A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.
Juliette Coignard,
Michael Lush,
Jonathan Beesley,
Tracy A O'Mara,
Joe Dennis,
Jonathan P Tyrer,
Daniel R Barnes,
Lesley McGuffog,
Goska Leslie,
Manjeet K Bolla,
Muriel A Adank,
Simona Agata,
Thomas Ahearn,
Kristiina Aittomäki,
Irene L Andrulis,
Hoda Anton-Culver,
Volker Arndt,
Norbert Arnold,
Kristan J Aronson,
Banu K Arun,
Annelie Augustinsson,
Jacopo Azzollini,
Daniel Barrowdale,
Caroline Baynes,
Heiko Becher,
Marina Bermisheva,
Leslie Bernstein,
Katarzyna Białkowska,
Carl Blomqvist,
Stig E Bojesen,
Bernardo Bonanni,
Ake Borg,
Hiltrud Brauch,
Hermann Brenner,
Barbara Burwinkel,
Saundra S Buys,
Trinidad Caldés,
Maria A Caligo,
Daniele Campa,
Brian D Carter,
Jose E Castelao,
Jenny Chang-Claude,
Stephen J Chanock,
Wendy K Chung,
Kathleen B M Claes,
Christine L Clarke,
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,
J Margriet Collée,
Don M Conroy,
Kamila Czene,
Mary B Daly,
Peter Devilee,
Orland Diez,
Yuan Chun Ding,
Susan M Domchek,
Thilo Dörk,
Isabel Dos-Santos-Silva,
Alison M Dunning,
Miriam Dwek,
Diana M Eccles,
A Heather Eliassen,
Christoph Engel,
Mikael Eriksson,
D Gareth Evans,
Peter A Fasching,
Henrik Flyger,
Florentia Fostira,
Eitan Friedman,
Lin Fritschi,
Debra Frost,
Manuela Gago-Dominguez,
Susan M Gapstur,
Judy Garber,
Vanesa Garcia-Barberan,
Montserrat García-Closas,
José A García-Sáenz,
Mia M Gaudet,
Simon A Gayther,
Andrea Gehrig,
Vassilios Georgoulias,
Graham G Giles,
Andrew K Godwin,
Mark S Goldberg,
David E Goldgar,
Anna González-Neira,
Mark H Greene,
Pascal Guénel,
Lothar Haeberle,
Eric Hahnen,
Christopher A Haiman,
Niclas Håkansson,
Per Hall,
Ute Hamann,
Patricia A Harrington,
Steven N Hart,
Wei He,
Frans B L Hogervorst,
Antoinette Hollestelle,
John L Hopper,
Darling J Horcasitas,
Peter J Hulick,
David J Hunter,
Evgeny N Imyanitov,
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,
,
Agnes Jager,
Anna Jakubowska,
Paul A James,
Uffe Birk Jensen,
Esther M John,
Michael E Jones,
Rudolf Kaaks,
Pooja Middha Kapoor,
Beth Y Karlan,
Renske Keeman,
Elza Khusnutdinova,
Johanna I Kiiski,
Yon-Dschun Ko,
Veli-Matti Kosma,
Peter Kraft,
Allison W Kurian,
Yael Laitman,
Diether Lambrechts,
Loic Le Marchand,
Jenny Lester,
Fabienne Lesueur,
Tricia Lindstrom,
Adria Lopez-Fernández,
Jennifer T Loud,
Craig Luccarini,
Arto Mannermaa,
Siranoush Manoukian,
Sara Margolin,
John W M Martens,
Noura Mebirouk,
Alfons Meindl,
Austin Miller,
Roger L Milne,
Marco Montagna,
Katherine L Nathanson,
Susan L Neuhausen,
Heli Nevanlinna,
Finn C Nielsen,
Katie M O'Brien,
Olufunmilayo I Olopade,
Janet E Olson,
Håkan Olsson,
Ana Osorio,
Laura Ottini,
Tjoung-Won Park-Simon,
Michael T Parsons,
Inge Sokilde Pedersen,
Beth Peshkin,
Paolo Peterlongo,
Julian Peto,
Paul D P Pharoah,
Kelly-Anne Phillips,
Eric C Polley,
Bruce Poppe,
Nadege Presneau,
Miquel Angel Pujana,
Kevin Punie,
Paolo Radice,
Johanna Rantala,
Muhammad U Rashid,
Gad Rennert,
Hedy S Rennert,
Mark Robson,
Atocha Romero,
Maria Rossing,
Emmanouil Saloustros,
Dale P Sandler,
Regina Santella,
Maren T Scheuner,
Marjanka K Schmidt,
Gunnar Schmidt,
Christopher Scott,
Priyanka Sharma,
Penny Soucy,
Melissa C Southey,
John J Spinelli,
Zoe Steinsnyder,
Jennifer Stone,
Dominique Stoppa-Lyonnet,
Anthony Swerdlow,
Rulla M Tamimi,
William J Tapper,
Jack A Taylor,
Mary Beth Terry,
Alex Teulé,
Darcy L Thull,
Marc Tischkowitz,
Amanda E Toland,
Diana Torres,
Alison H Trainer,
Thérèse Truong,
Nadine Tung,
Celine M Vachon,
Ana Vega,
Joseph Vijai,
Qin Wang,
Barbara Wappenschmidt,
Clarice R Weinberg,
Jeffrey N Weitzel,
Camilla Wendt,
Alicja Wolk,
Siddhartha Yadav,
Xiaohong R Yang,
Drakoulis Yannoukakos,
Wei Zheng,
Argyrios Ziogas,
Kristin K Zorn,
Sue K Park,
Mads Thomassen,
Kenneth Offit,
Rita K Schmutzler,
Fergus J Couch,
Jacques Simard,
Georgia Chenevix-Trench,
Douglas F Easton,
Nadine Andrieu,
Antonis C Antoniou
Abstract
Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.