M Escala-Garcia, Q Guo, T Dörk, S Canisius, R Keeman, J Dennis, J Beesley, J Lecarpentier, MK Bolla, Q Wang, J Abraham, IL Andrulis, H Anton-Culver, V Arndt, PL Auer, MW Beckmann, S Behrens, J Benitez, M Bermisheva, L Bernstein, C Blomqvist, B Boeckx, SE Bojesen, B Bonanni, A-L Børresen-Dale, H Brauch, H Brenner, A Brentnall, L Brinton, P Broberg, IW Brock, SY Brucker, B Burwinkel, C Caldas, T Caldés, D Campa, F Canzian, A Carracedo, BD Carter, JE Castelao, J Chang-Claude, SJ Chanock, G Chenevix-Trench, T-YD Cheng, S-F Chin, CL Clarke, NBCS Collaborators, E Cordina-Duverger, FJ Couch, DG Cox, A Cox, SS Cross, K Czene, MB Daly, P Devilee, JA Dunn, AM Dunning, L Durcan, M Dwek, HM Earl, AB Ekici, AH Eliassen, C Ellberg, C Engel, M Eriksson, DG Evans, J Figueroa, D Flesch-Janys, H Flyger, M Gabrielson, M Gago-Dominguez, E Galle, SM Gapstur, M García-Closas, JA García-Sáenz, MM Gaudet, A George, V Georgoulias, GG Giles, G Glendon, DE Goldgar, A González-Neira, GIG Alnæs, M Grip, P Guénel, L Haeberle, E Hahnen, CA Haiman, N Håkansson, P Hall, U Hamann, S Hankinson, EF Harkness, PA Harrington, SN Hart, JM Hartikainen, A Hein, P Hillemanns, L Hiller, B Holleczek, A Hollestelle, MJ Hooning, RN Hoover, JL Hopper, A Howell, G Huang, K Humphreys, DJ Hunter, W Janni, EM John, ME Jones, A Jukkola-Vuorinen, A Jung, R Kaaks, M Kabisch, K Kaczmarek, MJ Kerin, S Khan, E Khusnutdinova, JI Kiiski, CM Kitahara, JA Knight, Y-D Ko, LB Koppert, V-M Kosma, P Kraft, VN Kristensen, U Krüger, T Kühl, D Lambrechts, L Le Marchand, E Lee, F Lejbkowicz, L Li, A Lindblom, S Lindström, M Linet, J Lissowska, W-Y Lo, S Loibl, J Lubiński, MP Lux, RJ MacInnis, M Maierthaler, T Maishman, E Makalic, A Mannermaa, M Manoochehri, S Manoukian, S Margolin, ME Martinez, D Mavroudis, C McLean, A Meindl, P Middha, N Miller, RL Milne, F Moreno, AM Mulligan, C Mulot, R Nassir, SL Neuhausen, WT Newman, SF Nielsen, BG Nordestgaard, A Norman, H Olsson, N Orr, VS Pankratz, T-W Park-Simon, JIA Perez, C Pérez-Barrios, P Peterlongo, C Petridis, M Pinchev, K Prajzendanc, R Prentice, N Presneau, D Prokofieva, K Pylkäs, B Rack, P Radice, D Ramachandran, G Rennert, HS Rennert, V Rhenius, A Romero, R Roylance, E Saloustros, EJ Sawyer, DF Schmidt, RK Schmutzler, A Schneeweiss, MJ Schoemaker, F Schumacher, L Schwentner, RJ Scott, C Scott, C Seynaeve, M Shah, J Simard, A Smeets, C Sohn, MC Southey, AJ Swerdlow, A Talhouk, RM Tamimi, WJ Tapper, MR Teixeira, M Tengström, MB Terry, K Thöne, RAEM Tollenaar, I Tomlinson, D Torres, T Truong, C Turman, C Turnbull, H-U Ulmer, M Untch, C Vachon, CJ van Asperen, AMW van den Ouweland, EM van Veen, C Wendt, AS Whittemore, W Willett, R Winqvist, A Wolk, XR Yang, Y Zhang, DF Easton, PA Fasching, H Nevanlinna, DM Eccles, PDP Pharoah, MK Schmidt
Br J Cancer
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.