Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer.
Fergus J Couch,
Karoline B Kuchenbaecker,
Kyriaki Michailidou,
Gustavo A Mendoza-Fandino,
Silje Nord,
Janna Lilyquist,
Curtis Olswold,
Emily Hallberg,
Simona Agata,
Habibul Ahsan,
Kristiina Aittomäki,
Christine Ambrosone,
Irene L Andrulis,
Hoda Anton-Culver,
Volker Arndt,
Banu K Arun,
Brita Arver,
Monica Barile,
Rosa B Barkardottir,
Daniel Barrowdale,
Lars Beckmann,
Matthias W Beckmann,
Javier Benitez,
Stephanie V Blank,
Carl Blomqvist,
Natalia V Bogdanova,
Stig E Bojesen,
Manjeet K Bolla,
Bernardo Bonanni,
Hiltrud Brauch,
Hermann Brenner,
Barbara Burwinkel,
Saundra S Buys,
Trinidad Caldes,
Maria A Caligo,
Federico Canzian,
Jane Carpenter,
Jenny Chang-Claude,
Stephen J Chanock,
Wendy K Chung,
Kathleen B M Claes,
Angela Cox,
Simon S Cross,
Julie M Cunningham,
Kamila Czene,
Mary B Daly,
Francesca Damiola,
Hatef Darabi,
Miguel de la Hoya,
Peter Devilee,
Orland Diez,
Yuan C Ding,
Riccardo Dolcetti,
Susan M Domchek,
Cecilia M Dorfling,
Isabel Dos-Santos-Silva,
Martine Dumont,
Alison M Dunning,
Diana M Eccles,
Hans Ehrencrona,
Arif B Ekici,
Heather Eliassen,
Steve Ellis,
Peter A Fasching,
Jonine Figueroa,
Dieter Flesch-Janys,
Asta Försti,
Florentia Fostira,
William D Foulkes,
Tara Friebel,
Eitan Friedman,
Debra Frost,
Marike Gabrielson,
Marilie D Gammon,
Patricia A Ganz,
Susan M Gapstur,
Judy Garber,
Mia M Gaudet,
Simon A Gayther,
Anne-Marie Gerdes,
Maya Ghoussaini,
Graham G Giles,
Gord Glendon,
Andrew K Godwin,
Mark S Goldberg,
David E Goldgar,
Anna González-Neira,
Mark H Greene,
Jacek Gronwald,
Pascal Guénel,
Marc Gunter,
Lothar Haeberle,
Christopher A Haiman,
Ute Hamann,
Thomas V O Hansen,
Steven Hart,
Sue Healey,
Tuomas Heikkinen,
Brian E Henderson,
Josef Herzog,
Frans B L Hogervorst,
Antoinette Hollestelle,
Maartje J Hooning,
Robert N Hoover,
John L Hopper,
Keith Humphreys,
David J Hunter,
Tomasz Huzarski,
Evgeny N Imyanitov,
Claudine Isaacs,
Anna Jakubowska,
Paul James,
Ramunas Janavicius,
Uffe Birk Jensen,
Esther M John,
Michael Jones,
Maria Kabisch,
Siddhartha Kar,
Beth Y Karlan,
Sofia Khan,
Kay-Tee Khaw,
Muhammad G Kibriya,
Julia A Knight,
Yon-Dschun Ko,
Irene Konstantopoulou,
Veli-Matti Kosma,
Vessela Kristensen,
Ava Kwong,
Yael Laitman,
Diether Lambrechts,
Conxi Lazaro,
Eunjung Lee,
Loic Le Marchand,
Jenny Lester,
Annika Lindblom,
Noralane Lindor,
Sara Lindstrom,
Jianjun Liu,
Jirong Long,
Jan Lubinski,
Phuong L Mai,
Enes Makalic,
Kathleen E Malone,
Arto Mannermaa,
Siranoush Manoukian,
Sara Margolin,
Frederik Marme,
John W M Martens,
Lesley McGuffog,
Alfons Meindl,
Austin Miller,
Roger L Milne,
Penelope Miron,
Marco Montagna,
Sylvie Mazoyer,
Anna M Mulligan,
Taru A Muranen,
Katherine L Nathanson,
Susan L Neuhausen,
Heli Nevanlinna,
Børge G Nordestgaard,
Robert L Nussbaum,
Kenneth Offit,
Edith Olah,
Olufunmilayo I Olopade,
Janet E Olson,
Ana Osorio,
Sue K Park,
Petra H Peeters,
Bernard Peissel,
Paolo Peterlongo,
Julian Peto,
Catherine M Phelan,
Robert Pilarski,
Bruce Poppe,
Katri Pylkäs,
Paolo Radice,
Nazneen Rahman,
Johanna Rantala,
Christine Rappaport,
Gad Rennert,
Andrea Richardson,
Mark Robson,
Isabelle Romieu,
Anja Rudolph,
Emiel J Rutgers,
Maria-Jose Sanchez,
Regina M Santella,
Elinor J Sawyer,
Daniel F Schmidt,
Marjanka K Schmidt,
Rita K Schmutzler,
Fredrick Schumacher,
Rodney Scott,
Leigha Senter,
Priyanka Sharma,
Jacques Simard,
Christian F Singer,
Olga M Sinilnikova,
Penny Soucy,
Melissa Southey,
Doris Steinemann,
Marie Stenmark-Askmalm,
Dominique Stoppa-Lyonnet,
Anthony Swerdlow,
Csilla I Szabo,
Rulla Tamimi,
William Tapper,
Manuel R Teixeira,
Soo-Hwang Teo,
Mary B Terry,
Mads Thomassen,
Deborah Thompson,
Laima Tihomirova,
Amanda E Toland,
Robert A E M Tollenaar,
Ian Tomlinson,
Thérèse Truong,
Helen Tsimiklis,
Alex Teulé,
Rosario Tumino,
Nadine Tung,
Clare Turnbull,
Giski Ursin,
Carolien H M van Deurzen,
Elizabeth J van Rensburg,
Raymonda Varon-Mateeva,
Zhaoming Wang,
Shan Wang-Gohrke,
Elisabete Weiderpass,
Jeffrey N Weitzel,
Alice Whittemore,
Hans Wildiers,
Robert Winqvist,
Xiaohong R Yang,
Drakoulis Yannoukakos,
Song Yao,
M Pilar Zamora,
Wei Zheng,
Per Hall,
Peter Kraft,
Celine Vachon,
Susan Slager,
Georgia Chenevix-Trench,
Paul D P Pharoah,
Alvaro A N Monteiro,
Montserrat García-Closas,
Douglas F Easton,
Antonis C Antoniou
Abstract
Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.