/29 | 1.0 | Independent | – | – | |
LCIS-LCIS | |||||||||||
4 | 44 | LCIS1-LCIS2 | No | N/A | 11/46 | 11/30 | <0.001 | Clonal | – | – | |
5 | 67 | LCIS1-LCIS2 | No | N/A | 0.85 | Independent | |||||
8 | 47 | LCIS1-LCIS2 | No | N/A | 9/34 | 9/25 | <0.001 | Clonal | – | – | |
17 | 48 | LCIS1-LCIS2 | No | N/A | 13/26 | 13/27 | <0.001 | Clonal | √ | – | |
19 | 43 | LCIS1-LCIS2 | No | N/A | 12/24 | 12/185 | <0.001 | Clonal | – | – | |
24 | 57 | LCIS1-LCIS2 | No | N/A | 0/36 | 0/28 | 1.0 | Independent | – | – | |
38 | 73 | LCIS1-LCIS2 | Yes | N/A | 23/174 | 23/527 | <0.001 | Clonal | – | – | |
46 | 51 | LCIS-LCIS3 | No | N/A | 5/46 | 5/37 | <0.001 | Clonal | – | – | |
47 | 51 | LCIS1-LCIS2 | Yes | N/A | 8/29 | 8/22 | <0.001 | 0.59 | Clonal | √ | – |
48 | 37 | LCIS1-LCIS2 | No | N/A | 0/33 | 0/22 | 1.0 | 0.59 | Independent | – | – |
52 | 50 | LCIS-LCIS2 | Yes | N/A | 13/28 | 13/34 | <0.001 | 0.02 | Clonal | √ | √ |
53 | 41 | LCIS1-LCIS2 | Yes | N/A | 6/21 | 6/17 | <0.001 | 0.005 | Clonal | √ | – |
59 | 47 | LCIS-LCIS2 | No | N/A | 12/31 | 12/26 | <0.001 | 0.10 | Clonal | √ | – |
73 | 44 | LCIS3-LCIS4 | No | N/A | 0/14 | 0/11 | 1.0 | Independent | |||
74 | 61 | LCIS1-LCIS2 | No | N/A | 0/32 | 0/37 | 1.0 | 0.02 | Independent | – | – |
LCIS1-LCIS3 | No | N/A | 1/34 | 1/43 | 0.03 | Equivocal | – | – | |||
LCIS2-LCIS3 | No | N/A | 24/37 | 24/42 | <0.001 | Clonal | √ | – | |||
LCIS4-LCIS5 | No | N/A | 14/41 | 14/47 | <0.001 | Clonal | – | – | |||
LCIS-DCIS | |||||||||||
04 | 44 | LCIS1-DCIS1 | Yes | N/A | 15/46 | 15/703 | <0.001 | <0.001 | Clonal | – | – |
LCIS2-DCIS1 | No | N/A | 10/30 | 10/703 | <0.001 | Clonal | – | – | |||
LCIS1-DCIS2 | No | N/A | 13/46 | 13/24 | <0.001 | <0.001 | Clonal | – | – | ||
LCIS2-DCIS2 | Yes | N/A | 8/30 | 8/24 | <0.001 | Clonal | – | – | |||
06 | 57 | LCIS-DCIS | Yes | N/A | 6/50 | 6/75 | <0.001 | 0.81 | Clonal | – | – |
16 | 62 | LCIS-DCIS | No | N/A | 0/92 | 0/57 | 1.0 | Independent | – | – | |
26 | 54 | LCIS-DCIS | No | N/A | 0/29 | 0/34 | 1.0 | 0.14 | Independent | – | – |
47 | 51 | LCIS1-DCIS | Yes | N/A | 3/29 | 3/23 | <0.001 | 0.71 | Clonal | – | – |
LCIS2-DCIS | Yes | N/A | 0/22 | 0/23 | 1.0 | 0.03 | Independent | – | – | ||
59 | 47 | LCIS-DCIS | Yes | N/A | 6/31 | 6/31 | <0.001 | 0.74 | Clonal | – | – |
LCIS2-DCIS | No | N/A | 2/26 | 2/31 | 0.003 | 0.67 | Clonal | – | √ | ||
68 | 48 | LCIS1-DCIS | Yes | N/A | 8/44 | 8/33 | <0.001 | 0.03 | Clonal | – | – |
75 | 58 | LCIS2-DCIS | Yes | N/A | 0/22 | 0/38 | 1.0 | Independent | – | – |
Clonal relatedness of LCIS and invasive breast cancers
Clonal relatedness of distinct in situ lesions
Further observations from exome profiling
Gene | Mutations per geneb (20 cases) | Percent functional mutationsc
| |||||||
---|---|---|---|---|---|---|---|---|---|
Mutations | Casesd
| Clonal | Private | Percent clonal | Clonal | Private | |||
CDH1
| 24 | 16 | 11 | 13 | 54 % | 11/11 | 100 % | 13/13 | 100 % |
PIK3CA
| 13 | 11 | 9 | 4 | 9/9e
| 4/4 | |||
SPRR3
| 10 | 9 | 1 | 9 | 30 % | 1/1 | 55 % | 1/9 | 70 % |
CBFB
| 10 | 8 | 7 | 3 | 6/6 | 3/3 | |||
GATA3
| 9 | 6 | 2 | 7 | 2/2 | 6/7 | |||
NBPF1
| 8 | 8 | 2 | 6 | 2/2 | 4/6 | |||
MUC12
| 7 | 5 | 1 | 6 | 0/1 | 4/6 | |||
KMT2C
| 6 | 6 | 1 | 5 | 1/1 | 4/5 | |||
MUC4
| 6 | 5 | 2 | 4 | 0/2 | 3/4 | |||
TCEAL3
| 6 | 4 | 5 | 1 | 0/5 | 0/1 | |||
MAP3K1
| 6 | 4 | 3 | 3 | 3/3 | 3/3 | |||
BCLAF1
| 5 | 5 | 0 | 5 | 0/5 | 5/5 | |||
HMCN1
| 5 | 5 | 0 | 5 | 0/0 | 3/5 | |||
TMPRSS13
| 5 | 4 | 1 | 4 | 1/1 | 4/4 | |||
REXO1L1
| 4 | 4 | 0 | 4 | 13 % | 0/0 | 75 % | 0/4 | 79 % |
TDG
| 4 | 4 | 0 | 4 | 0/0 | 3/4 | |||
DDX11
| 4 | 4 | 1 | 3 | 1/1 | 2/3 | |||
ABCC5
| 4 | 4 | 0 | 4 | 0/0 | 3/4 | |||
MACF1
| 4 | 4 | 0 | 4 | 0/0 | 4/4 | |||
AGGF1
| 4 | 4 | 1 | 3 | 1/1 | 3/3 | |||
OR13C2
| 4 | 2 | 0 | 4 | 0/0 | 4/4 | |||
NASP
| 4 | 2 | 0 | 4 | 0/0 | 4/4 | |||
SERPINA3
| 4 | 2 | 0 | 4 | 0/0 | 4/4 | |||
28 genes | 3 | 3 | 14 | 70 | 10/14 | 50/70 | |||
159 genes | 2 | 2 | 69 | 249 | 16 % | 50/69 | 72 % | 164/249 | 66 % |
1477 genes | 1 | 1 | 224 | 1253 | 158/224 | 71 % | 854/1253 | 68 % |