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

Alison M. Dunning, Kyriaki Michailidou, Karoline Kuchenbaecker, Deborah J. 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 HillsMonika Jarosz, Suzie Drury, Sander Canisius, Manjeet KBolla, Joe Dennis, Qin Wang, John LHopper, Mellissa C. Southey, Annegien Broeks, M. K. Schmidt, Artitaya Lophatananon, Kenneth Muir, Matthias W. Beckmann, Peter A. Fasching, Isabel Dos-Santos-Silva, Julian Peto, Elinor J. Sawyer, Ian P M Tomlinson, Barbara Burwinkel, Frederik Marme, Pascal Guenel, Thérèse Truong, Stig E. Bojesen, Henrik Flyger, Anna Gonzlez-Neira, Ji Arias Pérez, 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, Natalia V. Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Veli Matti Kosma, Arto Mannermaa, Chiu Chen Tseng, Anna H. Wu, Diether Lambrechts, H. 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 Hwang Teo, Cheng Har Yip, Silje Nord, Anne Lise Børresen-Dale, Vessela Kristensen, Jirong Long, Wei Zheng, Katri Pylks, Robert Winqvist, Irene L. Andrulis, Julia A. Knight, Peter Devilee, Caroline Seynaeve, Jonine D. Figueroa, Mark E. Sherman, Kamila Czene, Hartef Darabi, Antoinette Hollestelle, Ans M W Van Den Ouweland, Keith Humphreys, Yu Tang Gao, Xiao Ou Shu, Angela Cox, Simon S. Cross, William J. 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 J. Swerdlow, Lesley McGuffog, Sue Healey, Andrew Lee, Miroslav K. Kapuscinski, Esther M. John, Mary B. Terry, Mary B. Daly, David 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 Weitzel, Bernardo Bonanni, Bernard Gilles Peissel, Siranoush Manoukian, Laura Papi, Laura Ottini, Irene Konstantopoulou, Paraskevi Apostolou, Judy E. Garber, Muhammad Usman Rashid, D. Frost, L. 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 Mensenkamp, Maartje J. Hooning, M. A. Rookus, A. Kwong, Edith Olah, Orland Diez, Joan Brunet, Miguel Angel Pujana, Jacek Gronwald, Tomasz Huzarski, Rosa Bjork 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 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, G. Maskarinec, Christy Woolcott, Christopher G. 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

Research output: Contribution to journalArticle

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
Publication statusPublished - Mar 29 2016

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ASJC Scopus subject areas

  • Genetics

Cite this

Dunning, A. M., Michailidou, K., Kuchenbaecker, K., Thompson, D. J., French, J. D., Beesley, J., Healey, C. S., Kar, S., Pooley, K. A., Lopez-Knowles, E., Dicks, E., Barrowdale, D., Sinnott-Armstrong, N. A., Sallari, R. C., Hillman, K. M., Kaufmann, S., Sivakumaran, H., Marjaneh, M. M., Lee, J. S., ... Edwards, S. L. (2016). Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nature Genetics, 48(4), 374-386. https://doi.org/10.1038/ng.3521