Identification of novel genetic markers of breast cancer survival.

Authors:
Qi Guo
Qi Guo
Tianjin Medical University
China
Marjanka K Schmidt
Marjanka K Schmidt
Netherlands Cancer Institute
Amsterdam | Netherlands
Peter Kraft
Peter Kraft
Harvard T.H. Chan School of Public Health
Boston | United States
Sander Canisius
Sander Canisius
Netherlands Cancer Institute
Amsterdam | Netherlands
Constance Chen
Constance Chen
Harvard School of Public Health
Boston | United States
Sofia Khan
Sofia Khan
University of Helsinki and Helsinki University Hospital
Helsinki | Finland
Jonathan Tyrer
Jonathan Tyrer
University of Cambridge
United Kingdom
Manjeet K Bolla
Manjeet K Bolla
University of Cambridge
United Kingdom
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

J Natl Cancer Inst 2015 May 18;107(5). Epub 2015 Apr 18.

Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, UK (QG, JT, AMD, MS, JEA, DFE, PDPP); Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands (MKS, SC, AB, FBH); Department of Epidemiology, Harvard School of Public Health, Boston, MA (PK, SH, DJH, SL); Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, MA (PK, CCh, DJH, SL); Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (SK, RF, TAM, HN); Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (MKB, QW, JD, KM, ML, SK, DFE, PDPP); Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia (JBee, GCT); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden (KC, HD, ME, JiL, JBr, KH, PH); Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium (DL); Vesalius Research Center, VIB, Leuven, Belgium (DL); Oncology Department, University Hospital Gasthuisberg, Leuven, Belgium (CW, KL); Copenhagen General Population Study, Herlev Hospital, Copenhagen, Denmark (SEB, BGN, SFN); Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Denmark (SEB, BGN, SFN); Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (SEB, BGN); Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Denmark (HF); Division of Cancer Epidemiology, German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg, Germany (JCC, AR, PS, DC, AHü, RK, MB); Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany (DFJ); Department of Oncology

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 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.

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.

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http://dx.doi.org/10.1093/jnci/djv081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4555642PMC

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May 2015
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