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Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Timothy R Rebbeck, Tara M Friebel, Nandita Mitra, Fei Wan, Stephanie Chen, Irene L Andrulis, Paraskevi Apostolou, Norbert Arnold, Banu K Arun, Daniel Barrowdale, et al. (2016) BREAST CANCER RESEARCH. 18.
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
UNKNOWN CLINICAL-SIGNIFICANCE, CANCER SUSCEPTIBILITY GENE, SPORADIC, BREAST-CANCER, DNA-SEQUENCE VARIANTS, WILD-TYPE CHROMOSOME, OVARIAN-CANCER, FANCONI-ANEMIA, DOUBLE HETEROZYGOSITY, GERMLINE, MUTATIONS, HETEROGENIC LOSS, Hereditary breast and ovarian cancer, Transheterozygosity, BRCA1, BRCA2
journal title
BREAST CANCER RESEARCH
Breast Cancer Res.
volume
18
article number
112
pages
19 pages
Web of Science type
Article
Web of Science id
000390899600001
JCR category
ONCOLOGY
JCR impact factor
6.345 (2016)
JCR rank
27/217 (2016)
JCR quartile
1 (2016)
ISSN
1465-542X
1465-5411
DOI
10.1186/s13058-016-0768-3
language
English
UGent publication?
yes
classification
A1
copyright statement
Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
id
8509902
handle
http://hdl.handle.net/1854/LU-8509902
date created
2017-02-17 08:45:56
date last changed
2017-02-17 08:46:28
@article{8509902,
  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 \%). {\textacutedbl}Cases{\textacutedbl} were defined as TH, and {\textacutedbl}controls{\textacutedbl} were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 {\textacutedbl}controls{\textacutedbl} carried a BRCA1 mutation found in the TH {\textacutedbl}case{\textacutedbl}. Matched SH2 {\textacutedbl}controls{\textacutedbl} carried a BRCA2 mutation found in the TH {\textacutedbl}case{\textacutedbl}. 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 {\textlangle} 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 {\textlangle} 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.},
  articleno    = {112},
  author       = {Rebbeck, Timothy R and Friebel, Tara M and Mitra, Nandita and Wan, Fei and Chen, Stephanie and Andrulis, Irene L and Apostolou, Paraskevi and Arnold, Norbert and Arun, Banu K and Barrowdale, Daniel and Benitez, Javier and Berger, Raanan and Berthet, Pascaline and Borg, Ake and Buys, Saundra S and Caldes, Trinidad and Carter, Jonathan and Chiquette, Jocelyne and Claes, Kathleen and Couch, Fergus J and Cybulski, Cezary and Daly, Mary B and de la Hoya, Miguel and Diez, Orland and Domchek, Susan M and Nathanson, Katherine L and Durda, Katarzyna and Ellis, Steve and Evans, D Gareth and Foretova, Lenka and Friedman, Eitan and Frost, Debra and Ganz, Patricia A and Garber, Judy and Glendon, Gord and Godwin, Andrew K and Greene, Mark H and Gronwald, Jacek and Hahnen, Eric and Hallberg, Emily and Hamann, Ute and Hansen, Thomas VO and Imyanitov, Evgeny N and Isaacs, Claudine and Jakubowska, Anna and Janavicius, Ramunas and Jaworska-Bieniek, Katarzyna and John, Esther M and Karlan, Beth Y and Kaufman, Bella and Kwong, Ava and Laitman, Yael and Lasset, Christine and Lazaro, Conxi and Lester, Jenny and Loman, Niklas and Lubinski, Jan and Manoukian, Siranoush and Mitchell, Gillian and Montagna, Marco and Neuhausen, Susan L and Nevanlinna, Heli and Niederacher, Dieter and Nussbaum, Robert L and Offit, Kenneth and Olah, Edith and Olopade, Olufunmilayo I and Park, Sue Kyung and Piedmonte, Marion and Radice, Paolo and Rappaport-Fuerhauser, Christine and Rookus, Matti A and Seynaeve, Caroline and Simard, Jacques and Singer, Christian F and Soucy, Penny and Southey, Melissa and Stoppa-Lyonnet, Dominique and Sukiennicki, Grzegorz and Szabo, Csilla I and Tancredi, Mariella and Teixeira, Manuel R and Teo, Soo-Hwang and Terry, Mary Beth and Thomassen, Mads and Tihomirova, Laima and Tischkowitz, Marc and Toland, Amanda Ewart and Toloczko-Grabarek, Aleksandra and Tung, Nadine and van Rensburg, Elizabeth J and Villano, Danylo and Wang-Gohrke, Shan and Wappenschmidt, Barbara and Weitzel, Jeffrey N and Zidan, Jamal and Zorn, Kristin K and McGuffog, Lesley and Easton, Douglas and Chenevix-Trench, Georgia and Antoniou, Antonis C and Ramus, Susan J},
  issn         = {1465-542X},
  journal      = {BREAST CANCER RESEARCH},
  keyword      = {UNKNOWN CLINICAL-SIGNIFICANCE,CANCER SUSCEPTIBILITY GENE,SPORADIC,BREAST-CANCER,DNA-SEQUENCE VARIANTS,WILD-TYPE CHROMOSOME,OVARIAN-CANCER,FANCONI-ANEMIA,DOUBLE HETEROZYGOSITY,GERMLINE,MUTATIONS,HETEROGENIC LOSS,Hereditary breast and ovarian cancer,Transheterozygosity,BRCA1,BRCA2},
  language     = {eng},
  pages        = {19},
  title        = {Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women},
  url          = {http://dx.doi.org/10.1186/s13058-016-0768-3},
  volume       = {18},
  year         = {2016},
}

Chicago
Rebbeck, Timothy R, Tara M Friebel, Nandita Mitra, Fei Wan, Stephanie Chen, Irene L Andrulis, Paraskevi Apostolou, et al. 2016. “Inheritance of Deleterious Mutations at Both BRCA1 and BRCA2 in an International Sample of 32,295 Women.” Breast Cancer Research 18.
APA
Rebbeck, T. R., Friebel, T. M., Mitra, N., Wan, F., Chen, S., Andrulis, I. L., Apostolou, P., et al. (2016). Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women. BREAST CANCER RESEARCH, 18.
Vancouver
1.
Rebbeck TR, Friebel TM, Mitra N, Wan F, Chen S, Andrulis IL, et al. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women. BREAST CANCER RESEARCH. 2016;18.
MLA
Rebbeck, Timothy R, Tara M Friebel, Nandita Mitra, et al. “Inheritance of Deleterious Mutations at Both BRCA1 and BRCA2 in an International Sample of 32,295 Women.” BREAST CANCER RESEARCH 18 (2016): n. pag. Print.