Abstract
Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.
| Original language | English (US) |
|---|---|
| Article number | 112 |
| Journal | Breast Cancer Research |
| Volume | 18 |
| Issue number | 1 |
| DOIs | |
| State | Published - Nov 11 2016 |
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Keywords
- BRCA1
- BRCA2
- Hereditary breast and ovarian cancer
- Transheterozygosity
ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women
AU - HEBON
AU - Rebbeck, Timothy R.
AU - Friebel, Tara M.
AU - Mitra, Nandita
AU - Wan, Fei
AU - Chen, Stephanie
AU - Andrulis, Irene L.
AU - Apostolou, Paraskevi
AU - Arnold, Norbert
AU - Arun, Banu K.
AU - Barrowdale, Daniel
AU - Benitez, Javier
AU - Berger, Raanan
AU - Berthet, Pascaline
AU - Borg, Ake
AU - Buys, Saundra S.
AU - Caldes, Trinidad
AU - Carter, Jonathan
AU - Chiquette, Jocelyne
AU - Claes, Kathleen B M
AU - Couch, Fergus J
AU - Cybulski, Cezary
AU - Daly, Mary B.
AU - de la Hoya, Miguel
AU - Diez, Orland
AU - Domchek, Susan M.
AU - Nathanson, Katherine L.
AU - Durda, Katarzyna
AU - Ellis, Steve
AU - Evans, D. Gareth
AU - Foretova, Lenka
AU - Friedman, Eitan
AU - Frost, Debra
AU - Ganz, Patricia A.
AU - Garber, Judy
AU - Glendon, Gord
AU - Godwin, Andrew K.
AU - Greene, Mark H.
AU - Gronwald, Jacek
AU - Hahnen, Eric
AU - Hallberg, Emily
AU - Hamann, Ute
AU - Hansen, Thomas V O
AU - Imyanitov, Evgeny N.
AU - Isaacs, Claudine
AU - Jakubowska, Anna
AU - Janavicius, Ramunas
AU - Jaworska-Bieniek, Katarzyna
AU - John, Esther M.
AU - Karlan, Beth Y.
AU - Kaufman, Bella
PY - 2016/11/11
Y1 - 2016/11/11
N2 - Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.
AB - Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.
KW - BRCA1
KW - BRCA2
KW - Hereditary breast and ovarian cancer
KW - Transheterozygosity
UR - http://www.scopus.com/inward/record.url?scp=85000995840&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85000995840&partnerID=8YFLogxK
U2 - 10.1186/s13058-016-0768-3
DO - 10.1186/s13058-016-0768-3
M3 - Article
C2 - 27836010
AN - SCOPUS:85000995840
VL - 18
JO - Breast Cancer Research
JF - Breast Cancer Research
SN - 1465-5411
IS - 1
M1 - 112
ER -