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Open Access Publications from the University of California

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

  • Author(s): Escala-Garcia, Maria
  • Guo, Qi
  • Dörk, Thilo
  • Canisius, Sander
  • Keeman, Renske
  • Dennis, Joe
  • Beesley, Jonathan
  • Lecarpentier, Julie
  • Bolla, Manjeet K
  • Wang, Qin
  • Abraham, Jean
  • Andrulis, Irene L
  • Anton-Culver, Hoda
  • Arndt, Volker
  • Auer, Paul L
  • Beckmann, Matthias W
  • Behrens, Sabine
  • Benitez, Javier
  • Bermisheva, Marina
  • Bernstein, Leslie
  • Blomqvist, Carl
  • Boeckx, Bram
  • Bojesen, Stig E
  • Bonanni, Bernardo
  • Børresen-Dale, Anne-Lise
  • Brauch, Hiltrud
  • Brenner, Hermann
  • Brentnall, Adam
  • Brinton, Louise
  • Broberg, Per
  • Brock, Ian W
  • Brucker, Sara Y
  • Burwinkel, Barbara
  • Caldas, Carlos
  • Caldés, Trinidad
  • Campa, Daniele
  • Canzian, Federico
  • Carracedo, Angel
  • Carter, Brian D
  • Castelao, Jose E
  • Chang-Claude, Jenny
  • Chanock, Stephen J
  • Chenevix-Trench, Georgia
  • Cheng, Ting-Yuan David
  • Chin, Suet-Feung
  • Clarke, Christine L
  • NBCS Collaborators
  • Cordina-Duverger, Emilie
  • Couch, Fergus J
  • Cox, David G
  • Cox, Angela
  • Cross, Simon S
  • Czene, Kamila
  • Daly, Mary B
  • Devilee, Peter
  • Dunn, Janet A
  • Dunning, Alison M
  • Durcan, Lorraine
  • Dwek, Miriam
  • Earl, Helena M
  • Ekici, Arif B
  • Eliassen, A Heather
  • Ellberg, Carolina
  • Engel, Christoph
  • Eriksson, Mikael
  • Evans, D Gareth
  • Figueroa, Jonine
  • Flesch-Janys, Dieter
  • Flyger, Henrik
  • Gabrielson, Marike
  • Gago-Dominguez, Manuela
  • Galle, Eva
  • Gapstur, Susan M
  • García-Closas, Montserrat
  • García-Sáenz, José A
  • Gaudet, Mia M
  • George, Angela
  • Georgoulias, Vassilios
  • Giles, Graham G
  • Glendon, Gord
  • Goldgar, David E
  • González-Neira, Anna
  • Alnæs, Grethe I Grenaker
  • Grip, Mervi
  • Guénel, Pascal
  • Haeberle, Lothar
  • Hahnen, Eric
  • Haiman, Christopher A
  • Håkansson, Niclas
  • Hall, Per
  • Hamann, Ute
  • Hankinson, Susan
  • Harkness, Elaine F
  • Harrington, Patricia A
  • Hart, Steven N
  • Hartikainen, Jaana M
  • Hein, Alexander
  • Hillemanns, Peter
  • Hiller, Louise
  • Holleczek, Bernd
  • Hollestelle, Antoinette
  • Hooning, Maartje J
  • Hoover, Robert N
  • Hopper, John L
  • Howell, Anthony
  • Huang, Guanmengqian
  • Humphreys, Keith
  • Hunter, David J
  • Janni, Wolfgang
  • John, Esther M
  • Jones, Michael E
  • Jukkola-Vuorinen, Arja
  • Jung, Audrey
  • Kaaks, Rudolf
  • Kabisch, Maria
  • Kaczmarek, Katarzyna
  • Kerin, Michael J
  • Khan, Sofia
  • Khusnutdinova, Elza
  • Kiiski, Johanna I
  • Kitahara, Cari M
  • Knight, Julia A
  • Ko, Yon-Dschun
  • Koppert, Linetta B
  • Kosma, Veli-Matti
  • Kraft, Peter
  • Kristensen, Vessela N
  • Krüger, Ute
  • Kühl, Tabea
  • Lambrechts, Diether
  • Le Marchand, Loic
  • Lee, Eunjung
  • Lejbkowicz, Flavio
  • Li, Lian
  • Lindblom, Annika
  • Lindström, Sara
  • Linet, Martha
  • Lissowska, Jolanta
  • Lo, Wing-Yee
  • Loibl, Sibylle
  • Lubiński, Jan
  • Lux, Michael P
  • MacInnis, Robert J
  • Maierthaler, Melanie
  • Maishman, Tom
  • Makalic, Enes
  • Mannermaa, Arto
  • Manoochehri, Mehdi
  • Manoukian, Siranoush
  • Margolin, Sara
  • Martinez, Maria Elena
  • Mavroudis, Dimitrios
  • McLean, Catriona
  • Meindl, Alfons
  • Middha, Pooja
  • Miller, Nicola
  • Milne, Roger L
  • Moreno, Fernando
  • Mulligan, Anna Marie
  • Mulot, Claire
  • Nassir, Rami
  • Neuhausen, Susan L
  • Newman, William T
  • Nielsen, Sune F
  • Nordestgaard, Børge G
  • Norman, Aaron
  • Olsson, Håkan
  • Orr, Nick
  • Pankratz, V Shane
  • Park-Simon, Tjoung-Won
  • Perez, Jose IA
  • Pérez-Barrios, Clara
  • Peterlongo, Paolo
  • Petridis, Christos
  • Pinchev, Mila
  • Prajzendanc, Karoliona
  • Prentice, Ross
  • Presneau, Nadege
  • Prokofieva, Darya
  • Pylkäs, Katri
  • Rack, Brigitte
  • Radice, Paolo
  • Ramachandran, Dhanya
  • Rennert, Gadi
  • Rennert, Hedy S
  • Rhenius, Valerie
  • Romero, Atocha
  • Roylance, Rebecca
  • Saloustros, Emmanouil
  • Sawyer, Elinor J
  • Schmidt, Daniel F
  • Schmutzler, Rita K
  • Schneeweiss, Andreas
  • Schoemaker, Minouk J
  • Schumacher, Fredrick
  • Schwentner, Lukas
  • Scott, Rodney J
  • Scott, Christopher
  • Seynaeve, Caroline
  • Shah, Mitul
  • Simard, Jacques
  • Smeets, Ann
  • Sohn, Christof
  • Southey, Melissa C
  • Swerdlow, Anthony J
  • Talhouk, Aline
  • Tamimi, Rulla M
  • Tapper, William J
  • Teixeira, Manuel R
  • Tengström, Maria
  • Terry, Mary Beth
  • Thöne, Kathrin
  • Tollenaar, Rob AEM
  • Tomlinson, Ian
  • Torres, Diana
  • Truong, Thérèse
  • Turman, Constance
  • Turnbull, Clare
  • Ulmer, Hans-Ulrich
  • Untch, Michael
  • Vachon, Celine
  • van Asperen, Christi J
  • van den Ouweland, Ans MW
  • van Veen, Elke M
  • Wendt, Camilla
  • Whittemore, Alice S
  • Willett, Walter
  • Winqvist, Robert
  • Wolk, Alicja
  • Yang, Xiaohong R
  • Zhang, Yan
  • Easton, Douglas F
  • Fasching, Peter A
  • Nevanlinna, Heli
  • Eccles, Diana M
  • Pharoah, Paul DP
  • Schmidt, Marjanka K
  • et al.
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.

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