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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 KBolla, Joe 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 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 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 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
  • University of Cambridge
  • Queensland Institute of Medical Research
  • Breakthrough Breast Cancer Research Centre
  • Royal Marsden Hospital
  • Stanford University School of Medicine
  • Massachusetts Institute of Technology
  • Antoni van Leeuwenhoek Hospital
  • University of Melbourne
  • University of Warwick
  • University of Manchester
  • Friedrich-Alexander University Erlangen-Nürnberg
  • University of California at Los Angeles
  • London School of Hygiene and Tropical Medicine
  • Guy’s Hospital
  • University of Oxford
  • German Cancer Research Center
  • Heidelberg University 
  • Occupational and Social Determinants of Health
  • APHP – Paris Saclay University
  • Copenhagen University Hospital – Herlev and Gentofte
  • University of Copenhagen
  • Centro de Investigación en Red de Enfermedades Raras
  • Hospital Monte Naranco
  • University of California, Irvine
  • Keck School of Medicine of USC
  • Technical University of Munich
  • University of Cologne
  • Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
  • University of Tübingen
  • Helsinki University Hospital
  • Aichi Cancer Center Hospital and Research Institute
  • Hannover Medical School
  • Karolinska Institutet
  • University of Eastern Finland
  • Vesalius Research Center
  • KU Leuven
  • University Hospitals Leuven
  • University of Hamburg
  • FIRC Institute of Molecular Oncology
  • IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano
  • Mayo Clinic Rochester, MN
  • Cancer Council Victoria
  • McGill University
  • McGill University Health Centre, Royal Victoria Hospital
  • Sime Darby Medical Centre
  • University of Malaya
  • University of Oslo
  • Vanderbilt University
  • University of Oulu
  • Northern Finland Laboratory Centre NordLab
  • University of Toronto
  • Leiden University
  • Erasmus University Rotterdam
  • National Cancer Institute (NCI)
  • Shanghai Cancer Institute
  • University of Sheffield
  • International Epidemiology Institute
  • Seoul National University
  • MOH Holdings Pte Ltd.
  • National University of Singapore
  • Pomeranian Medical University in Szczecin
  • International Agency for Research on Cancer
  • The National Cancer Institute
  • Roswell Park Cancer Institute
  • Ohio State University
  • China Medical University Taichung
  • Academia Sinica - Institute of Biomedical Sciences
  • Institute of Cancer Research
  • Centre for Epidemiology and Biostatistics
  • Cancer Prevention Institute of California
  • Columbia University
  • Fox Chase Cancer Center
  • University of Utah School of Medicine
  • State Research Institute Centre for Innovative Medicine
  • Latvian Biomedical Research and Study Centre
  • Beth Israel Deaconess Medical Center
  • University of Pretoria
  • City of Hope National Med Center
  • Rigshospitalet
  • Centre for Biomedical Research on Rare Diseases (CIBERER)
  • European Institute of Oncology
  • University of Florence
  • University of Rome La Sapienza
  • Demokritos National Centre for Scientific Research
  • Dana-Farber Cancer Institute
  • Shaukat Khanum Memorial Cancer Hospital and Research Centre
  • Guy's and St Thomas' NHS Foundation Trust
  • University of Kansas
  • University Hospital of Schleswig-Holstein
  • Heinrich Heine University Düsseldorf
  • Institute of Human Genetics
  • Centre de Recherche en Cancérologie de Lyon
  • Institut Curie
  • Université Paris Cité
  • Hospices Civils de LyonCentre Léon Bérard
  • Georgetown University
  • Ghent University Hospital
  • Hospital Clinico San Carlos
  • University of Helsinki
  • Radboud University Nijmegen
  • Netherlands Cancer Institute
  • Hong Kong Sanatorium & Hospital
  • The University of Hong Kong
  • National Institute of Oncology
  • Vall d'Hebron University Hospital
  • Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta
  • Institute Catala Oncologia
  • Department of Pathology
  • Université Laval Research Center
  • IRCCS Istituto Oncologico Veneto - Padova
  • North Region Cancer Registry, Portuguese Oncology Institute
  • University of Porto
  • Masaryk University
  • Memorial Sloan-Kettering Cancer Center
  • Medical University of Vienna
  • Moffitt Cancer Center
  • National Institute of Health Bogotá
  • Lady Davis Carmel Medical Center
  • Carmel Medical Center and Technion Faculty of Medicine
  • N.N. Petrov Institute of Oncology
  • NorthShore University HealthSystem
  • Peter Maccallum Cancer Centre
  • University Health Network
  • University of Southern Denmark
  • Odense University Hospital
  • University of Pisa
  • The Gertner Institute
  • Lund University
  • Uppsala University
  • The University of Chicago
  • University of California at San Francisco
  • University of Pennsylvania Health System
  • University of Texas Health Science Center at Houston
  • Cedars-Sinai Medical Center
  • University of Hawaii Cancer Center
  • Dalhousie University, Faculty of Medicine
  • University of Western Australia
  • Harvard University
  • Harvard T.H. Chan School of Public Health

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

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.

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

  1. SDG 3 - Good Health and Well-being
    SDG 3 Good Health and Well-being

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