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Morra A , Escala-Garcia M , Beesley J , Keeman R , Canisius S , Ahearn TU , Andrulis IL , Anton-Culver H , Arndt V , Auer PL , Augustinsson A , Beane Freeman LE , Becher H , Beckmann MW , Behrens S , Bojesen SE , Bolla MK , Brenner H , Brüning T , Buys SS , Caan B , Campa D , Canzian F , Castelao JE , Chang-Claude J , Chanock SJ , Cheng TD , Clarke CL , Colonna SV , Couch FJ , Cox A , Cross SS , Czene K , Daly MB , Dennis J , Dörk T , Dossus L , Dunning AM , Dwek M , Eccles DM , Ekici AB , Eliassen AH , Eriksson M , Evans DG , Fasching PA , Flyger H , Fritschi L , Gago-Dominguez M , García-Sáenz JA , Giles GG , Grip M , Guénel P , Gündert M , Hahnen E , Haiman CA , Håkansson N , Hall P , Hamann U , Hart SN , Hartikainen JM , Hartmann A , He W , Hooning MJ , Hoppe R , Hopper JL , Howell A , Hunter DJ , Jager A , Jakubowska A , Janni W , John EM , Jung AY , Kaaks R , Keupers M , Kitahara CM , Koutros S , Kraft P , Kristensen VN , Kurian AW , Lacey JV , Lambrechts D , Le Marchand L , Lindblom A , Linet M , Luben RN , Lubiński J , Lush M , Mannermaa A , Manoochehri M , Margolin S , Martens JWM , Martinez ME , Mavroudis D , Michailidou K , Milne RL , Mulligan AM , Muranen TA , Nevanlinna H , Newman WG , Nielsen SF , Nordestgaard BG , Olshan AF , Olsson H , Orr N , Park-Simon TW , Patel AV , Peissel B , Peterlongo P , Plaseska-Karanfilska D , Prajzendanc K , Prentice R , Presneau N , Rack B , Rennert G , Rennert HS , Rhenius V , Romero A , Roylance R , Ruebner M , Saloustros E , Sawyer EJ , Schmutzler RK , Schneeweiss A , Scott C , Shah M , Smichkoska S , Southey MC , Stone J , Surowy H , Swerdlow AJ , Tamimi RM , Tapper WJ , Teras LR , Terry MB , Tollenaar Raem , Tomlinson I , Troester MA , Truong T , Vachon CM , Wang Q , Hurson AN , Winqvist R , Wolk A , Ziogas A , Brauch H , García-Closas M , Pharoah PDP , Easton DF , Chenevix-Trench G , Schmidt MK
Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment
Breast Cancer Res. 2021 Aug 18;23(1) :86
PMID: 34407845    PMCID: PMC8371820    URL: https://www.ncbi.nlm.nih.gov/pubmed/34407845
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Abstract
BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
Notes
1465-542x Morra, Anna Escala-Garcia, Maria Beesley, Jonathan Keeman, Renske Canisius, Sander Ahearn, Thomas U Andrulis, Irene L Anton-Culver, Hoda Arndt, Volker Auer, Paul L Augustinsson, Annelie Beane Freeman, Laura E Becher, Heiko Beckmann, Matthias W Behrens, Sabine Bojesen, Stig E Bolla, Manjeet K Brenner, Hermann Brüning, Thomas Buys, Saundra S Caan, Bette Campa, Daniele Canzian, Federico Castelao, Jose E Chang-Claude, Jenny Chanock, Stephen J Cheng, Ting-Yuan David Clarke, Christine L NBCS Collaborators Colonna, Sarah V Couch, Fergus J Cox, Angela Cross, Simon S Czene, Kamila Daly, Mary B Dennis, Joe Dörk, Thilo Dossus, Laure Dunning, Alison M Dwek, Miriam Eccles, Diana M Ekici, Arif B Eliassen, A Heather Eriksson, Mikael Evans, D Gareth Fasching, Peter A Flyger, Henrik Fritschi, Lin Gago-Dominguez, Manuela García-Sáenz, José A Giles, Graham G Grip, Mervi Guénel, Pascal Gündert, Melanie Hahnen, Eric Haiman, Christopher A Håkansson, Niclas Hall, Per Hamann, Ute Hart, Steven N Hartikainen, Jaana M Hartmann, Arndt He, Wei Hooning, Maartje J Hoppe, Reiner Hopper, John L Howell, Anthony Hunter, David J ABCTB Investigators kConFab Investigators Jager, Agnes Jakubowska, Anna Janni, Wolfgang John, Esther M Jung, Audrey Y Kaaks, Rudolf Keupers, Machteld Kitahara, Cari M Koutros, Stella Kraft, Peter Kristensen, Vessela N Kurian, Allison W Lacey, James V Lambrechts, Diether Le Marchand, Loic Lindblom, Annika Linet, Martha Luben, Robert N Lubiński, Jan Lush, Michael Mannermaa, Arto Manoochehri, Mehdi Margolin, Sara Martens, John W M Martinez, Maria Elena Mavroudis, Dimitrios Michailidou, Kyriaki Milne, Roger L Mulligan, Anna Marie Muranen, Taru A Nevanlinna, Heli Newman, William G Nielsen, Sune F Nordestgaard, Børge G Olshan, Andrew F Olsson, Håkan Orr, Nick Park-Simon, Tjoung-Won Patel, Alpa V Peissel, Bernard Peterlongo, Paolo Plaseska-Karanfilska, Dijana Prajzendanc, Karolina Prentice, Ross Presneau, Nadege Rack, Brigitte Rennert, Gad Rennert, Hedy S Rhenius, Valerie Romero, Atocha Roylance, Rebecca Ruebner, Matthias Saloustros, Emmanouil Sawyer, Elinor J Schmutzler, Rita K Schneeweiss, Andreas Scott, Christopher Shah, Mitul Smichkoska, Snezhana Southey, Melissa C Stone, Jennifer Surowy, Harald Swerdlow, Anthony J Tamimi, Rulla M Tapper, William J Teras, Lauren R Terry, Mary Beth Tollenaar, Rob A E M Tomlinson, Ian Troester, Melissa A Truong, Thérèse Vachon, Celine M Wang, Qin Hurson, Amber N Winqvist, Robert Wolk, Alicja Ziogas, Argyrios Brauch, Hiltrud García-Closas, Montserrat Pharoah, Paul D P Easton, Douglas F Chenevix-Trench, Georgia Schmidt, Marjanka K Orcid: 0000-0002-2228-429x C1287/A16563/CRUK_/Cancer Research UK/United Kingdom C1287/A10118/CRUK_/Cancer Research UK/United Kingdom C1287/A10710/CRUK_/Cancer Research UK/United Kingdom C12292/A11174/CRUK_/Cancer Research UK/United Kingdom C1281/A12014/CRUK_/Cancer Research UK/United Kingdom C5047/A8384/CRUK_/Cancer Research UK/United Kingdom C5047/A15007/CRUK_/Cancer Research UK/United Kingdom C5047/A10692/CRUK_/Cancer Research UK/United Kingdom C8197/A16565/CRUK_/Cancer Research UK/United Kingdom 634935/Horizon 2020 Research and Innovation Programme/ 633784/Horizon 2020 Research and Innovation Programme/ HEALTH-F2-2009-223175/FP7 Ideas: European Research Council/ U19 CA148065/NH/NIH HHS/United States CA128978/NH/NIH HHS/United States GPH-129344/CAPMC/CIHR/Canada PSRSIIRI-701/Ministère de l'Économie, de la Science et de l'Innovation - Québec/ 1U19 CA148537/Post-Cancer GWAS/ 1U19 CA148065/Post-Cancer GWAS/ 1u19 ca148112/game-on/ W81XWH-10-1-0341/U.S. Department of Defense/ Journal Article Breast Cancer Res. 2021 Aug 18;23(1):86. doi: 10.1186/s13058-021-01450-7.