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.; ... ; NBCS Collaborators (2019)

Article / Letter to editor

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 similar to 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 x 10(-8). For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 x 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 x 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.

• All authors: 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.M.Q.; 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.; Ko, Y.D.; Koppert, L.B.; Kosma, V.M.; Kraft, P.; Kristensen, V.N.; Kruger, U.; Kuhl, T.; Lambrechts, D.; Marchand, L. le; 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.; Asperen, C.J. van; Ouweland, A.M.W. van den; Veen, E.M. van; 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.; NBCS Collaborators
• Date: 2019-03-19
• Journal: British Journal of Cancer
• Volume: 120
• Issue: 6
• Pages: 647 - 657
• DOI: doi:10.1038/s41416-019-0393-x