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

Escala-Garcia, Maria; Guo, Qi; Doerk, 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; Böckx, Bram; Bojesen, Stig E.; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Brauch, Hiltrud; Brenner, Hermann; Brentnall, Adam; Brinton, Louise; Broberg, Per; Brock, Ian W.; Brucker, Sara Y.; Burwinkel, Barbara; Caldas, Carlos; Caldes, 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.; 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.; Garcia-Closas, Montserrat; Garcia-Saenz, Jose A.; Gaudet, Mia M.; George, Angela; Georgoulias, Vassilios; Giles, Graham G.; Glendon, Gord; Goldgar, David E.; Gonzalez-Neira, Anna; Alnaes, Grethe I. Grenaker; Grip, Mervi; Guenel, Pascal; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A.; Hakansson, 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; Kitahara, Cari M.; Knight, Julia A.; Ko, Yon-Dschun; Koppert, Linetta B.; Kosma, Veli-Matti; Kraft, Peter; Kristensen, Vessela N.; Krüger, Ute; Kuehl, Tabea; Lambrechts, Diether; Le Marchand, Loic; Lee, Eunjung; Lejbkowicz, Flavio; Li, Lian; Lindblom, Annika; Lindstrom, Sara; Linet, Martha; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Lubinski, 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, Borge G.; Norman, Aaron; Olsson, Hakan; Orr, Nick; Pankratz, V. Shane; Park-Simon, Tjoung-Won; Perez, Jose I. A.; Perez-Barrios, Clara; Peterlongo, Paolo; Petridis, Christos; Pinchev, Mila; Prajzendanc, Karoliona; Prentice, Ross; Presneau, Nadege; Prokofieva, Darya; Pylkas, 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.; Tengstrom, Maria; Terry, Mary Beth; Thoene, Kathrin; Tollenaar, Rob A. E. M.; Tomlinson, Ian; Torres, Diana; Truong, Therese; Turman, Constance; Turnbull, Clare; Ulmer, Hans-Ulrich; Untch, Michael; Vachon, Celine; van Asperen, Christi J.; van den Ouweland, Ans M. W.; 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 D. P.; Schmidt, Marjanka K. (2019): Genome-wide association study of germline variants and breast cancer-specific mortality. In: British Journal of Cancer, Vol. 120, No. 6: pp. 647-657

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 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.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 0007-0920
• Language: English