Rebbeck, Timothy R., Friebel, Tara M., Mitra, Nandita, Wan, Fei, Chen, Stephanie, Andrulis, Irene L., Apostolou, Paraskevi, Arnold, Norbert ORCID: 0000-0003-4523-8808, Arun, Banu K., Barrowdale, Daniel ORCID: 0000-0003-1661-3939, Benitez, Javier, Berger, Raanan, Berthet, Pascaline, Borg, Ake, Buys, Saundra S., Caldes, Trinidad, Carter, Jonathan ORCID: 0000-0003-3871-2815, Chiquette, Jocelyne, Claes, Kathleen B. M., Couch, Fergus J., Cybulski, Cezary, Daly, Mary B., de la Hoya, Miguel ORCID: 0000-0002-8113-1410, Diez, Orland, Domchek, Susan M., Nathanson, Katherine L., Durda, Katarzyna, Ellis, Steve, Evans, D. Gareth, Foretova, Lenka, Friedman, Eitan, Frost, Debra, Ganz, Patricia A., Garber, Judy, Glendon, Gord, Godwin, Andrew K., Greene, Mark H., Gronwald, Jacek ORCID: 0000-0002-3643-2871, Hahnen, Eric, Hallberg, Emily, Hamann, Ute, Hansen, Thomas V. O., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna ORCID: 0000-0002-5650-0501, Janavicius, Ramunas, Jaworska-Bieniek, Katarzyna, John, Esther M., Karlan, Beth Y., Kaufman, Bella, Kwong, Ava ORCID: 0000-0002-6968-9489, Laitman, Yael, Lasset, Christine, Lazaro, Conxi, Lester, Jenny, Loman, Niklas, Lubinski, Jan ORCID: 0000-0003-2931-3003, Manoukian, Siranoush, Mitchell, Gillian, Montagna, Marco, Neuhausen, Susan L., Nevanlinna, Heli, Niederacher, Dieter, Nussbaum, Robert L., Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Park, Sue Kyung, Piedmonte, Marion, Radice, Paolo ORCID: 0000-0001-6298-4111, Rappaport-Fuerhauser, Christine, Rookus, Matti A., Seynaeve, Caroline, Simard, Jacques, Singer, Christian F., Soucy, Penny, Southey, Melissa ORCID: 0000-0002-6313-9005, Stoppa-Lyonnet, Dominique, Sukiennicki, Grzegorz, Szabo, Csilla I., Tancredi, Mariella, Teixeira, Manuel R., Teo, Soo-Hwang, Terry, Mary Beth, Thomassen, Mads, Tihomirova, Laima, Tischkowitz, Marc ORCID: 0000-0002-7880-0628, Toland, Amanda Ewart, Toloczko-Grabarek, Aleksandra, Tung, Nadine, van Rensburg, Elizabeth J., Villano, Danylo, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Zidan, Jamal, Zorn, Kristin K., McGuffog, Lesley, Easton, Douglas, Chenevix-Trench, Georgia ORCID: 0000-0002-1878-2587, Antoniou, Antonis C. and Ramus, Susan J. (2016). Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women. Breast Cancer Res., 18. LONDON: BIOMED CENTRAL LTD. ISSN 1465-5411

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rebbeck, Timothy R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Friebel, Tara M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mitra, NanditaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wan, FeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrulis, Irene L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Apostolou, ParaskeviUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arnold, NorbertUNSPECIFIEDorcid.org/0000-0003-4523-8808UNSPECIFIED
Arun, Banu K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barrowdale, DanielUNSPECIFIEDorcid.org/0000-0003-1661-3939UNSPECIFIED
Benitez, JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berger, RaananUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berthet, PascalineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borg, AkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buys, Saundra S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caldes, TrinidadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carter, JonathanUNSPECIFIEDorcid.org/0000-0003-3871-2815UNSPECIFIED
Chiquette, JocelyneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claes, Kathleen B. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Couch, Fergus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cybulski, CezaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daly, Mary B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de la Hoya, MiguelUNSPECIFIEDorcid.org/0000-0002-8113-1410UNSPECIFIED
Diez, OrlandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Domchek, Susan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nathanson, Katherine L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Durda, KatarzynaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ellis, SteveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Evans, D. GarethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Foretova, LenkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Friedman, EitanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frost, DebraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ganz, Patricia A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garber, JudyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glendon, GordUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Godwin, Andrew K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Greene, Mark H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gronwald, JacekUNSPECIFIEDorcid.org/0000-0002-3643-2871UNSPECIFIED
Hahnen, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallberg, EmilyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamann, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansen, Thomas V. O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Imyanitov, Evgeny N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isaacs, ClaudineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jakubowska, AnnaUNSPECIFIEDorcid.org/0000-0002-5650-0501UNSPECIFIED
Janavicius, RamunasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jaworska-Bieniek, KatarzynaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
John, Esther M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karlan, Beth Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaufman, BellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kwong, AvaUNSPECIFIEDorcid.org/0000-0002-6968-9489UNSPECIFIED
Laitman, YaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lasset, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lazaro, ConxiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lester, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loman, NiklasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lubinski, JanUNSPECIFIEDorcid.org/0000-0003-2931-3003UNSPECIFIED
Manoukian, SiranoushUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mitchell, GillianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montagna, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhausen, Susan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nevanlinna, HeliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niederacher, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nussbaum, Robert L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Offit, KennethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olah, EdithUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olopade, Olufunmilayo I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Park, Sue KyungUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piedmonte, MarionUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radice, PaoloUNSPECIFIEDorcid.org/0000-0001-6298-4111UNSPECIFIED
Rappaport-Fuerhauser, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rookus, Matti A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seynaeve, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simard, JacquesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Singer, Christian F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soucy, PennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Southey, MelissaUNSPECIFIEDorcid.org/0000-0002-6313-9005UNSPECIFIED
Stoppa-Lyonnet, DominiqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sukiennicki, GrzegorzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szabo, Csilla I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tancredi, MariellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teixeira, Manuel R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teo, Soo-HwangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Terry, Mary BethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomassen, MadsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tihomirova, LaimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tischkowitz, MarcUNSPECIFIEDorcid.org/0000-0002-7880-0628UNSPECIFIED
Toland, Amanda EwartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toloczko-Grabarek, AleksandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tung, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Rensburg, Elizabeth J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Villano, DanyloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang-Gohrke, ShanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wappenschmidt, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weitzel, Jeffrey N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zidan, JamalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zorn, Kristin K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McGuffog, LesleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Easton, DouglasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chenevix-Trench, GeorgiaUNSPECIFIEDorcid.org/0000-0002-1878-2587UNSPECIFIED
Antoniou, Antonis C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramus, Susan J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-255764
DOI: 10.1186/s13058-016-0768-3
Journal or Publication Title: Breast Cancer Res.
Volume: 18
Date: 2016
Publisher: BIOMED CENTRAL LTD
Place of Publication: LONDON
ISSN: 1465-5411
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
UNKNOWN CLINICAL-SIGNIFICANCE; CANCER SUSCEPTIBILITY GENE; SPORADIC BREAST-CANCER; DNA-SEQUENCE VARIANTS; WILD-TYPE CHROMOSOME; OVARIAN-CANCER; FANCONI-ANEMIA; DOUBLE HETEROZYGOSITY; GERMLINE MUTATIONS; HETEROGENIC LOSSMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/25576

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