Introduction
Methods
Breast cancer patient datasets
Assessment of tumor genomic DNA copy number changes
Determining subtype-specific CNAs
Supplemental methods
Results
Identifying subtype-specific regions of copy number aberration
UNC-NW | All (n = 180) | ||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Basal (n = 40) | Claudin (n = 15) | Her2 (n = 21) | LumA (n = 52) | LumB (n = 40) | Normal-like (n = 12) |
P-Valuea
| No. | % | |||||||
No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | ||||
(a) Deletions | |||||||||||||||
No 5q Genes Lost | 13 | 32.5 | 11 | 73.3 | 11 | 52.4 | 42 | 80.8 | 32 | 80.0 | 10 | 83.3 | <0.001 | 119 | 66.1 |
5q13.2 (RAD17) | 5 | 12.5 | 1 | 6.7 | 1 | 4.8 | 4 | 7.7 | 2 | 5.0 | 1 | 8.3 | <0.001 | 14 | 7.8 |
5q31.1 (RAD50) | 1 | 2.5 | 0 | 0.0 | 1 | 4.8 | 0 | 0.0 | 2 | 5.0 | 0 | 0.0 | <0.001 | 4 | 2.2 |
5q35.2 (RAP80) | 1 | 2.5 | 1 | 6.7 | 0 | 0.0 | 2 | 3.8 | 2 | 5.0 | 0 | 0.0 | 0.001 | 6 | 3.3 |
RAD17/RAD50 | 5 | 12.5 | 2 | 13.3 | 3 | 14.3 | 2 | 3.8 | 0 | 0.0 | 0 | 0.0 | <0.001 | 12 | 6.7 |
RAD17/RAP80 | 1 | 2.5 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | 2.5 | 1 | 8.3 | <0.001 | 3 | 1.7 |
RAD50/RAP80 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | 1.9 | 1 | 2.5 | 0 | 0.0 | <0.001 | 2 | 1.1 |
RAD17/RAD50/RAP80 | 14 | 35.0 | 0 | 0.0 | 5 | 23.8 | 1 | 1.9 | 0 | 0.0 | 0 | 0.0 | <0.001 | 20 | 11.1 |
10q23.31 (PTEN) | 9 | 22.5 | 1 | 6.7 | 5 | 23.8 | 12 | 23.1 | 12 | 30.0 | 2 | 16.7 | 0.6 | 41 | 22.8 |
13q14.2 (RB1) | 18 | 45.0 | 3 | 20.0 | 7 | 33.3 | 11 | 21.1 | 33 | 82.5 | 4 | 33.3 | <0.001 | 76 | 42.2 |
17p13.1 (TP53) | 20 | 50.0 | 6 | 40.0 | 12 | 57.1 | 18 | 34.6 | 20 | 50.0 | 4 | 33.3 | 0.4 | 80 | 44.4 |
17q21 (BRCA1) | 17 | 42.5 | 2 | 12.5 | 11 | 52.4 | 11 | 21.2 | 7 | 17.5 | 3 | 25.0 | 0.01 | 51 | 28.3 |
13q12.1 (BRCA2) | 12 | 30.0 | 3 | 18.8 | 5 | 23.8 | 8 | 15.4 | 21 | 52.5 | 3 | 25.0 | 0.01 | 52 | 28.9 |
4q31.21 (INPP4B) | 16 | 40.0 | 1 | 11.1 | 1 | 4.8 | 6 | 11.5 | 4 | 10.0 | 1 | 8.3 | 0.002 | 29 | 16.1 |
(b) Amplifications | |||||||||||||||
17q12 (ERBB2) | 9 | 22.5 | 2 | 13.3 | 12 | 57.1 | 9 | 17.3 | 15 | 37.5 | 2 | 16.7 | 0.007 | 49 | 27.2 |
12p12.1 (KRAS) | 14 | 35.0 | 4 | 26.7 | 5 | 23.8 | 9 | 17.3 | 9 | 22.5 | 2 | 16.7 | 0.5 | 43 | 23.9 |
12q15 (MDM2) | 6 | 15.0 | 1 | 6.7 | 4 | 19.0 | 12 | 23.1 | 18 | 45.0 | 1 | 8.3 | 0.01 | 42 | 23.3 |
8q24.21 (MYC) | 26 | 65.0 | 7 | 46.7 | 10 | 47.6 | 18 | 34.6 | 29 | 72.5 | 3 | 25.0 | 0.002 | 93 | 51.7 |
10p11.23 (MAP3K8) | 16 | 40.0 | 1 | 6.7 | 6 | 28.6 | 3 | 5.8 | 3 | 7.5 | 2 | 16.7 | <0.001 | 31 | 17.2 |
10p11.22 (ZEB1) | 16 | 40.0 | 1 | 6.7 | 5 | 23.8 | 3 | 5.8 | 3 | 7.5 | 2 | 16.7 | <0.001 | 30 | 16.7 |
10p13 (FAM107B) | 20 | 50.0 | 1 | 6.7 | 5 | 23.8 | 4 | 7.7 | 6 | 15.0 | 1 | 8.3 | <0.001 | 37 | 20.6 |
(c) | |||||||||||||||
Average # of Gains | 3943 | 1543 | 2970 | 2847 | 3885 | 2326 | 3192 | ||||||||
Average # of Losses | 4854 | 1906 | 3347 | 2560 | 4634 | 2891 | 3590 | ||||||||
Total # of Aberrations | 8797 | 3450 | 6317 | 5408 | 8519 | 5218 | 6782 | ||||||||
Average # of Segments | 194 | 143 | 223 | 150 | 222 | 139 | 183 | ||||||||
Segment Length (kb | 14988 | 20421 | 13068 | 19424 | 13113 | 21062 | 15923 | ||||||||
(d) | |||||||||||||||
% Tumor Cellularity (ASCAT) | 52.5 | 38.4 | 38.2 | 53.0 | 50.2 | 38.1 | 48.4 | ||||||||
% Tumor Purity (genoCNA) | 75.0 | 78.0 | 79.5 | 68.0 | 68.0 | 70.0 | 71.0 | ||||||||
(e) Co-occurrence of 5qb loss with additional gene loss | |||||||||||||||
N
| No. | % |
P-Valuec
| ||||||||||||
10q23.31 (PTEN) Loss | 32 | 14 | 43.8 | <0.001 | |||||||||||
13q14.2 (RB1) Loss | 32 | 26 | 81.3 | <0.001 | |||||||||||
17q21 (BRCA1) Loss | 32 | 17 | 53.1 | <0.001 | |||||||||||
10p Amplicon | 32 | 15 | 46.9 | <0.001 | |||||||||||
17p13.1 (TP53) Loss | 32 | 19 | 59.4 | 0.08 | |||||||||||
4q31.21 (INPP4B) Loss | 32 | 16 | 50.0 | <0.001 |
Jonsson | All (n = 356) | ||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Basal (n = 61) | Claudin (n = 43) | Her2 (n = 46) | LumA (n = 117) | LumB (n = 55) | Normal-like (n = 34) |
P-Valuea
| No. | % | |||||||
No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | ||||
(a) Deletions | |||||||||||||||
No 5q Genes Lost | 15 | 24.6 | 29 | 67.4 | 28 | 58.3 | 107 | 90.7 | 44 | 80.0 | 26 | 76.5 | <0.001 | 249 | 69.9 |
5q13.2 (RAD17) | 9 | 14.8 | 4 | 9.3 | 3 | 6.3 | 3 | 2.5 | 5 | 9.1 | 3 | 8.8 | <0.001 | 27 | 7.6 |
5q31.1 (RAD50) | 4 | 6.6 | 0 | 0.0 | 2 | 4.2 | 3 | 2.5 | 3 | 5.5 | 1 | 2.9 | <0.001 | 13 | 3.7 |
5q35.2 (RAP80) | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 2 | 1.7 | 0 | 0.0 | 1 | 2.9 | <0.001 | 3 | 0.8 |
RAD17/RAD50 | 16 | 26.2 | 2 | 4.7 | 12 | 25.0 | 2 | 1.7 | 2 | 3.6 | 2 | 5.9 | <0.001 | 36 | 10.1 |
RAD17/RAP80 | 3 | 4.9 | 1 | 2.3 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | <0.001 | 4 | 1.1 |
RAD50/RAP80 | 2 | 3.3 | 0 | 0.0 | 1 | 2.1 | 0 | 0.0 | 1 | 1.8 | 0 | 0.0 | <0.001 | 4 | 1.1 |
RAD17/RAD50/RAP80 | 12 | 19.7 | 7 | 16.3 | 2 | 4.2 | 1 | 0.8 | 0 | 0.0 | 1 | 2.9 | <0.001 | 23 | 6.5 |
10q23.31 (PTEN) | 21 | 34.4 | 10 | 23.3 | 9 | 18.8 | 14 | 11.9 | 17 | 30.9 | 2 | 5.9 | <0.001 | 73 | 20.5 |
13q14.2 (RB1) | 33 | 54.1 | 16 | 37.2 | 13 | 27.1 | 32 | 27.1 | 31 | 56.4 | 8 | 23.5 | <0.001 | 133 | 37.4 |
17p13.1 (TP53) | 21 | 34.4 | 6 | 14.0 | 17 | 35.4 | 33 | 28,0 | 19 | 34.5 | 11 | 32.4 | 0.2 | 107 | 30.1 |
17q21 (BRCA1) | 19 | 31.1 | 6 | 14.0 | 7 | 15.2 | 12 | 10.3 | 5 | 9.1 | 5 | 14.7 | <0.001 | 54 | 15.2 |
13q12.1 (BRCA2) | 22 | 36.1 | 13 | 30.2 | 12 | 26.1 | 26 | 22.2 | 30 | 54.5 | 7 | 20.6 | <0.001 | 110 | 30.9 |
4q31.21 (INPP4B) | 29 | 47.5 | 14 | 32.6 | 16 | 34.8 | 13 | 11.1 | 11 | 20.0 | 2 | 5.9 | <0.001 | 85 | 23.9 |
(b) Amplifications | |||||||||||||||
17q12 (ERBB2) | 9 | 14.8 | 5 | 11.6 | 31 | 64.6 | 23 | 19.5 | 17 | 30.9 | 6 | 17.6 | <0.001 | 91 | 25.6 |
12p12.1 (KRAS) | 12 | 19.7 | 7 | 16.3 | 3 | 6.5 | 3 | 2.5 | 10 | 18.2 | 0 | 0.0 | <0.001 | 35 | 9.8 |
12q15 (MDM2) | 2 | 3.3 | 4 | 9.3 | 7 | 15.2 | 13 | 11.1 | 17 | 30.9 | 0 | 0.0 | <0.001 | 43 | 12.1 |
8q24.21 (MYC) | 42 | 68.9 | 19 | 44.2 | 22 | 47.8 | 48 | 41.0 | 44 | 80.0 | 14 | 41.2 | <0.001 | 189 | 53.1 |
10p11.23 (MAP3K8) | 16 | 26.2 | 8 | 18.6 | 7 | 14.6 | 6 | 5.1 | 8 | 14.5 | 1 | 2.9 | 0.001 | 46 | 12.9 |
10p11.22 (ZEB1) | 16 | 26.2 | 8 | 18.6 | 8 | 16.7 | 6 | 5.1 | 8 | 14.5 | 1 | 2.9 | <0.001 | 47 | 13.2 |
10p13 (FAM107B) | 29 | 47.5 | 10 | 23.3 | 6 | 12.5 | 6 | 5.1 | 11 | 20.0 | 3 | 8.8 | <0.001 | 65 | 18.3 |
c) | |||||||||||||||
Average # of Gains | 2853 | 2169 | 2481 | 1963 | 3281 | 1469 | 4675 | ||||||||
Average # of Losses | 5089 | 3171 | 3523 | 2430 | 3872 | 2395 | 6597 | ||||||||
Total # of Aberrations | 7942 | 5341 | 6003 | 4393 | 7153 | 3864 | 11272 | ||||||||
Average # of Segments | 167 | 130 | 134 | 97 | 129 | 93 | 122 | ||||||||
Segment Length (kb) | 16522 | 21289 | 20573 | 28542 | 21462 | 29841 | 22610 | ||||||||
(d) Co-occurrence of 5qb loss with additional gene loss | |||||||||||||||
N
| No. | % |
P-Valuec
| ||||||||||||
10q23.31 (PTEN) Loss | 67 | 28 | 41.8 | <0.001 | |||||||||||
13q14.2 (RB1) Loss | 67 | 39 | 58.2 | <0.001 | |||||||||||
17q21 (BRCA1) Loss | 67 | 24 | 35.8 | <0.001 | |||||||||||
10p Amplicon | 67 | 15 | 22.4 | 0.02 | |||||||||||
17p13.1 (TP53) Loss | 67 | 29 | 43.3 | 0.01 | |||||||||||
4q31.21 (INPP4B) Loss | 67 | 31 | 46.3 | <0.001 |
Jonsson subtypes | |||||||
---|---|---|---|---|---|---|---|
Amplifier | Luminal-complex | Mixed | 17q12 | Luminal-simple | Basal-complex | ||
PAM50+Claudin low subtypes | Basal | 7 | 4 | 4 | 3 | 1 | 42 |
LumA | 18 | 42 | 15 | 10 | 31 | 2 | |
Claudin | 11 | 4 | 8 | 4 | 3 | 13 | |
LumB | 11 | 36 | 3 | 2 | 1 | 2 | |
Her2 | 1 | 9 | 3 | 30 | 0 | 5 | |
Normal-like | 4 | 10 | 5 | 2 | 10 | 3 |
Increased genomic instability of tumors associated with loss of specific regions/genes
Average gain | Average loss | Average total | |
---|---|---|---|
Average amount of CNA by event and class in combined UNC/Norway dataset | |||
All samples mean (n = 180) | 3,192 | 3,590 | 6,783 |
All samples median (n = 180) | 2,790 | 3,230 | 6,560 |
RAD17 + RAD50 (n = 12) | 3,948 (P = 0.1) | 5,614 (P = 0.0004*) | 9,562 (P = 0.003*) |
RAD17 + RAD50 +/− RAP80 (n = 32) | 4,451 (P = 0.0002*) | 6,681 (P < 0.00001*) | 11,131 (P < 0.00001*) |
RAD17 + RAD50 + RAP80 (n = 20) | 4,752 (P = 0.0002*) | 7,320 (P < 0.00001*) | 12,073 (P < 0.00001*) |
Other (n = 148) | 2,920 | 2,922 | 5,842 |
10q23.31 (PTEN) loss (n = 31) | 4,202 (P = 0.009*) | 6,169 (P < 0.00001*) | 10,371 (P < 0.00001*) |
No 10q23.31 (PTEN) loss (n = 149) | 2,982 | 3,054 | 6,036 |
13q14.2 (RB1) loss (n = 66) | 4,127 (P = 0.00002*) | 5,638 (P < 0.00001*) | 9,765 (P < 0.00001*) |
No 13q14.2 (RB1) loss (n = 114) | 2,652 | 2,404 | 5,056 |
17p13.1 (TP53) loss (n = 80) | 3,900 (P = 0.00008*) | 4,8578 (P < .00001*) | 8,757 (P < 0.00001*) |
No 17p13.1 (TP53) loss (n = 100) | 2,627 | 2,576 | 5,203 |
10p Amplicon (n = 34) | 5,016 (P < 0.00001*) | 5,232 (P = 0.0002*) | 10,248 (P < 0.00001*) |
No 10p Amplicon (n = 146) | 2,768 | 3,208 | 5,975 |