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Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers

2013; Elsevier BV; Volume: 92; Issue: 4 Linguagem: Inglês

10.1016/j.ajhg.2013.01.002

1537-6605

Juliet D. French, Maya Ghoussaini, Stacey L. Edwards, Kerstin B. Meyer, Kyriaki Michailidou, Shahana Ahmed, Sofia Khan, Mel Maranian, Martin O’Reilly, Kristine M. Hillman, Joshua A. Betts, Thomas Carroll, Peter J. Bailey, Ed Dicks, Jonathan Beesley, Jonathan P. Tyrer, Ana-Teresa Maia, Andrew Beck, Nicholas Knoblauch, Constance Chen, Peter Kraft, Daniel R. Barnes, Anna González‐Neira, M. Rosario Alonso, Daniel Herrero, Daniel C. Tessier, Daniel Vincent, François Bacot, Craig Luccarini, Caroline Baynes, Don Conroy, Joe Dennis, Manjeet K. Bolla, Qin Wang, John L. Hopper, Melissa C. Southey, Marjanka K. Schmidt, Annegien Broeks, Senno Verhoef, Sten Cornelissen, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart‐Brown, Pornthep Siriwanarangsan, Peter A. Fasching, Christian R. Loehberg, Arif B. Ekici, Matthias W. Beckmann, Julian Peto, Isabel dos‐Santos‐Silva, Nichola Johnson, Zoe Aitken, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Frederik Marmé, Andreas Schneeweiß, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Pierre Laurent‐Puig, F. Ménégaux, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Roger L. Milne, M. Pilar Zamora, José Ignacio Arias Pérez, Javier Benı́tez, Hoda Anton‐Culver, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K. Schmutzler, Christoph Engel, Hiltrud Brauch, Ute Hamann, Christina Justenhoven, Kirsimari Aaltonen, Päivi Heikkilä, Kristiina Aittomäki, Carl Blomqvist, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Aiko Sueta, Natalia Bogdanova, Natalia Antonenkova, Thilo Dörk, Annika Lindblom, Sara Margolin, Graham J. Mann, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Anna H. Wu, Chiu-Chen Tseng, David Van Den Berg, Daniel O. Stram, Diether Lambrechts, Stéphanie Peeters, Ann Smeets, Giuseppe Floris, Jenny Chang‐Claude, Anja Rudolph, Stefan Nickels, Dieter Flesch‐Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Domenico Sardella, Fergus J. Couch, Xianshu Wang, V. Shane Pankratz, Adam F. Lee, Graham G. Giles, Gianluca Severi, Laura Baglietto, Christopher A. Haiman, Brian E. Henderson, Fredrick R. Schumacher, Loı̈c Le Marchand, Jacques Simard, Mark S. Goldberg, France Labrèche, Martine Dumont, Soo‐Hwang Teo, Cheng Har Yip, Char-Hong Ng, Eranga N. Vithana, Vessela Kristensen, Wei Zheng, Sandra Deming-Halverson, Martha J. Shrubsole, Jirong Long, Robert Winqvist, Katri Pylkäs, Arja Jukkola‐Vuorinen, Mervi Grip, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Peter Devilee, Caroline Seynaeve, Montserrat García‐Closas, Jonine D. Figueroa, Stephen J. Chanock, Jolanta Lissowska, Kamila Czene, Daniel Klevebring, Nils Schoof, Maartje J. Hooning, John W.M. Martens, J. Margriet Collée, Madeleine M.A. Tilanus‐Linthorst, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Xiao‐Ou Shu, Wei Lü, Yu-Tang Gao, Hui Cai, Angela Cox, Sabapathy P. Balasubramanian, William J. Blot, Lisa B. Signorello, Qiuyin Cai, Paul D.P. Pharoah, Catherine S. Healey, Mitul Shah, Karen A. Pooley, Daehee Kang, Keun-Young Yoo, Dong‐Young Noh, Mikael Hartman, Hui Miao, Jen-Hwei Sng, Xueling Sim, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska–Bieniek, Katarzyna Durda, Suleeporn Sangrajrang, Valérie Gaborieau, James McKay, Amanda E. Toland, Christine B. Ambrosone, Drakoulis Yannoukakos, Andrew K. Godwin, Chen‐Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Shou-Tung Chen, Anthony J. Swerdlow, Alan Ashworth, Nick Orr, Minouk J. Schoemaker, Bruce A.J. Ponder, Heli Nevanlinna, Melissa A. Brown, Georgia Chenevix‐Trench, Douglas F. Easton, Alison M. Dunning,

Cancer-related Molecular Pathways

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1. Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.