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

Rebbeck, Timothy R.; Friebel, Tara M.; Mitra, Nandita; Wan, Fei; Chen, Stephanie; Andrulis, Irene L.; Apostolou, Paraskevi; Arnold, Norbert; Arun, Banu K. and Barrowdale, Daniel, et al. (2016) In Breast Cancer Research 18(1).
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 %)... (More)

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.

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keywords
BRCA1, BRCA2, Hereditary breast and ovarian cancer, Transheterozygosity
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Breast Cancer Research
volume
18
issue
1
publisher
BioMed Central
external identifiers
  • scopus:85000995840
  • wos:000390899600001
ISSN
1465-5411
DOI
10.1186/s13058-016-0768-3
language
English
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yes
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e9fbd2af-125e-425d-84cf-fbd3c4ea8799
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2016-12-29 12:14:54
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2017-09-18 11:34:09
@article{e9fbd2af-125e-425d-84cf-fbd3c4ea8799,
  abstract     = {<p>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 &lt; 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 &lt; 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.</p>},
  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, Åke and Buys, Saundra S. and Caldes, Trinidad and Carter, Jonathan and Chiquette, Jocelyne and Claes, Kathleen B M 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 V O 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         = {1465-5411},
  keyword      = {BRCA1,BRCA2,Hereditary breast and ovarian cancer,Transheterozygosity},
  language     = {eng},
  month        = {11},
  number       = {1},
  publisher    = {BioMed Central},
  series       = {Breast Cancer Research},
  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},
}