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

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.

• Authors: 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 Benitez, Marina Bermisheva, Leslie Bernstein, Carl Blomqvist, Bram Boeckx, Stig E Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Hermann Brenner, Adam Brentnall, Louise Brinton, Per Broberg, Ian W Brock, Sara Y Brucker, Barbara Burwinkel, Carlos Caldas, Trinidad Caldés, Daniele Campa, Federico Canzian, Angel 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, NBCS Collaborators, Emilie Cordina-Duverger, Fergus J Couch, David G Cox, Angela Cox, Simon S Cross, Kamila Czene, Mary B Daly, Peter Devilee, Janet A Dunn, Alison M Dunning, Lorraine Durcan, Miriam Dwek, Helena M Earl, Arif B Ekici, A Heather Eliassen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, D Gareth Evans, Jonine Figueroa, Dieter Flesch-Janys, Henrik Flyger, Marike Gabrielson, Manuela Gago-Dominguez, Eva Galle, Susan M Gapstur, Montserrat García-Closas, José A García-Sáenz, Mia M Gaudet, Angela George, Vassilios Georgoulias, Graham G Giles, Gord Glendon, David E Goldgar, Anna González-Neira, Grethe I Grenaker Alnæs, Mervi Grip, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Susan Hankinson, Elaine F Harkness, Patricia A 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, Elza Khusnutdinova, 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, Loic Le Marchand, Eunjung Lee, Flavio Lejbkowicz, Lian Li, Annika Lindblom, Sara Lindström, Martha Linet, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jan Lubiński, Michael P Lux, Robert J MacInnis, Melanie Maierthaler, Tom Maishman, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, 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 T Newman, Sune F Nielsen, Børge G Nordestgaard, Aaron Norman, Håkan Olsson, Nick Orr, V Shane Pankratz, Tjoung-Won Park-Simon, Jose I A Perez, Clara Pérez-Barrios, Paolo Peterlongo, Christos Petridis, Mila Pinchev, Karoliona Prajzendanc, Ross Prentice, Nadege Presneau, Darya Prokofieva, Katri Pylkäs, Brigitte Rack, Paolo Radice, Dhanya Ramachandran, Gadi 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 Schumacher, Lukas Schwentner, Rodney J Scott, Christopher Scott, Caroline Seynaeve, Mitul Shah, Jacques Simard, Ann Smeets, Christof Sohn, Melissa C Southey, Anthony J Swerdlow, Aline Talhouk, Rulla M Tamimi, William J 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 Vachon, Christi J van Asperen, Ans M W van den Ouweland, Elke M van Veen, Camilla Wendt, Alice S Whittemore, Walter Willett, Robert Winqvist, Alicja Wolk, Xiaohong R Yang, Yan Zhang, Douglas F Easton, Peter A Fasching, Heli Nevanlinna, Diana M Eccles, Paul D P Pharoah, Marjanka K Schmidt
• Journal: British journal of cancer (Br J Cancer) Vol. 120 Issue 6 Pg. 647-657 (Mar 2019) ISSN: 1532-1827 [Electronic] England
• PMID: 30787463 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Receptors, Estrogen

Topics

• Bayes Theorem
• Breast Neoplasms (genetics, metabolism, mortality)
• Chromosomes, Human, Pair 7
• Female
• Genetic Variation
• Genome-Wide Association Study
• Humans
• Prognosis
• Proportional Hazards Models
• Receptors, Estrogen (genetics, metabolism)
• White People (genetics)