Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

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Authors

  • Alison M. Dunning
  • Kyriaki Michailidou
  • Karoline B. Kuchenbaecker
  • Deborah J. Thompson
  • Juliet D. French
  • Jonathan Beesley
  • And 242 others
  • 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 KBolla
  • Joe G. Dennis
  • Qin Wang
  • John LHopper
  • 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
  • Thérse Truong
  • Stig E. Bojesen
  • Henrik Flyger
  • Anna Gonzlez-Neira
  • Jose I.A. Perez
  • Hoda Anton-Culver
  • Lee Eunjung
  • Volker Arndt
  • Hermann Brenner
  • Alfons Meindl
  • Rita K. Schmutzler
  • Hiltrud Brauch
  • Ute Hamann
  • Kristiina Aittomki
  • 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 EOlson
  • Graham GGiles
  • 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 Pylks
  • 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 R 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. OHansen
  • 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. MClaes
  • 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 M. Lindor
  • Fergus J. Couch
  • Marc Tischkowitz
  • Lenka Foretova
  • Joseph Vijai
  • Kenneth Offit
  • Christian F. Singer
  • Christine Rappaport
  • Catherine MPhelan
  • 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 LNathanson
  • 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 N Luben
  • Kay Tee Khaw
  • Slaug Helland
  • Vilde Haakensen
  • Mitch Dowsett
  • Paul D.P. Pharoah
  • Jacques Simard
  • Per Hall
  • Montserrat Garca-Closas
  • Celine Vachon
  • Georgia Chenevix-Trench
  • Antonis C. Antoniou
  • Douglas F. Easton
  • Stacey L. Edwards

Research units

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.

Peer-reviewedYes
Original languageEnglish
Pages (from-to)374-386
Number of pages13
JournalNature Genetics
Volume48
Issue number4
DOIs
StatePublished - 29 Mar 2016

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