Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.
Pooja Middha Kapoor,
Nasim Mavaddat,
Parichoy Pal Choudhury,
Amber N Wilcox,
Sara Lindström,
Sabine Behrens,
Kyriaki Michailidou,
Joe Dennis,
Manjeet K Bolla,
Qin Wang,
Audrey Jung,
Zomoroda Abu-Ful,
Thomas Ahearn,
Irene L Andrulis,
Hoda Anton-Culver,
Volker Arndt,
Kristan J Aronson,
Paul L Auer,
Laura E Beane Freeman,
Heiko Becher,
Matthias W Beckmann,
Alicia Beeghly-Fadiel,
Javier Benitez,
Leslie Bernstein,
Stig E Bojesen,
Hiltrud Brauch,
Hermann Brenner,
Thomas Brüning,
Qiuyin Cai,
Daniele Campa,
Federico Canzian,
Angel Carracedo,
Brian D Carter,
Jose E Castelao,
Stephen J Chanock,
Nilanjan Chatterjee,
Georgia Chenevix-Trench,
Christine L Clarke,
Fergus J Couch,
Angela Cox,
Simon S Cross,
Kamila Czene,
James Y Dai,
H Shelton Earp,
Arif B Ekici,
A Heather Eliassen,
Mikael Eriksson,
D Gareth Evans,
Peter A Fasching,
Jonine Figueroa,
Lin Fritschi,
Marike Gabrielson,
Manuela Gago-Dominguez,
Chi Gao,
Susan M Gapstur,
Mia M Gaudet,
Graham G Giles,
Anna González-Neira,
Pascal Guénel,
Lothar Haeberle,
Christopher A Haiman,
Niclas Håkansson,
Per Hall,
Ute Hamann,
Sigrid Hatse,
Jane Heyworth,
Bernd Holleczek,
Robert N Hoover,
John L Hopper,
Anthony Howell,
David J Hunter,
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,
Esther M John,
Michael E Jones,
Rudolf Kaaks,
Renske Keeman,
Cari M Kitahara,
Yon-Dschun Ko,
Stella Koutros,
Allison W Kurian,
Diether Lambrechts,
Loic Le Marchand,
Eunjung Lee,
Flavio Lejbkowicz,
Martha Linet,
Jolanta Lissowska,
Ana Llaneza,
Robert J MacInnis,
Maria Elena Martinez,
Tabea Maurer,
Catriona McLean,
Susan L Neuhausen,
William G Newman,
Aaron Norman,
Katie M O'Brien,
Andrew F Olshan,
Janet E Olson,
Håkan Olsson,
Nick Orr,
Charles M Perou,
Guillermo Pita,
Eric C Polley,
Ross L Prentice,
Gad Rennert,
Hedy S Rennert,
Kathryn J Ruddy,
Dale P Sandler,
Christobel Saunders,
Minouk J Schoemaker,
Ben Schöttker,
Fredrick Schumacher,
Christopher Scott,
Rodney J Scott,
Xiao-Ou Shu,
Ann Smeets,
Melissa C Southey,
John J Spinelli,
Jennifer Stone,
Anthony J Swerdlow,
Rulla M Tamimi,
Jack A Taylor,
Melissa A Troester,
Celine M Vachon,
Elke M van Veen,
Xiaoliang Wang,
Clarice R Weinberg,
Caroline Weltens,
Walter Willett,
Stacey J Winham,
Alicja Wolk,
Xiaohong R Yang,
Wei Zheng,
Argyrios Ziogas,
Alison M Dunning,
Paul D P Pharoah,
Marjanka K Schmidt,
Peter Kraft,
Douglas F Easton,
Roger L Milne,
Montserrat García-Closas,
Jenny Chang-Claude
Abstract
We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.