Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.
Alison M Dunning,
Kyriaki Michailidou,
Karoline B Kuchenbaecker,
Deborah Thompson,
Juliet D French,
Jonathan Beesley,
Catherine S Healey,
Siddhartha Kar,
Karen A Pooley,
Elena Lopez-Knowles,
Ed Dicks,
Daniel Barrowdale,
Nicholas A Sinnott-Armstrong,
Richard C Sallari,
Kristine M Hillman,
Susanne Kaufmann,
Haran Sivakumaran,
Mahdi Moradi Marjaneh,
Jason S Lee,
Margaret Hills,
Monika Jarosz,
Suzie Drury,
Sander Canisius,
Manjeet K Bolla,
Joe Dennis,
Qin Wang,
John L Hopper,
Melissa C Southey,
Annegien Broeks,
Marjanka K Schmidt,
Artitaya Lophatananon,
Kenneth Muir,
Matthias W Beckmann,
Peter A Fasching,
Isabel Dos-Santos-Silva,
Julian Peto,
Elinor J Sawyer,
Ian Tomlinson,
Barbara Burwinkel,
Frederik Marme,
Pascal Guénel,
Thérèse Truong,
Stig E Bojesen,
Henrik Flyger,
Anna González-Neira,
Jose I A Perez,
Hoda Anton-Culver,
Lee Eunjung,
Volker Arndt,
Hermann Brenner,
Alfons Meindl,
Rita K Schmutzler,
Hiltrud Brauch,
Ute Hamann,
Kristiina Aittomäki,
Carl Blomqvist,
Hidemi Ito,
Keitaro Matsuo,
Natasha Bogdanova,
Thilo Dörk,
Annika Lindblom,
Sara Margolin,
Veli-Matti Kosma,
Arto Mannermaa,
Chiu-Chen Tseng,
Anna H Wu,
Diether Lambrechts,
Hans Wildiers,
Jenny Chang-Claude,
Anja Rudolph,
Paolo Peterlongo,
Paolo Radice,
Janet E Olson,
Graham G Giles,
Roger L Milne,
Christopher A Haiman,
Brian E Henderson,
Mark S Goldberg,
Soo H Teo,
Cheng Har Yip,
Silje Nord,
Anne-Lise Borresen-Dale,
Vessela Kristensen,
Jirong Long,
Wei Zheng,
Katri Pylkäs,
Robert Winqvist,
Irene L Andrulis,
Julia A Knight,
Peter Devilee,
Caroline Seynaeve,
Jonine Figueroa,
Mark E Sherman,
Kamila Czene,
Hatef Darabi,
Antoinette Hollestelle,
Ans M W van den Ouweland,
Keith Humphreys,
Yu-Tang Gao,
Xiao-Ou Shu,
Angela Cox,
Simon S Cross,
William Blot,
Qiuyin Cai,
Maya Ghoussaini,
Barbara J Perkins,
Mitul Shah,
Ji-Yeob Choi,
Daehee Kang,
Soo Chin Lee,
Mikael Hartman,
Maria Kabisch,
Diana Torres,
Anna Jakubowska,
Jan Lubinski,
Paul Brennan,
Suleeporn Sangrajrang,
Christine B Ambrosone,
Amanda E Toland,
Chen-Yang Shen,
Pei-Ei Wu,
Nick Orr,
Anthony Swerdlow,
Lesley McGuffog,
Sue Healey,
Andrew Lee,
Miroslav Kapuscinski,
Esther M John,
Mary Beth Terry,
Mary B Daly,
David E Goldgar,
Saundra S Buys,
Ramunas Janavicius,
Laima Tihomirova,
Nadine Tung,
Cecilia M Dorfling,
Elizabeth J van Rensburg,
Susan L Neuhausen,
Bent Ejlertsen,
Thomas V O Hansen,
Ana Osorio,
Javier Benitez,
Rachel Rando,
Jeffrey N Weitzel,
Bernardo Bonanni,
Bernard Peissel,
Siranoush Manoukian,
Laura Papi,
Laura Ottini,
Irene Konstantopoulou,
Paraskevi Apostolou,
Judy Garber,
Muhammad Usman Rashid,
Debra Frost,
,
Louise Izatt,
Steve Ellis,
Andrew K Godwin,
Norbert Arnold,
Dieter Niederacher,
Kerstin Rhiem,
Nadja Bogdanova-Markov,
Charlotte Sagne,
Dominique Stoppa-Lyonnet,
Francesca Damiola,
,
Olga M Sinilnikova,
Sylvie Mazoyer,
Claudine Isaacs,
Kathleen B M Claes,
Kim De Leeneer,
Miguel de la Hoya,
Trinidad Caldes,
Heli Nevanlinna,
Sofia Khan,
Arjen R Mensenkamp,
,
Maartje J Hooning,
Matti A Rookus,
Ava Kwong,
Edith Olah,
Orland Diez,
Joan Brunet,
Miquel Angel Pujana,
Jacek Gronwald,
Tomasz Huzarski,
Rosa B Barkardottir,
Rachel Laframboise,
Penny Soucy,
Marco Montagna,
Simona Agata,
Manuel R Teixeira,
,
Sue Kyung Park,
Noralane Lindor,
Fergus J Couch,
Marc Tischkowitz,
Lenka Foretova,
Joseph Vijai,
Kenneth Offit,
Christian F Singer,
Christine Rappaport,
Catherine M Phelan,
Mark H Greene,
Phuong L Mai,
Gad Rennert,
Evgeny N Imyanitov,
Peter J Hulick,
Kelly-Anne Phillips,
Marion Piedmonte,
Anna Marie Mulligan,
Gord Glendon,
Anders Bojesen,
Mads Thomassen,
Maria A Caligo,
Sook-Yee Yoon,
Eitan Friedman,
Yael Laitman,
Ake Borg,
Anna von Wachenfeldt,
Hans Ehrencrona,
Johanna Rantala,
Olufunmilayo I Olopade,
Patricia A Ganz,
Robert L Nussbaum,
Simon A Gayther,
Katherine L Nathanson,
Susan M Domchek,
Banu K Arun,
Gillian Mitchell,
Beth Y Karlan,
Jenny Lester,
Gertraud Maskarinec,
Christy Woolcott,
Christopher Scott,
Jennifer Stone,
Carmel Apicella,
Rulla Tamimi,
Robert Luben,
Kay-Tee Khaw,
Åslaug Helland,
Vilde Haakensen,
Mitch Dowsett,
Paul D P Pharoah,
Jacques Simard,
Per Hall,
Montserrat García-Closas,
Celine Vachon,
Georgia Chenevix-Trench,
Antonis C Antoniou,
Douglas F Easton,
Stacey L Edwards
Abstract
We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.