Open AccessGenome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses
Author(s) -
Haoyu Zhang,
Thomas U. Ahearn,
Julie Lecarpentier,
Daniel R. Barnes,
Jonathan Beesley,
Guanghao Qi,
Xia Jiang,
Tracy O’Mara,
Ni Zhao,
Manjeet K. Bolla,
Alison M. Dunning,
Joe Dennis,
Qin Wang,
Zumuruda Abu Ful,
Kristiina Aittomäki,
Irene L. Andrulis,
Hoda AntonCulver,
Volker Arndt,
Kristan J. Aronson,
Banu K. Arun,
Paul L. Auer,
Jacopo Azzollini,
Daniel Barrowdale,
Heiko Becher,
Matthias W. Beckmann,
Sabine Behrens,
Javier Benı́tez,
Marina Bermisheva,
Katarzyna Białkowska,
Ana Blanco,
Carl Blomqvist,
Natalia Bogdanova,
Stig E. Bojesen,
Bernardo Bonanni,
Davide Bondavalli,
Åke Borg,
Hiltrud Brauch,
Hermann Brenner,
Ignacio Briceño,
Annegien Broeks,
Sara Y. Brucker,
Thomas Brüning,
Barbara Burwinkel,
Saundra S. Buys,
Helen Byers,
Trinidad Caldés,
Maria A. Caligo,
Mariarosaria Calvello,
Daniele Campa,
Jose E. Castelao,
Jenny ChangClaude,
Stephen J. Chanock,
Melissa Christiaens,
Hans Christiansen,
Wendy K. Chung,
Kathleen Claes,
Christine L. Clarke,
Sten Cornelissen,
Fergus J. Couch,
Angela Cox,
Simon S. Cross,
Kamila Czene,
Mary B. Daly,
Peter Devilee,
Orland Dı́ez,
Susan M. Domchek,
Thilo Dörk,
Miriam Dwek,
Diana Eccles,
Arif B. Ekici,
D. Gareth Evans,
Peter A. Fasching,
Jonine D. Figueroa,
Lenka Foretová,
Florentia Fostira,
Eitan Friedman,
Debra Frost,
Manuela Gago-Domínguez,
Susan M. Gapstur,
Judy E. Garber,
José Á. García-Sáenz,
Mia M. Gaudet,
Simon A. Gayther,
Graham G. Giles,
Andrew K. Godwin,
Mark S. Goldberg,
David E. Goldgar,
Anna GonzálezNeira,
Mark H. Greene,
Jacek Gronwald,
Pascal Guénel,
Lothar Häberle,
Eric Hahnen,
Christopher A. Haiman,
Christopher R. Hake,
Per Hall,
Ute Hamann,
Elaine Harkness,
Bernadette A M Heemskerk-Gerritsen,
Peter Hillemanns,
Frans B.L. Hogervorst,
Bernd Holleczek,
Antoinette Hollestelle,
Maartje J. Hooning,
Robert N. Hoover,
John L. Hopper,
Anthony Howell,
Hanna Huebner,
Peter J. Hulick,
Evgeny N. Imyanitov,
Claudine Isaacs,
Louise Izatt,
Agnes Jager,
Milena Jakimovska,
Anna Jakubowska,
Paul James,
Ramūnas Janavičius,
Wolfgang Janni,
Esther M. John,
Michael E. Jones,
Audrey Jung,
Rudolf Kaaks,
Pooja Middha,
Beth Y. Karlan,
Renske Keeman,
Sofia Khan,
Elza Khusnutdinova,
Cari M. Kitahara,
YonDschun Ko,
Irene Konstantopoulou,
Linetta B. Koppert,
Stella Koutros,
Vessela Kristensen,
AnneVibeke Lænkholm,
Diether Lambrechts,
Susanna C. Larsson,
Pierre LaurentPuig,
Conxi Lázaro,
Emilija Lazarova,
Flavio Lejbkowicz,
Goska Leslie,
Fabienne Lesueur,
Annika Lindblom,
Jolanta Lissowska,
WingYee Lo,
Jennifer T. Loud,
Jan Lubiński,
Alicja Łukomska,
Robert J. MacInnis,
Arto Mannermaa,
Mehdi Manoochehri,
Siranoush Manoukian,
Sara Margolin,
Marı́a Elena Martı́nez,
Laura Matricardi,
Lesley McGuffog,
Catriona McLean,
Noura Mebirouk,
Alfons Meindl,
Usha Me,
Austin Miller,
Elvira Mingazheva,
Marco Montagna,
Anna Marie Mulligan,
Claire Mulot,
Taru A. Muranen,
Katherine L. Nathanson,
Susan L. Neuhausen,
Heli Nevanlinna,
Patrick Neven,
William G. Newman,
Finn C. Nielsen,
Liene Ņikitina-Zaķe,
Jesse Nodora,
Kenneth Offit,
Edith Oláh,
Olufunmilayo I. Olopade,
Håkan Olsson,
Nick Orr,
Laura Papi,
J. Papp,
TjoungWon ParkSimon,
Michael T. Parsons,
Bernard Peissel,
Ana Peixoto,
Beth N. Peshkin,
Paolo Peterlongo,
Julian Peto,
KellyAnne Phillips,
Marion Piedmonte,
Dijana PlaseskaKaranfilska,
Karolina Prajzendanc,
Ross L. Prentice,
Darya Prokofyeva,
Brigitte Rack,
Paolo Radice,
Susan J. Ramus,
Johanna Rantala,
Muhammad Usman Rashid,
Gad Rennert,
Gad Rennert,
Harvey A. Risch,
Atocha Romero,
Matti A. Rookus,
Matthias Rübner,
Thomas Rüdiger,
Emmanouil Saloustros,
Sarah Sampson,
Dale P. Sandler,
Elinor Sawyer,
Maren T. Scheuner,
Rita K. Schmutzler,
Andreas Schneeweiß,
Minouk J. Schoemaker,
Ben Schöttker,
Peter Schürmann,
Leigha Senter,
Priyanka Sharma,
Mark E. Sherman,
XiaoOu Shu,
Christian F. Singer,
Snezhana Smichkoska,
Penny Soucy,
Melissa C. Southey,
John J. Spinelli,
Jennifer Stone,
Dominique StoppaLyonnet,
Anthony J. Swerdlow,
Csilla I. Szabo,
Rulla M. Tamimi,
William J. Tapper,
Jack A. Taylor,
Manuel R. Teixeira,
Mary Beth Terry,
Mads Thomassen,
Darcy L. Thull,
Marc Tischkowitz,
Amanda EwartToland,
Rob A.E.M. Tollenaar,
Ian Tomlinson,
Diana Torres,
Melissa A. Troester,
Thérèse Truong,
Nadine Tung,
Michael Untch,
Celine M. Vachon,
Ans M.W. van den Ouweland,
Lizet E. van der Kolk,
Elke M. van Veen,
Elizabeth J. van Rensburg,
Ana Vega,
Barbara Wappenschmidt,
Clarice R. Weinberg,
Jeffrey N. Weitzel,
Hans Wildiers,
Robert Winqvist,
Alicja Wolk,
Xiaohong R. Yang,
Drakoulis Yannoukakos,
Zheng Wang,
Kristin K. Zorn,
Roger L. Milne,
Peter Kraft,
Jacques Simard,
Paul Pharoah,
Kyriaki Michailidou,
Antonis C. Antoniou,
Marjanka K. Schmidt,
Georgia Chenevix-Trench,
Douglas F. Easton,
Nilanjan Chatterjee,
Montserrat García-Closas
Publication year - 2020
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-020-0609-2
Subject(s) - biology , breast cancer , genome wide association study , estrogen receptor , genetic association , genetics , heritability , disease , genetic predisposition , cancer , odds ratio , oncology , single nucleotide polymorphism , medicine , genotype , gene
Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype 1-3 . To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10 -8 ), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.