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Genome-wide association study of germline variants and breast cancer-specific mortality.

  • Author(s): Escala-Garcia, Maria;
  • Guo, Qi;
  • Dörk, Thilo;
  • Canisius, Sander;
  • Keeman, Renske;
  • Dennis, Joe;
  • Beesley, Jonathan;
  • Lecarpentier, Julie;
  • Bolla, Manjeet K;
  • Wang, Qin;
  • Abraham, Jean;
  • Andrulis, Irene L;
  • Anton-Culver, Hoda;
  • Arndt, Volker;
  • Auer, Paul L;
  • Beckmann, Matthias W;
  • Behrens, Sabine;
  • Benitez, Javier;
  • Bermisheva, Marina;
  • Bernstein, Leslie;
  • Blomqvist, Carl;
  • Boeckx, Bram;
  • Bojesen, Stig E;
  • Bonanni, Bernardo;
  • Børresen-Dale, Anne-Lise;
  • Brauch, Hiltrud;
  • Brenner, Hermann;
  • Brentnall, Adam;
  • Brinton, Louise;
  • Broberg, Per;
  • Brock, Ian W;
  • Brucker, Sara Y;
  • Burwinkel, Barbara;
  • Caldas, Carlos;
  • Caldés, Trinidad;
  • Campa, Daniele;
  • Canzian, Federico;
  • Carracedo, Angel;
  • Carter, Brian D;
  • Castelao, Jose E;
  • Chang-Claude, Jenny;
  • Chanock, Stephen J;
  • Chenevix-Trench, Georgia;
  • Cheng, Ting-Yuan David;
  • Chin, Suet-Feung;
  • Clarke, Christine L;
  • NBCS Collaborators;
  • Cordina-Duverger, Emilie;
  • Couch, Fergus J;
  • Cox, David G;
  • Cox, Angela;
  • Cross, Simon S;
  • Czene, Kamila;
  • Daly, Mary B;
  • Devilee, Peter;
  • Dunn, Janet A;
  • Dunning, Alison M;
  • Durcan, Lorraine;
  • Dwek, Miriam;
  • Earl, Helena M;
  • Ekici, Arif B;
  • Eliassen, A Heather;
  • Ellberg, Carolina;
  • Engel, Christoph;
  • Eriksson, Mikael;
  • Evans, D Gareth;
  • Figueroa, Jonine;
  • Flesch-Janys, Dieter;
  • Flyger, Henrik;
  • Gabrielson, Marike;
  • Gago-Dominguez, Manuela;
  • Galle, Eva;
  • Gapstur, Susan M;
  • García-Closas, Montserrat;
  • García-Sáenz, José A;
  • Gaudet, Mia M;
  • George, Angela;
  • Georgoulias, Vassilios;
  • Giles, Graham G;
  • Glendon, Gord;
  • Goldgar, David E;
  • González-Neira, Anna;
  • Alnæs, Grethe I Grenaker;
  • Grip, Mervi;
  • Guénel, Pascal;
  • Haeberle, Lothar;
  • Hahnen, Eric;
  • Haiman, Christopher A;
  • Håkansson, Niclas;
  • Hall, Per;
  • Hamann, Ute;
  • Hankinson, Susan;
  • Harkness, Elaine F;
  • Harrington, Patricia A;
  • Hart, Steven N;
  • Hartikainen, Jaana M;
  • Hein, Alexander;
  • Hillemanns, Peter;
  • Hiller, Louise;
  • Holleczek, Bernd;
  • Hollestelle, Antoinette;
  • Hooning, Maartje J;
  • Hoover, Robert N;
  • Hopper, John L;
  • Howell, Anthony;
  • Huang, Guanmengqian;
  • Humphreys, Keith;
  • Hunter, David J;
  • Janni, Wolfgang;
  • John, Esther M;
  • Jones, Michael E;
  • Jukkola-Vuorinen, Arja;
  • Jung, Audrey;
  • Kaaks, Rudolf;
  • Kabisch, Maria;
  • Kaczmarek, Katarzyna;
  • Kerin, Michael J;
  • Khan, Sofia;
  • Khusnutdinova, Elza;
  • Kiiski, Johanna I;
  • Kitahara, Cari M;
  • Knight, Julia A;
  • Ko, Yon-Dschun;
  • Koppert, Linetta B;
  • Kosma, Veli-Matti;
  • Kraft, Peter;
  • Kristensen, Vessela N;
  • Krüger, Ute;
  • Kühl, Tabea;
  • Lambrechts, Diether;
  • Le Marchand, Loic;
  • Lee, Eunjung;
  • Lejbkowicz, Flavio;
  • Li, Lian;
  • Lindblom, Annika;
  • Lindström, Sara;
  • Linet, Martha;
  • Lissowska, Jolanta;
  • Lo, Wing-Yee;
  • Loibl, Sibylle;
  • Lubiński, Jan;
  • Lux, Michael P;
  • MacInnis, Robert J;
  • Maierthaler, Melanie;
  • Maishman, Tom;
  • Makalic, Enes;
  • Mannermaa, Arto;
  • Manoochehri, Mehdi;
  • Manoukian, Siranoush;
  • Margolin, Sara;
  • Martinez, Maria Elena;
  • Mavroudis, Dimitrios;
  • McLean, Catriona;
  • Meindl, Alfons;
  • Middha, Pooja;
  • Miller, Nicola;
  • Milne, Roger L;
  • Moreno, Fernando;
  • Mulligan, Anna Marie;
  • Mulot, Claire;
  • Nassir, Rami;
  • Neuhausen, Susan L;
  • Newman, William T;
  • Nielsen, Sune F;
  • Nordestgaard, Børge G;
  • Norman, Aaron;
  • Olsson, Håkan;
  • Orr, Nick;
  • Pankratz, V Shane;
  • Park-Simon, Tjoung-Won;
  • Perez, Jose IA;
  • Pérez-Barrios, Clara;
  • Peterlongo, Paolo;
  • Petridis, Christos;
  • Pinchev, Mila;
  • Prajzendanc, Karoliona;
  • Prentice, Ross;
  • Presneau, Nadege;
  • Prokofieva, Darya;
  • Pylkäs, Katri;
  • Rack, Brigitte;
  • Radice, Paolo;
  • Ramachandran, Dhanya;
  • Rennert, Gadi;
  • Rennert, Hedy S;
  • Rhenius, Valerie;
  • Romero, Atocha;
  • Roylance, Rebecca;
  • Saloustros, Emmanouil;
  • Sawyer, Elinor J;
  • Schmidt, Daniel F;
  • Schmutzler, Rita K;
  • Schneeweiss, Andreas;
  • Schoemaker, Minouk J;
  • Schumacher, Fredrick;
  • Schwentner, Lukas;
  • Scott, Rodney J;
  • Scott, Christopher;
  • Seynaeve, Caroline;
  • Shah, Mitul;
  • Simard, Jacques;
  • Smeets, Ann;
  • Sohn, Christof;
  • Southey, Melissa C;
  • Swerdlow, Anthony J;
  • Talhouk, Aline;
  • Tamimi, Rulla M;
  • Tapper, William J;
  • Teixeira, Manuel R;
  • Tengström, Maria;
  • Terry, Mary Beth;
  • Thöne, Kathrin;
  • Tollenaar, Rob AEM;
  • Tomlinson, Ian;
  • Torres, Diana;
  • Truong, Thérèse;
  • Turman, Constance;
  • Turnbull, Clare;
  • Ulmer, Hans-Ulrich;
  • Untch, Michael;
  • Vachon, Celine;
  • van Asperen, Christi J;
  • van den Ouweland, Ans MW;
  • van Veen, Elke M;
  • Wendt, Camilla;
  • Whittemore, Alice S;
  • Willett, Walter;
  • Winqvist, Robert;
  • Wolk, Alicja;
  • Yang, Xiaohong R;
  • Zhang, Yan;
  • Easton, Douglas F;
  • Fasching, Peter A;
  • Nevanlinna, Heli;
  • Eccles, Diana M;
  • Pharoah, Paul DP;
  • Schmidt, Marjanka K
  • et al.
Abstract

Background

We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.

Methods

Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).

Results

We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.

Conclusions

We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

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