Introduction
Materials and methods
Study process
Direct sequencing for mutation detection of BRCA1 and BRCA2, and nomenclature
Multiplex ligation-dependent probe amplification
Risk factors and statistical analysis
Results
Mutational status according to subjects’ characteristics
Risk category | Total |
BRCA1 mutation |
BRCA2 mutation |
BRCA1/2 mutation |
---|---|---|---|---|
N (%d) |
N (%e) |
N (%e) |
N (%e) | |
Family history
| ||||
Breast cancer family only (without ovarian cancer)§
| 303 (63.4) | 14 (4.6) | 29 (9.6) | 43 (14.2) |
1 breast cancer family | 253 (52.9) | 11 (4.4) | 17 (6.7) | 28 (11.1) |
2 ≤breast cancer families*,§
| 50 (10.5) | 3 (6.0) | 12 (24.0) | 15 (30.0) |
Breast cancer families in 1st degree relativesb
| 217 (45.4) | 13 (6.0) | 20 (9.2) | 33 (15.2) |
Breast cancer families in second/third degree relativesb,§
| 86 (18.0) | 1 (1.2) | 9 (10.5) | 10 (11.6) |
Ovarian cancer familyb
| ||||
Without breast cancer§
| 29 (6.1) | 6 (20.7) | 0 (0.0) | 6 (20.7) |
With breast cancer* | 13 (2.7) | 4 (30.8) | 2 (15.4) | 6 (46.2) |
Any of breast/ovarian cancer familiesc,* | 345 (72.2) | 24 (7.0) | 31 (9.0) | 55 (15.9) |
No family history* | 133 (27.8) | 6 (4.5) | 2 (1.5) | 8 (6.0) |
Personal history
| ||||
Early-onset breast cancer (age < 40) | 199 (41.6) | 12 (6.0) | 11 (5.5) | 23 (11.6) |
Bilateral breast cancer | 47 (9.8) | 2 (4.3) | 5 (10.6) | 7 (14.9) |
Multiple organ cancersf
| 27 (5.6) | 0 (0.0) | 2 (7.4) | 2 (7.4) |
Both breast and ovarian cancer* | 6 (1.3) | 3 (50.0) | 1 (16.7) | 4 (66.7) |
Male breast cancer | 4 (0.8) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Clinicopathological factor
| ||||
Age at diagnosis | ||||
<40 | 186 (38.9) | 12 (6.5) | 11 (6.8) | 23 (14.3) |
40–49 | 172 (36.0) | 10 (5.8) | 15 (8.7) | 25 (14.5) |
50–59 | 89 (18.6) | 7 (7.9) | 6 (6.7) | 13 (14.6) |
60–79 | 31 (6.5) | 1 (3.3) | 1 (3.3) | 2 (6.5) |
Stage* | ||||
0 | 55 (11.5) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
I | 173 (36.2) | 12 (6.9) | 12 (6.9) | 24 (13.9) |
II | 159 (33.3) | 12 (7.6) | 18 (11.3) | 30 (18.9) |
III+ | 88 (18.4) | 5 (7.4) | 2 (2.9) | 7 (10.3) |
Unknown | 3 (0.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Hormone receptor status*,§
| ||||
ER+ & PR+ | 307 (64.2) | 5 (1.6) | 25 (8.1) | 20 (9.8) |
ER+ & PR− | 44 (9.2) | 1 (2.3) | 4 (9.1) | 5 (11.4) |
ER− & PR+ | 7 (1.5) | 1 (14.3) | 0 (0.0) | 1 (14.3) |
ER− & PR− | 115 (24.1) | 23 (20.0) | 4 (3.5) | 27 (23.5) |
Unknown | 5 (1.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Subtype according to hormone receptor and HER2 status*,§
| ||||
HR+ & HER2− | 252 (52.7) | 6 (2.4) | 19 (7.5) | 25 (9.9) |
HR− & HER2+ | 28 (5.9) | 1 (3.6) | 0 (0.0) | 1 (3.6) |
HR+ & HER2+ | 37 (7.7) | 0 (0.0) | 2 (5.4) | 2 (5.4) |
Triple-negative | 76 (15.9) | 19 (25.0) | 3 (4.0) | 22 (29.0) |
Unclassifiable | 85 (17.8) | 4 (4.7) | 9 (10.6) | 13 (15.3) |
Total | 478 (100.0) | 30 (6.3) | 33 (6.9) | 63 (13.2) |
Patients with large genomic rearrangements
Personal factor | Familial factor | Mutation carrier risk | ||||||
---|---|---|---|---|---|---|---|---|
Pt | Early-onset BC (age at diagnosis) | Bilateral BC | Both BC and OC | TNBC | Family history of BC (number, closest degree) | Family history of OC (number, closest degree) | Other cancer | BRCAPRO/Myriad |
A | No (51) | No | No | Yes | Yes (2, second degree) | No | Liver Cervix Stomach Thyroid Colon | 0.8/5.3 |
B | Yes (35) | No | No | Yes | Yes (1, second degree) | Yes (1, 1st degree) | Thyroid | 57.2/39.2 |
C | Yes (33) | Yes | Yes | No | Yes (1, first degree) | No | Lung | 51.2/15.8 |
Pathogenic variants of BRCA1/2 genes found in this study
Gene | Exon/intron | BIC nomenclature | HGVS cDNA | HGVS protein |
N
|
---|---|---|---|---|---|
BRCA1
| IVS5 | IVS5+1G>A | c.212+1G>A | – | 1 |
7 | 509C>A | c.390C>A | p.Tyr130* | 3 | |
11 | 1041_1042delAG | c.922_923delAG | p.Ser308Glufs* | 1 | |
11 | c.922_924delAGCinsT | p.Ser308* | 1 | ||
11 | 1137delG | c.1018delG | p.Val340Glyfs* | 1 | |
11 | 1599C>T | c.1480C>T | p.Gln494* | 1 | |
11 | c.14923_1494delTC | p.Leu498Hisfs* | 1 | ||
11 | 1630dupG | c.1511dupG | p.Lys505* | 1 | |
11 | c.1516delA | p.Arg506Glysfs* | 2 | ||
11 | c.2354T>A | p.Leu785* | 1 | ||
11 | 3415delC | c.3296delC | p.Pro1099Leufs* | 1 | |
11 | 3746dupA | c.3627dupA | p.Leu1210Glufs* | 1 | |
11 | 3819del5 | c.3700_3704delGTAAA | p.Val1210Aspfs* | 1 | |
c.4110C>T | p.Glu1331* | 1 | |||
16 | 5100G>T | c.4981G>T | p.Glu1661* | 2 | |
20 | 5379G>T | c.5260G>T | p.Glu1754* | 2 | |
IVS21 | c.5332+4delA | – | 1 | ||
23 | c.5445G>A | p.Trp1815* | 2 | ||
IVS23 | IVS23+1G | c.5467+1G>A | – | 1 | |
24 | 5602delG | c.5483delG | p.Cys1828Leufs* | 1 | |
24 | 5615del11insA | c.5496_5506delGGTGACCCGAGinsA | p.Val1833Serfs* | 1 | |
1–14 | Exon 1–14 deletion | 1 | |||
5–8 | Exon 5–8 deletion | 1 | |||
22–24 | Exon 22–24 deletion | 1 | |||
BRCA2
| 7 | 173G>T | c.518G>T | p.Gly173Val | 1 |
9 | 983del4 | c.755_758delACAG | p.Asp252Serfs* | 2 | |
10 | 1222delA | c.994delA | p.Ile332Phefs* | 1 | |
10 | 1627A>T | c.1399A>T | p.Lys467* | 4 | |
11 | 3026delCA | c.2798_2799delCA | p.Thr933Argfs* | 1 | |
11 | c.3096_3110delAGATATTGAAGAAC | p.Asp1033Ilefs* | 1 | ||
11 | 3972del4 | c.3744_3747delTGAC | p.Ser1248Glufs* | 3 | |
11 | 6019C>T | c.5791C>T | p.Gln1931* | 1 | |
11 | 6781delG | c.6553delG | p.Ala2185Leufs* | 1 | |
14 | c.7258G>T | p.Glu2420* | 2 | ||
15 | 7708C>T | c.7480C>T | p.Arg2494* | 9 | |
15 | c.7486G>T | p.Glu2420* | 1 | ||
18 | c.8300_8301insAC | p.Pro2767Hisfs* | 1 | ||
22 | 9179C>G | c.8951C>G | p.Ser2984* | 1 | |
23 | 9304C>T | c.9076C>T | p.Gln3026* | 1 | |
24 | c.9253delA | p.Thr3085Glnfs* | 1 | ||
25 | 9503del2 | c.9275_9276delAT | p.Tyr3092Phefs* | 1 | |
25 | 9641T>G | c.9413T>G | p.Leu3138* | 1 |