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 \textless 5 \times 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 \times 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 \times 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 \textless 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.

DOI: 10.1038/s41416-019-0393-x

Projects: GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Publication type: Journal article

Journal: British journal of cancer

Human Diseases: Hereditary breast ovarian cancer syndrome

Citation: Br J Cancer 120(6):647-657

Date Published: 1st Mar 2019

Registered Mode: imported from a bibtex file

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, 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

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Escala-Garcia, M., , Guo, Q., Dörk, T., Canisius, S., Keeman, R., Dennis, J., Beesley, J., Lecarpentier, J., Bolla, M. K., Wang, Q., Abraham, J., Andrulis, I. L., Anton-Culver, H., Arndt, V., Auer, P. L., Beckmann, M. W., Behrens, S., Benitez, J., … Schmidt, M. K. (2019). Genome-wide association study of germline variants and breast cancer-specific mortality. In British Journal of Cancer (Vol. 120, Issue 6, pp. 647–657). Springer Science and Business Media LLC. https://doi.org/10.1038/s41416-019-0393-x
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