Identification of Novel Genetic Markers of Breast Cancer Survival
Authors: Qi Guo, Marjanka K Schmidt, Peter Kraft, Sander Canisius, Constance Chen, Sofia Khan, Jonathan Tyrer, Manjeet K Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Michael Lush, Siddhartha Kar, Jonathan Beesley, Alison M Dunning, Mitul Shah, Kamila Czene, Hatef Darabi, Mikael Eriksson, Diether Lambrechts, Caroline Weltens, Karin Leunen, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Carl Blomqvist, Kristiina Aittomäki, Rainer Fagerholm, Taru A Muranen, Fergus J Couch, Janet E Olson, Celine Vachon, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Annegien Broeks, Frans B Hogervorst, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, John L Hopper, Helen Tsimiklis, Carmel Apicella, Melissa C Southey, Angela Cox, Simon S Cross, Malcolm W R Reed, Graham G Giles, Roger L Milne, Catriona McLean, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Maartje J Hooning, Antoinette Hollestelle, John W M Martens, Ans M W van den Ouweland, Federik 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, Aida Karina Dieffenbach, Volker Arndt, Bernd Holleczek, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Jingmei Li, Judith S Brand, Keith Humphreys, Peter Devilee, Rob A E M Tollenaar, Caroline Seynaeve, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Paolo Mariani, Peter A Fasching, Matthias W Beckmann, Alexander Hein, Arif B Ekici, Georgia Chenevix-Trench, Rosemary Balleine, Kelly-Anne Phillips, Javier Benitez, M Pilar Zamora, Jose Ignacio Arias Perez, Primitiva Menéndez, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Ute Hamann, Maria Kabisch, Hans Ulrich Ulmer, Thomas Rüdiger, Sara Margolin, Vessela Kristensen, Silje Nord, D Gareth Evans, Jean E Abraham, Helena M Earl, Louise Hiller, Janet A Dunn, Sarah Bowden, Christine Berg, Daniele Campa, W Ryan Diver, Susan M Gapstur, Mia M Gaudet, Susan E 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 García-Closas, Per Hall, Douglas F Easton, Diana M Eccles, Nazneen Rahman, Heli Nevanlinna, Paul D P Pharoah
Journal: JNCI Journal of the National Cancer Institute (2015)

Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer–specific survival. We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)–negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided. We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10–8). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.