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

Research output: Contribution to journalArticle

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.

Details

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
  • 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
  • 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
  • Evgeny N. Imyanitov
  • Claudine Isaacs
  • Anna Jakubowska
  • Ramunas Janavicius
  • Katarzyna Jaworska-Bieniek
  • Esther M. John
  • Beth Y. Karlan
  • Bella Kaufman
  • Ava Kwong
  • Yael Laitman
  • Christine Lasset
  • Conxi Lazaro
  • Jenny Lester
  • 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
Organisations
External organisations
  • Dana-Farber Cancer Institute
  • University of Pennsylvania
  • Kaiser Permanente Research Institute
  • University of Southern California
  • University of Toronto
  • National Centre for Scientific Research Demokritos
  • University Medical Center Schleswig-Holstein Campus Kiel
  • University of Texas
  • QIMR Berghofer Medical Research Institute
  • Spanish National Cancer Research Center (CNIO)
  • Sheba Medical Center
  • Centre François Baclesse
  • Skåne University Hospital
  • Huntsman Cancer Institute
  • Hospital Clinico San Carlos de Madrid
  • Royal Prince Alfred Hospital
  • Hôpital du Saint-Sacrement
  • Ghent University Hospital
  • Mayo Clinic Minnesota
  • Pomeranian Medical University
  • Fox Chase Cancer Center
  • Vall d'Hebron University Hospital
  • Cochin Hospital
  • University of Cambridge
  • Masaryk Memorial Cancer Institute
  • Tel-Aviv University
  • Jonsson Comprehensive Cancer Center
  • Mount Sinai Hospital of University of Toronto
  • University of Kansas Medical Center
  • National Cancer Institute, USA
  • University Hospital of Cologne
  • Mayo Clinic Scottsdale-Phoenix, Arizona
  • German Cancer Research Centre
  • Copenhagen University Hospital
  • N. N. Petrov Institute of Oncology
  • Lombardi Comprehensive Cancer Center
  • State Research Institute Centre for Innovative Medicine
  • Cancer Prevention Institute of California
  • Cedars-Sinai Medical Center
  • University of Hong Kong
  • Centre Léon Bérard
  • Bellvitge Biomedical Research Institute
  • Istituto Nazionale dei Tumori
  • University of Melbourne
  • Veneto Institute of Oncology
  • City of Hope National Medical Center
  • University of Helsinki
  • Universitätsklinikum Düsseldorf
  • Memorial Sloan-Kettering Cancer Center
  • National Institute of Oncology, Budapest
  • Seoul National University
  • Roswell Park Cancer Institute
  • Medical University of Vienna
  • Netherlands Cancer Institute
  • Erasmus University Medical Center
  • Laval University
  • Curie Institute, Paris
  • National Human Genome Research Institute
  • University Hospital of Pisa
  • Instituto Português de Oncologia do Porto Francisco Gentil (IPO)
  • University of Malaya
  • Columbia University
  • Odense University Hospital
  • Latvian Biomedical Research and Study Centre
  • McGill University
  • Ohio State University
  • Beth Israel Deaconess Medical Center
  • University of Pretoria
  • University Hospital of Ulm
  • Bar-Ilan University
  • University of New South Wales
  • University of Manchester
  • Central Manchester University Hospitals
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
  • Medical Genetics

Keywords

  • BRCA1, BRCA2, Hereditary breast and ovarian cancer, Transheterozygosity
Original languageEnglish
Article number112
JournalBreast Cancer Research
Volume18
Issue number1
Publication statusPublished - 2016 Nov 11
Publication categoryResearch
Peer-reviewedYes