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

Escala-Garcia, M.; Guo, Q.; Dork, 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.; Bermisheva, M.; Bernstein, L.; Blomqvist, C.; Boeckx, B.; Bojesen, S. E.; Bonanni, B.; Borresen-Dale, A. -L.; Brauch, H.; Brenner, H.; Brentnall, A.; Brinton, L.; Broberg, P.; Brock, I. W.; Brucker, S. Y.; Burwinkel, B.; Caldas, C.; Caldes, T.; Campa, D.; Canzian, F.; Carracedo, A.; Carter, B. D.; Castelao, J. E.; Chang-Claude, J.; Chanock, S. J.; Chenevix-Trench, G.; Cheng, T. -Y. D.; Chin, S. -F.; Clarke, C. L.; Cordina-Duverger, E.; Couch, F. J.; Cox, D. G.; Cox, A.; Cross, S. S.; Czene, K.; Daly, M. B.; Devilee, P.; Dunn, J. A.; Dunning, A. M.; Durcan, L.; Dwek, M.; Earl, H. M.; Ekici, A. B.; Eliassen, A. H.; Ellberg, C.; Engel, C.; Eriksson, M.; Evans, D. G.; Figueroa, J.; Flesch-Janys, D.; Flyger, H.; Gabrielson, M.; Gago-Dominguez, M.; Galle, E.; Gapstur, S. M.; Garcia-Closas, M.; Garcia-Saenz, J. A.; Gaudet, M. M.; George, A.; Georgoulias, V.; Giles, G. G.; Glendon, G.; Goldgar, D. E.; Gonzalez-Neira, A.; Alnaes, G. I. G.; Grip, M.; Guenel, P.; Haeberle, L.; Hahnen, E.; Haiman, C. A.; Hakansson, N.; Hall, P.; Hamann, U.; Hankinson, S.; Harkness, E. F.; Harrington, P. A.; Hart, S. N.; Hartikainen, J. M.; Hein, A.; Hillemanns, P.; Hiller, L.; Holleczek, B.; Hollestelle, A.; Hooning, M. J.; Hoover, R. N.; Hopper, J. L.; Howell, A.; Huang, G.; Humphreys, K.; Hunter, D. J.; Janni, W.; John, E. M.; Jones, M. E.; Jukkola-Vuorinen, A.; Jung, A.; Kaaks, R.; Kabisch, M.; Kaczmarek, K.; Kerin, M. J.; Khan, S.; Khusnutdinova, E.; Kiiski, J. I.; Kitahara, C. M.; Knight, J. A.; Y. -D., Ko; Koppert, L. B.; Kosma, V. -M.; Kraft, P.; Kristensen, V. N.; Kruger, U.; Kuhl, T.; Lambrechts, D.; Le Marchand, L.; Lee, E.; Lejbkowicz, F.; Li, L.; Lindblom, A.; Lindstrom, S.; Linet, M.; Lissowska, J.; W. -Y., Lo; Loibl, S.; Lubinski, J.; Lux, M. P.; Macinnis, R. J.; Maierthaler, M.; Maishman, T.; Makalic, E.; Mannermaa, A.; Manoochehri, M.; Manoukian, S.; Margolin, S.; Martinez, M. E.; Mavroudis, D.; Mclean, C.; Meindl, A.; Middha, P.; Miller, N.; Milne, R. L.; Moreno, F.; Mulligan, A. M.; Mulot, C.; Nassir, R.; Neuhausen, S. L.; Newman, W. T.; Nielsen, S. F.; Nordestgaard, B. G.; Norman, A.; Olsson, H.; Orr, N.; Pankratz, V. S.; Park-Simon, T. -W.; Perez, J. I. A.; Perez-Barrios, C.; Peterlongo, P.; Petridis, C.; Pinchev, M.; Prajzendanc, K.; Prentice, R.; Presneau, N.; Prokofieva, D.; Pylkas, K.; Rack, B.; Radice, P.; Ramachandran, D.; Rennert, G.; Rennert, H. S.; Rhenius, V.; Romero, A.; Roylance, R.; Saloustros, E.; Sawyer, E. J.; Schmidt, D. F.; Schmutzler, R. K.; Schneeweiss, A.; Schoemaker, M. J.; Schumacher, F.; Schwentner, L.; Scott, R. J.; Scott, C.; Seynaeve, C.; Shah, M.; Simard, J.; Smeets, A.; Sohn, C.; Southey, M. C.; Swerdlow, A. J.; Talhouk, A.; Tamimi, R. M.; Tapper, W. J.; Teixeira, M. R.; Tengstrom, M.; Terry, M. B.; Thone, K.; Tollenaar, R. A. E. M.; Tomlinson, I.; Torres, D.; Truong, T.; Turman, C.; Turnbull, C.; Ulmer, H. -U.; Untch, M.; Vachon, C.; van Asperen, C. J.; van den Ouweland, A. M. W.; van Veen, E. M.; Wendt, C.; Whittemore, A. S.; Willett, W.; Winqvist, R.; Wolk, A.; Yang, X. R.; Zhang, Y.; Easton, D. F.; Fasching, P. A.; Nevanlinna, H.; Eccles, D. M.; Pharoah, P. D. P.; Schmidt, M. K.

doi:10.1038/s41416-019-0393-x

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.