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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-12

AUTHORS

Timothy R. Rebbeck, Tara M. Friebel, Nandita Mitra, Fei Wan, Stephanie Chen, Irene L. Andrulis, Paraskevi Apostolou, Norbert Arnold, Banu K. Arun, Daniel Barrowdale, Javier Benitez, Raanan Berger, Pascaline Berthet, Ake Borg, Saundra S. Buys, Trinidad Caldes, Jonathan Carter, Jocelyne Chiquette, Kathleen B. M. Claes, Fergus J. Couch, Cezary Cybulski, Mary B. Daly, Miguel de la Hoya, Orland Diez, Susan M. Domchek, Katherine L. Nathanson, Katarzyna Durda, Steve Ellis, EMBRACE, D. Gareth Evans, Lenka Foretova, Eitan Friedman, Debra Frost, Patricia A. Ganz, Judy Garber, Gord Glendon, Andrew K. Godwin, Mark H. Greene, Jacek Gronwald, Eric Hahnen, Emily Hallberg, Ute Hamann, Thomas V. O. Hansen, HEBON, Evgeny N. Imyanitov, Claudine Isaacs, Anna Jakubowska, Ramunas Janavicius, Katarzyna Jaworska-Bieniek, Esther M. John, Beth Y. Karlan, Bella Kaufman, KConFab investigators, Ava Kwong, Yael Laitman, Christine Lasset, Conxi Lazaro, Jenny Lester, Niklas Loman, Jan Lubinski, Siranoush Manoukian, Gillian Mitchell, Marco Montagna, Susan L. Neuhausen, Heli Nevanlinna, Dieter Niederacher, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Sue Kyung Park, Marion Piedmonte, Paolo Radice, Christine Rappaport-Fuerhauser, Matti A. Rookus, Caroline Seynaeve, Jacques Simard, Christian F. Singer, Penny Soucy, Melissa Southey, Dominique Stoppa-Lyonnet, Grzegorz Sukiennicki, Csilla I. Szabo, Mariella Tancredi, Manuel R. Teixeira, Soo-Hwang Teo, Mary Beth Terry, Mads Thomassen, Laima Tihomirova, Marc Tischkowitz, Amanda Ewart Toland, Aleksandra Toloczko-Grabarek, Nadine Tung, Elizabeth J. van Rensburg, Danylo Villano, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N. Weitzel, Jamal Zidan, Kristin K. Zorn, Lesley McGuffog, Douglas Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Susan J. Ramus

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. More... »

PAGES

112

References to SciGraph publications

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  • Journal

    TITLE

    Breast Cancer Research

    ISSUE

    1

    VOLUME

    18

    Author Affiliations

  • University of Pennsylvania
  • Group Health Cooperative
  • University of Southern California
  • University of Toronto
  • National Centre of Scientific Research Demokritos
  • The University of Texas MD Anderson Cancer Center
  • QIMR Berghofer Medical Research Institute
  • Spanish National Cancer Research Centre
  • Sheba Medical Center
  • Centre Franois Baclesse
  • Skåne University Hospital
  • Huntsman Cancer Institute
  • Hospital Clínico San Carlos
  • Royal Prince Alfred Hospital
  • Hôpital du Saint-Sacrement
  • Ghent University
  • Mayo Clinic
  • Pomeranian Medical University
  • Temple University Health System
  • Hospital Universitari Vall d'Hebron
  • University of Cambridge
  • University of Manchester
  • Masaryk Memorial Cancer Institute
  • Tel Aviv University
  • University of California Los Angeles
  • Mount Sinai Hospital
  • University of Kansas Medical Center
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases
  • University Hospital Cologne
  • Mayo Clinic
  • German Cancer Research Center
  • Antoni van Leeuwenhoek Hospital
  • Institute of Oncology NN Petrov
  • Georgetown University
  • State Research Institute Centre for Innovative Medicine
  • Cancer Prevention Institute of California
  • Cedars-Sinai Medical Center
  • Peter MacCallum Cancer Centre
  • University of Hong Kong
  • Centre Léon Bérard
  • Institut d'Investigació Biomédica de Bellvitge
  • University of Melbourne
  • City Of Hope National Medical Center
  • Helsinki University Central Hospital
  • Memorial Sloan Kettering Cancer Center
  • National Institute of Oncology
  • Seoul National University
  • Roswell Park Cancer Institute
  • Medical University of Vienna
  • Institute Curie
  • National Human Genome Research Institute
  • Azienda Ospedaliera Universitaria Pisana
  • Portuguese Oncology Institute
  • University of Malaya
  • Columbia University
  • Odense University Hospital
  • Latvian Biomedical Research and Study Centre
  • McGill University
  • The Ohio State University
  • Beth Israel Deaconess Medical Center
  • University of Pretoria
  • University Hospital Ulm
  • Bar-Ilan University
  • Garvan Institute of Medical Research
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s13058-016-0768-3

    DOI

    http://dx.doi.org/10.1186/s13058-016-0768-3

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1037742468

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/27836010


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    58 schema:description 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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