Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

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Abstract

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

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Authors
  • Fergus J. Couch
  • Xianshu Wang
  • Lesley McGuffog
  • Andrew Lee
  • Curtis Olswold
  • Karoline B. Kuchenbaecker
  • Penny Soucy
  • Zachary Fredericksen
  • Daniel Barrowdale
  • Joe Dennis
  • Mia M. Gaudet
  • Ed Dicks
  • Matthew Kosel
  • Sue Healey
  • Olga M. Sinilnikova
  • Adam Lee
  • Francois Bacot
  • Daniel Vincent
  • Frans B. L. Hogervorst
  • Susan Peock
  • Dominique Stoppa-Lyonnet
  • Anna Jakubowska
  • Paolo Radice
  • Rita Katharina Schmutzler
  • Susan M. Domchek
  • Marion Piedmonte
  • Christian F. Singer
  • Eitan Friedman
  • Mads Thomassen
  • Thomas V. O. Hansen
  • Susan L. Neuhausen
  • Csilla I. Szabo
  • Ignacio Blanco
  • Mark H. Greene
  • Beth Y. Karlan
  • Judy Garber
  • Catherine M. Phelan
  • Jeffrey N. Weitzel
  • Marco Montagna
  • Edith Olah
  • Irene L. Andrulis
  • Andrew K. Godwin
  • Drakoulis Yannoukakos
  • David E. Goldgar
  • Trinidad Caldes
  • Heli Nevanlinna
  • Ana Osorio
  • Mary Beth Terry
  • Mary B. Daly
  • Elizabeth J. van Rensburg
  • Ute Hamann
  • Susan J. Ramus
  • Amanda Ewart Toland
  • Maria A. Caligo
  • Olufunmilayo I. Olopade
  • Nadine Tung
  • Kathleen Claes
  • Mary S. Beattie
  • Melissa C. Southey
  • Evgeny N. Imyanitov
  • Marc Tischkowitz
  • Ramunas Janavicius
  • Esther M. John
  • Ava Kwong
  • Orland Diez
  • Judith Balmana
  • Rosa B. Barkardottir
  • Banu K. Arun
  • Gad Rennert
  • Soo-Hwang Teo
  • Patricia A. Ganz
  • Ian Campbell
  • Annemarie H. van der Hout
  • Carolien H. M. van Deurzen
  • Caroline Seynaeve
  • Encarna B. Gomez Garcia
  • Flora E. van Leeuwen
  • Hanne E. J. Meijers-Heijboer
  • Johannes J. P. Gille
  • Margreet G. E. M. Ausems
  • Marinus J. Blok
  • Marjolijn J. L. Ligtenberg
  • Matti A. Rookus
  • Peter Devilee
  • Senno Verhoef
  • Theo A. M. van Os
  • Juul T. Wijnen
  • Debra Frost
  • Steve Ellis
  • Elena Fineberg
  • Radka Platte
  • D. Gareth Evans
  • Louise Izatt
  • Rosalind A. Eeles
  • Julian Adlard
  • Diana M. Eccles
  • Jackie Cook
  • Carole Brewer
  • Fiona Douglas
  • Shirley Hodgson
  • Patrick J. Morrison
  • Lucy E. Side
  • Alan Donaldson
  • Catherine Houghton
  • Mark T. Rogers
  • Huw Dorkins
  • Jacqueline Eason
  • Helen Gregory
  • Emma McCann
  • Alex Murray
  • Alain Calender
  • Agnes Hardouin
  • Pascaline Berthet
  • Capucine Delnatte
  • Catherine Nogues
  • Christine Lasset
  • Claude Houdayer
  • Dominique Leroux
  • Etienne Rouleau
  • Fabienne Prieur
  • Francesca Damiola
  • Hagay Sobol
  • Isabelle Coupier
  • Laurence Venat-Bouvet
  • Laurent Castera
  • Marion Gauthier-Villars
  • Melanie Leone
  • Pascal Pujol
  • Sylvie Mazoyer
  • Yves-Jean Bignon
  • Elzbieta Zlowocka-Perlowska
  • Jacek Gronwald
  • Jan Lubinski
  • Katarzyna Durda
  • Katarzyna Jaworska
  • Tomasz Huzarski
  • Amanda B. Spurdle
  • Alessandra Viel
  • Bernard Peissel
  • Bernardo Bonanni
  • Giulia Melloni
  • Laura Ottini
  • Laura Papi
  • Liliana Varesco
  • Maria Grazia Tibiletti
  • Paolo Peterlongo
  • Sara Volorio
  • Siranoush Manoukian
  • Valeria Pensotti
  • Norbert Arnold
  • Christoph Engel
  • Helmut Deissler
  • Dorothea Gadzicki
  • Andrea Gehrig
  • Karin Kast
  • Kerstin Rhiem
  • Alfons Meindl
  • Dieter Niederacher
  • Nina Ditsch
  • Hansjoerg Plendl
  • Sabine Preisler-Adams
  • Stefanie Engert
  • Christian Sutter
  • Raymonda Varon-Mateeva
  • Barbara Wappenschmidt
  • Bernhard H. F. Weber
  • Brita Arver
  • Marie Stenmark-Askmalm
  • Richard Rosenquist
  • Zakaria Einbeigi
  • Katherine L. Nathanson
  • Timothy R. Rebbeck
  • Stephanie V. Blank
  • David E. Cohn
  • Gustavo C. Rodriguez
  • Laurie Small
  • Michael Friedlander
  • Victoria L. Bae-Jump
  • Anneliese Fink-Retter
  • Christine Rappaport
  • Daphne Gschwantler-Kaulich
  • Georg Pfeiler
  • Muy-Kheng Tea
  • Noralane M. Lindor
  • Bella Kaufman
  • Shani Shimon Paluch
  • Yael Laitman
  • Anne-Bine Skytte
  • Anne-Marie Gerdes
  • Inge Sokilde Pedersen
  • Sanne Traasdahl Moeller
  • Torben A. Kruse
  • Uffe Birk Jensen
  • Joseph Vijai
  • Kara Sarrel
  • Mark Robson
  • Noah Kauff
  • Anna Marie Mulligan
  • Gord Glendon
  • Hilmi Ozcelik
  • Bent Ejlertsen
  • Finn C. Nielsen
  • Lars Jonson
  • Mette K. Andersen
  • Yuan Chun Ding
  • Linda Steele
  • Lenka Foretova
  • Alex Teule
  • Conxi Lazaro
  • Joan Brunet
  • Miquel Angel Pujana
  • Phuong L. Mai
  • Jennifer T. Loud
  • Christine Walsh
  • Jenny Lester
  • Sandra Orsulic
  • Steven A. Narod
  • Josef Herzog
  • Sharon R. Sand
  • Silvia Tognazzo
  • Simona Agata
  • Tibor Vaszko
  • Joellen Weaver
  • Alexandra V. Stavropoulou
  • Saundra S. Buys
  • Atocha Romero
  • Miguel de la Hoya
  • Kristiina Aittomaki
  • Taru A. Muranen
  • Mercedes Duran
  • Wendy K. Chung
  • Adriana Lasa
  • Cecilia M. Dorfling
  • Alexander Miron
  • Javier Benitez
  • Leigha Senter
  • Dezheng Huo
  • Salina B. Chan
  • Anna P. Sokolenko
  • Jocelyne Chiquette
  • Laima Tihomirova
  • Tara M. Friebel
  • Bjarni A. Agnarsson
  • Karen H. Lu
  • Flavio Lejbkowicz
  • Paul A. James
  • Per Hall
  • Alison M. Dunning
  • Daniel Tessier
  • Julie Cunningham
  • Susan L. Slager
  • Chen Wang
  • Steven Hart
  • Kristen Stevens
  • Jacques Simard
  • Tomi Pastinen
  • Vernon S. Pankratz
  • Kenneth Offit
  • Douglas F. Easton
  • Georgia Chenevix-Trench
  • Antonis C. Antoniou
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Article numbere1003212
JournalPLoS Genetics
Volume9
Issue number3
Publication statusPublished - 2013
Publication categoryResearch
Peer-reviewedYes

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