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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer.

  • Author(s): Couch, Fergus J;
  • Kuchenbaecker, Karoline B;
  • Michailidou, Kyriaki;
  • Mendoza-Fandino, Gustavo A;
  • Nord, Silje;
  • Lilyquist, Janna;
  • Olswold, Curtis;
  • Hallberg, Emily;
  • Agata, Simona;
  • Ahsan, Habibul;
  • Aittomäki, Kristiina;
  • Ambrosone, Christine;
  • Andrulis, Irene L;
  • Anton-Culver, Hoda;
  • Arndt, Volker;
  • Arun, Banu K;
  • Arver, Brita;
  • Barile, Monica;
  • Barkardottir, Rosa B;
  • Barrowdale, Daniel;
  • Beckmann, Lars;
  • Beckmann, Matthias W;
  • Benitez, Javier;
  • Blank, Stephanie V;
  • Blomqvist, Carl;
  • Bogdanova, Natalia V;
  • Bojesen, Stig E;
  • Bolla, Manjeet K;
  • Bonanni, Bernardo;
  • Brauch, Hiltrud;
  • Brenner, Hermann;
  • Burwinkel, Barbara;
  • Buys, Saundra S;
  • Caldes, Trinidad;
  • Caligo, Maria A;
  • Canzian, Federico;
  • Carpenter, Jane;
  • Chang-Claude, Jenny;
  • Chanock, Stephen J;
  • Chung, Wendy K;
  • Claes, Kathleen BM;
  • Cox, Angela;
  • Cross, Simon S;
  • Cunningham, Julie M;
  • Czene, Kamila;
  • Daly, Mary B;
  • Damiola, Francesca;
  • Darabi, Hatef;
  • de la Hoya, Miguel;
  • Devilee, Peter;
  • Diez, Orland;
  • Ding, Yuan C;
  • Dolcetti, Riccardo;
  • Domchek, Susan M;
  • Dorfling, Cecilia M;
  • Dos-Santos-Silva, Isabel;
  • Dumont, Martine;
  • Dunning, Alison M;
  • Eccles, Diana M;
  • Ehrencrona, Hans;
  • Ekici, Arif B;
  • Eliassen, Heather;
  • Ellis, Steve;
  • Fasching, Peter A;
  • Figueroa, Jonine;
  • Flesch-Janys, Dieter;
  • Försti, Asta;
  • Fostira, Florentia;
  • Foulkes, William D;
  • Friebel, Tara;
  • Friedman, Eitan;
  • Frost, Debra;
  • Gabrielson, Marike;
  • Gammon, Marilie D;
  • Ganz, Patricia A;
  • Gapstur, Susan M;
  • Garber, Judy;
  • Gaudet, Mia M;
  • Gayther, Simon A;
  • Gerdes, Anne-Marie;
  • Ghoussaini, Maya;
  • Giles, Graham G;
  • Glendon, Gord;
  • Godwin, Andrew K;
  • Goldberg, Mark S;
  • Goldgar, David E;
  • González-Neira, Anna;
  • Greene, Mark H;
  • Gronwald, Jacek;
  • Guénel, Pascal;
  • Gunter, Marc;
  • Haeberle, Lothar;
  • Haiman, Christopher A;
  • Hamann, Ute;
  • Hansen, Thomas VO;
  • Hart, Steven;
  • Healey, Sue;
  • Heikkinen, Tuomas;
  • Henderson, Brian E;
  • Herzog, Josef;
  • Hogervorst, Frans BL;
  • Hollestelle, Antoinette;
  • Hooning, Maartje J;
  • Hoover, Robert N;
  • Hopper, John L;
  • Humphreys, Keith;
  • Hunter, David J;
  • Huzarski, Tomasz;
  • Imyanitov, Evgeny N;
  • Isaacs, Claudine;
  • Jakubowska, Anna;
  • James, Paul;
  • Janavicius, Ramunas;
  • Jensen, Uffe Birk;
  • John, Esther M;
  • Jones, Michael;
  • Kabisch, Maria;
  • Kar, Siddhartha;
  • Karlan, Beth Y;
  • Khan, Sofia;
  • Khaw, Kay-Tee;
  • Kibriya, Muhammad G;
  • Knight, Julia A;
  • Ko, Yon-Dschun;
  • Konstantopoulou, Irene;
  • Kosma, Veli-Matti;
  • Kristensen, Vessela;
  • Kwong, Ava;
  • Laitman, Yael;
  • Lambrechts, Diether;
  • Lazaro, Conxi;
  • Lee, Eunjung;
  • Le Marchand, Loic;
  • Lester, Jenny;
  • Lindblom, Annika;
  • Lindor, Noralane;
  • Lindstrom, Sara;
  • Liu, Jianjun;
  • Long, Jirong;
  • Lubinski, Jan;
  • Mai, Phuong L;
  • Makalic, Enes;
  • Malone, Kathleen E;
  • Mannermaa, Arto;
  • Manoukian, Siranoush;
  • Margolin, Sara;
  • Marme, Frederik;
  • Martens, John WM;
  • McGuffog, Lesley;
  • Meindl, Alfons;
  • Miller, Austin;
  • Milne, Roger L;
  • Miron, Penelope;
  • Montagna, Marco;
  • Mazoyer, Sylvie;
  • Mulligan, Anna M;
  • Muranen, Taru A;
  • Nathanson, Katherine L;
  • Neuhausen, Susan L;
  • Nevanlinna, Heli;
  • Nordestgaard, Børge G;
  • Nussbaum, Robert L;
  • Offit, Kenneth;
  • Olah, Edith;
  • Olopade, Olufunmilayo I;
  • Olson, Janet E;
  • Osorio, Ana;
  • Park, Sue K;
  • Peeters, Petra H;
  • Peissel, Bernard;
  • Peterlongo, Paolo;
  • Peto, Julian;
  • Phelan, Catherine M;
  • Pilarski, Robert;
  • Poppe, Bruce;
  • Pylkäs, Katri;
  • Radice, Paolo;
  • Rahman, Nazneen;
  • Rantala, Johanna;
  • Rappaport, Christine;
  • Rennert, Gad;
  • Richardson, Andrea;
  • Robson, Mark;
  • Romieu, Isabelle;
  • Rudolph, Anja;
  • Rutgers, Emiel J;
  • Sanchez, Maria-Jose;
  • Santella, Regina M;
  • Sawyer, Elinor J;
  • Schmidt, Daniel F;
  • Schmidt, Marjanka K;
  • Schmutzler, Rita K;
  • Schumacher, Fredrick;
  • Scott, Rodney;
  • Senter, Leigha;
  • Sharma, Priyanka;
  • Simard, Jacques;
  • Singer, Christian F;
  • Sinilnikova, Olga M;
  • Soucy, Penny;
  • Southey, Melissa;
  • Steinemann, Doris;
  • Stenmark-Askmalm, Marie;
  • Stoppa-Lyonnet, Dominique;
  • Swerdlow, Anthony;
  • Szabo, Csilla I;
  • Tamimi, Rulla;
  • Tapper, William;
  • Teixeira, Manuel R;
  • Teo, Soo-Hwang;
  • Terry, Mary B;
  • Thomassen, Mads;
  • Thompson, Deborah;
  • Tihomirova, Laima;
  • Toland, Amanda E;
  • Tollenaar, Robert AEM;
  • Tomlinson, Ian;
  • Truong, Thérèse;
  • Tsimiklis, Helen;
  • Teulé, Alex;
  • Tumino, Rosario;
  • Tung, Nadine;
  • Turnbull, Clare;
  • Ursin, Giski;
  • van Deurzen, Carolien HM;
  • van Rensburg, Elizabeth J;
  • Varon-Mateeva, Raymonda;
  • Wang, Zhaoming;
  • Wang-Gohrke, Shan;
  • Weiderpass, Elisabete;
  • Weitzel, Jeffrey N;
  • Whittemore, Alice;
  • Wildiers, Hans;
  • Winqvist, Robert;
  • Yang, Xiaohong R;
  • Yannoukakos, Drakoulis;
  • Yao, Song;
  • Zamora, M Pilar;
  • Zheng, Wei;
  • Hall, Per;
  • Kraft, Peter;
  • Vachon, Celine;
  • Slager, Susan;
  • Chenevix-Trench, Georgia;
  • Pharoah, Paul DP;
  • Monteiro, Alvaro AN;
  • García-Closas, Montserrat;
  • Easton, Douglas F;
  • Antoniou, Antonis C
  • et al.
Abstract

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

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