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Multicenter Study
. 2016 Nov 11;18(1):112.
doi: 10.1186/s13058-016-0768-3.

Inheritance of Deleterious Mutations at Both BRCA1 and BRCA2 in an International Sample of 32,295 Women

Timothy R Rebbeck  1 Tara M Friebel  2 Nandita Mitra  3 Fei Wan  4 Stephanie Chen  5 Irene L Andrulis  6   7 Paraskevi Apostolou  8 Norbert Arnold  9 Banu K Arun  10 Daniel Barrowdale  11 Javier Benitez  12   13   14 Raanan Berger  15 Pascaline Berthet  16 Ake Borg  17 Saundra S Buys  18 Trinidad Caldes  19 Jonathan Carter  20 Jocelyne Chiquette  21 Kathleen B M Claes  22 Fergus J Couch  23 Cezary Cybulski  24 Mary B Daly  25 Miguel de la Hoya  19 Orland Diez  26 Susan M Domchek  27 Katherine L Nathanson  27 Katarzyna Durda  24 Steve Ellis  28 EMBRACED Gareth Evans  29 Lenka Foretova  30 Eitan Friedman  31   32 Debra Frost  28 Patricia A Ganz  33 Judy Garber  2 Gord Glendon  34 Andrew K Godwin  35   36 Mark H Greene  37 Jacek Gronwald  24 Eric Hahnen  38 Emily Hallberg  39 Ute Hamann  40 Thomas V O Hansen  41 HEBONEvgeny N Imyanitov  42 Claudine Isaacs  43 Anna Jakubowska  24 Ramunas Janavicius  44   45 Katarzyna Jaworska-Bieniek  24 Esther M John  46 Beth Y Karlan  47 Bella Kaufman  15 KConFab Investigators  48 Ava Kwong  49   50 Yael Laitman  31   32 Christine Lasset  51 Conxi Lazaro  52 Jenny Lester  47 Niklas Loman  53 Jan Lubinski  24 Siranoush Manoukian  54 Gillian Mitchell  55   56 Marco Montagna  57 Susan L Neuhausen  58 Heli Nevanlinna  59 Dieter Niederacher  60 Robert L Nussbaum  61 Kenneth Offit  62 Edith Olah  63 Olufunmilayo I Olopade  64 Sue Kyung Park  65 Marion Piedmonte  66 Paolo Radice  67 Christine Rappaport-Fuerhauser  68 Matti A Rookus  69 Caroline Seynaeve  70 Jacques Simard  71 Christian F Singer  72 Penny Soucy  71 Melissa Southey  73 Dominique Stoppa-Lyonnet  74 Grzegorz Sukiennicki  24 Csilla I Szabo  75 Mariella Tancredi  76 Manuel R Teixeira  77 Soo-Hwang Teo  78   79 Mary Beth Terry  80 Mads Thomassen  81 Laima Tihomirova  82 Marc Tischkowitz  83 Amanda Ewart Toland  84 Aleksandra Toloczko-Grabarek  24 Nadine Tung  85 Elizabeth J van Rensburg  86 Danylo Villano  87 Shan Wang-Gohrke  88 Barbara Wappenschmidt  38 Jeffrey N Weitzel  89 Jamal Zidan  90   91 Kristin K Zorn  92 Lesley McGuffog  93 Douglas Easton  93 Georgia Chenevix-Trench  11 Antonis C Antoniou  93 Susan J Ramus  5   94
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Free PMC article
Multicenter Study

Inheritance of Deleterious Mutations at Both BRCA1 and BRCA2 in an International Sample of 32,295 Women

Timothy R Rebbeck et al. Breast Cancer Res. .
Free PMC article

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.

Keywords: BRCA1; BRCA2; Hereditary breast and ovarian cancer; Transheterozygosity.

Figures

Fig. 1
Fig. 1
Age of breast and ovarian cancer diagnosis by mutation status

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