Identification of Novel Genetic Markers of Breast Cancer Survival

Q Guo, MK (Marjanka) Schmidt, P Kraft, S Canisius, C (Christopher Li Hsian) Chen, Salima Khan, J Tyrer, MK Bolla, Q (Qing) Wang, J Dennis, K Michailidou, M Lush, S Kar, J Beesley, AM Dunning, M Shah, K Czene, H Darabi, M Eriksson, D LambrechtsC Weltens, K Leunen, SE Bojesen, BG Nordestgaard, SF Nielsen, H Flyger, J Chang-Claude, A Rudolph, P Seibold, D Flesch-Janys, C Blomqvist, K Aittomaki, R Fagerholm, TA Muranen, FJ Couch, JE Olson, C Vachon, IL Andrulis, JA Knight, G Glendon, AM Mulligan, A Broeks, FB Hogervorst, CA Haiman, BE Henderson, F Schumacher, L Le Marchand, JL Hopper, H Tsimiklis, C Apicella, MC Southey, A Cox, SS Cross, MWR Reed, GG Giles, RL Milne, C McLean, R Winqvist, K Pylkas, A Jukkola-Vuorinen, M Grip, Maartje Hooning, Antoinette Hollestelle, John Martens, Ans van den Ouweland, F Marme, A Schneeweiss, RX Yang, B Burwinkel, J Figueroa, SJ Chanock, J Lissowska, EJ Sawyer, I Tomlinson, MJ Kerin, N Miller, H Brenner, AK Dieffenbach, V Arndt, B Holleczek, A Mannermaa, V Kataja, VM Kosma, JM Hartikainen, JM Li, JS Brand, K Humphreys, P Devilee, RAEM Tollenaar, Caroline Seynaeve, P Radice, P Peterlongo, B Bonanni, P Mariani, PA Fasching, MW Beckmann, A Hein, AB Ekici, G Chenevix-Trench, R Balleine, KA Phillips, J Benitez, MP Zamora, JIA Perez, P Menendez, A Jakubowska, J Lubinski, K Jaworska-Bieniek, K Durda, U Hamann, M Kabisch, HU Ulmer, T Rudiger, S Margolin, V Kristensen, S Nord, DG Evans, JE Abraham, HM Earl, L Hiller, JA Dunn, S Bowden, Conny Berg, D Campa, WR Diver, SM Gapstur, MM Gaudet, SE Hankinson, RN Hoover, A Husing, R Kaaks, MJ Machiela, W Willett, M Barrdahl, F Canzian, SF Chin, C Caldas, DJ Hunter, S Lindstrom, M Garcia-Closas, P Hall, DF Easton, DM Eccles, N Rahman, H Nevanlinna, PDP Pharoah

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Abstract

Background: 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. Methods: We conducted a large meta-analysis of studies in populations of European ancestry, including 37 954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200 000 and 900 000 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 23 059 ER-positive patients (1333 events). All statistical tests were two-sided. Results: 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. Conclusions: 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.
Original languageUndefined/Unknown
JournalJournal of the National Cancer Institute
Volume107
Issue number5
DOIs
Publication statusPublished - 2015

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