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

2019; Springer Nature; Volume: 120; Issue: 6 Linguagem: Inglês

10.1038/s41416-019-0393-x

1532-1827

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

Nutrition, Genetics, and Disease

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