Genome-wide association studies identify four ER negative–specific breast cancer risk loci

Montserrat Garcia-Closas, Fergus J Couch, Sara Lindstrom, Kyriaki Michailidou, Marjanka K Schmidt, Mark N Brook, Nick Orr, Suhn Kyong Rhie, Elio Riboli, Heather S Feigelson, Loic Le Marchand, Julie E Buring, Diana Eccles, Penelope Miron, Peter A Fasching, Hiltrud Brauch, Jenny Chang-Claude, Jane Carpenter, Andrew K Godwin, Heli Nevanlinna, Graham G Giles, Angela Cox, John L Hopper, Manjeet K Bolla, Qin Wang, Joe Dennis, Ed Dicks, Will J Howat, Nils Schoof, Stig E Bojesen, Diether Lambrechts, Annegien Broeks, Irene L Andrulis, Pascal Guénel, Barbara Burwinkel, Elinor J Sawyer, Antoinette Hollestelle, Olivia Fletcher, Robert Winqvist, Hermann Brenner, Arto Mannermaa, Ute Hamann, Alfons Meindl, Annika Lindblom, Wei Zheng, Peter Devillee, Mark S Goldberg, Jan Lubinski, Vessela Kristensen, Anthony Swerdlow, Hoda Anton-Culver, Thilo Dörk, Kenneth Muir, Keitaro Matsuo, Anna H Wu, Paolo Radice, Soo Hwang Teo, Xiao-Ou Shu, William Blot, Daehee Kang, Mikael Hartman, Suleeporn Sangrajrang, Chen-Yang Shen, Melissa C Southey, Daniel J Park, Fleur Hammet, Jennifer Stone, Laura J Van't Veer, Emiel J Rutgers, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Julian Peto, Michael G Schrauder, Arif B Ekici, Matthias W Beckmann, Isabel dos Santos Silva, Nichola Johnson, Helen Warren, Ian Tomlinson, Michael J Kerin, Nicola Miller, Federick Marme, Andreas Schneeweiss, Christof Sohn, Therese Truong, Pierre Laurent-Puig, Pierre Kerbrat, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, Primitiva Menéndez, Heiko Müller, Volker Arndt, Christa Stegmaier, Peter Lichtner, Magdalena Lochmann, Christina Justenhoven, Yon-Dschun Ko, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Dario Greco, Tuomas Heikkinen, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Natalia N Antonenkova, Sara Margolin, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Rosemary Balleine, Chiu-Chen Tseng, David Van Den Berg, Daniel O Stram, Patrick Neven, Anne-Sophie Dieudonné, Karin Leunen, Anja Rudolph, Stefan Nickels, Dieter Flesch-Janys, Paolo Peterlongo, Bernard Peissel, Loris Bernard, Janet E Olson, Xianshu Wang, Kristen Stevens, Gianluca Severi, Laura Baglietto, Catriona McLean, Gerhard A Coetzee, Ye Feng, Brian E Henderson, Fredrick Schumacher, Natalia V Bogdanova, France Labrèche, Martine Dumont, Cheng Har Yip, Nur Aishah Mohd Taib, Ching-Yu Cheng, Martha Shrubsole, Jirong Long, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Robertus A E M Tollenaar, Caroline M Seynaeve, Mieke Kriege, Maartje J Hooning, Ans M W van den Ouweland, Carolien H M van Deurzen, Wei Lu, Yu-Tang Gao, Hui Cai, Sabapathy P Balasubramanian, Simon S Cross, Malcolm W R Reed, Lisa Signorello, Qiuyin Cai, Mitul Shah, Hui Miao, Ching Wan Chan, Kee Seng Chia, Anna Jakubowska, Katarzyna Jaworska, Katarzyna Durda, Chia-Ni Hsiung, Pei-Ei Wu, Jyh-Cherng Yu, Alan Ashworth, Michael Jones, Daniel C Tessier, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Daniel Vincent, Francois Bacot, Christine B Ambrosone, Elisa V Bandera, Esther M John, Gary K Chen, Jennifer J Hu, Jorge L Rodriguez-Gil, Leslie Bernstein, Michael F Press, Regina G Ziegler, Robert M Millikan, Sandra L Deming-Halverson, Sarah Nyante, Sue A Ingles, Quinten Waisfisz, Helen Tsimiklis, Enes Makalic, Daniel Schmidt, Minh Bui, Lorna Gibson, Bertram Müller-Myhsok, Rita K Schmutzler, Rebecca Hein, Norbert Dahmen, Lars Beckmann, Kirsimari Aaltonen, Kamila Czene, Astrid Irwanto, Jianjun Liu, Clare Turnbull, Nazneen Rahman, Hanne Meijers-Heijboer, Andre G Uitterlinden, Fernando Rivadeneira, Curtis Olswold, Susan Slager, Robert Pilarski, Foluso Ademuyiwa, Irene Konstantopoulou, Nicholas G Martin, Grant W Montgomery, Dennis J Slamon, Claudia Rauh, Michael P Lux, Sebastian M Jud, Thomas Bruning, JoEllen Weaver, Priyanka Sharma, Harsh Pathak, Will Tapper, Sue Gerty, Lorraine Durcan, Dimitrios Trichopoulos, Rosario Tumino, Petra H Peeters, Rudolf Kaaks, Daniele Campa, Federico Canzian, Elisabete Weiderpass, Mattias Johansson, Kay-Tee Khaw, Ruth Travis, Françoise Clavel-Chapelon, Laurence N Kolonel, Constance Chen, Andy Beck, Susan E Hankinson, Christine D Berg, Robert N Hoover, Jolanta Lissowska, Jonine D Figueroa, Daniel I Chasman, Mia M Gaudet, W Ryan Diver, Walter C Willett, David J Hunter, Jacques Simard, Javier Benitez, Alison M Dunning, Mark E Sherman, Georgia Chenevix-Trench, Stephen J Chanock, Per Hall, Paul D P Pharoah, Celine Vachon, Douglas F Easton, Christopher A Haiman, Peter Kraft

Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.