Common germline polymorphisms associated with breast cancer-specific survival

Ailith Pirie, Qi Guo, Peter Kraft, Sander Canisius, Diana M Eccles, Nazneen Rahman, Heli Nevanlinna, Constance Chen, Sofia Khan, Jonathan Tyrer, Manjeet K Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Michael Lush, Alison M Dunning, Mitul Shah, Kamila Czene, Hatef Darabi, Mikael Eriksson, Dieter Lambrechts, Caroline Weltens, Karin Leunen, Chantal van Ongeval, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Carl Blomqvist, Kristiina Aittomäki, Rainer Fagerholm, Taru A Muranen, Janet E Olsen, Emily Hallberg, Celine Vachon, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Annegien Broeks, Sten Cornelissen, Christopher A Haiman, Brian E Henderson, Frederick Schumacher, Loic Le Marchand, John L Hopper, Helen Tsimiklis, Carmel Apicella, Melissa C Southey, Simon S Cross, Malcolm WR Reed, Graham G Giles, Roger L Milne, Catriona McLean, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Maartje J Hooning, Antoinette Hollestelle, John WM Martens, Ans MW van den Ouweland, Federick Marme, Andreas Schneeweiss, Rongxi Yang, Barbara Burwinkel, Jonine Figueroa, Stephen J Chanock, Jolanta Lissowska, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Hermann Brenner, Katja Butterbach, Bernd Holleczek, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Jingmei Li, Judith S Brand, Keith Humphreys, Peter Devilee, Robert AEM Tollenaar, Caroline Seynaeve, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Filomena Ficarazzi, Matthias W Beckmann, Alexander Hein, Arif B Ekici, Rosemary Balleine, Kelly-Anne Phillips, kConFab Investigators, Javier Benitez, M Pilar Zamora, Jose Ignacio Arias Perez, Primitiva Menéndez, Anna Jakubowska, Jan Lubinski, Jacek Gronwald, Katarzyna Durda, Ute Hamann, Maria Kabisch, Hans Ulrich Ulmer, Thomas Rüdiger, Sara Margolin, Vessela Kristensen, Siljie Nord, NBCS Investigators, D Gareth Evans, Jean Abraham, Helena Earl, Christopher J Poole, Louise Hiller, Janet A Dunn, Sarah Bowden, Rose Yang, Daniele Campa, W Ryan Diver, Susan M Gapstur, Mia M Gaudet, Susan Hankinson, Robert N Hoover, Anika Hüsing, Rudolf Kaaks, Mitchell J Machiela, Walter Willett, Myrto Barrdahl, Federico Canzian, Suet-Feung Chin, Carlos Caldas, David J Hunter, Sara Lindstrom, Montserrat Garcia-Closas, Fergus J Couch, Georgia Chenevix-Trench, Arto Mannermaa, Irene L Andrulis, Per Hall, Jenny Chang-Claude, Douglas F Easton, Stig E Bojesen, Angela Cox, Peter A Fasching, Paul DP Pharoah, Marjanka K Schmidt

Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer specific survival, overall survival and disease-free survival. All associations which reached the nominal significance level of p-value < 0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect. Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (p < 0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (p < 0.05) with ER positive disease. Although no variants reached genome-wide significance (p < 5 x 10(-8)), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multi-national collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.