title: Common germline polymorphisms associated with breast cancer-specific survival.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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 that 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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 multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.
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authors.initials: P
authors.lastname: Peterlongo
authors.affiliation: Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Dei Tumori (INT), Via Adamello 16, Milan, 20139, Italy. siranoush.manoukian@istitutotumori.mi.it.
authors.forename: Siranoush
authors.initials: S
authors.lastname: Manoukian
authors.affiliation: IFOM, Fondazione Istituto FIRC Di Oncologia Molecolare, Via Adamello 16, 20139, Milan, Italy. filomena.ficarazzi@ifom.eu.|Cogentech Cancer Genetic Test Laboratory, Via Adamello 16, 20139, Milan, Italy. filomena.ficarazzi@ifom.eu.
authors.forename: Filomena
authors.initials: F
authors.lastname: Ficarazzi
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Emn, Universitaetsstrasse 21-23, 91054, Erlangen, Germany. fk-direktion@uk-erlangen.de.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Emn, Universitaetsstrasse 21-23, 91054, Erlangen, Germany. alexander.hein@uk-erlangen.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hein
authors.affiliation: Institute of Human Genetics; University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Emn, Universitaetsstrasse 21-23, 91054, Erlangen, Germany. arif.ekici@uk-erlangen.de.
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.affiliation: Western Sydney and Nepean Blue Mountains Local Health Districts, Westmead Millennium Institute for Medical Research, University of Sydney, 176 Hawkesbury Road, Sydney, NSW 2145, Australia. rosemary.balleine@sydney.edu.au.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Balleine
authors.affiliation: Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC, 3010, Australia. Kelly.Phillips@petermac.org.|Peter Maccallum Cancer Center, 2 St Andrews Place, Melbourne, VIC, 3002, Australia. Kelly.Phillips@petermac.org.|Sir Peter Maccallum Department of Oncology, University of Melbourne, 2 St Andrews Place, Melbourne, VIC, 3002, Australia. Kelly.Phillips@petermac.org.
authors.forename: Kelly-Anne
authors.initials: KA
authors.lastname: Phillips
authors.affiliation: Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Calle de Melchor Fernández, Almagro, 3, 28029, Madrid, Spain. jbenitez@cnio.es.|Centro de Investigación En Red De Enfermedades Raras (CIBERER), Calle de Álvaro de Bazán, 10 Bajo, 46010, Valencia, Spain. jbenitez@cnio.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Benitez
authors.affiliation: Servicio de Oncología Médica, Hospital Universitario La Paz, Paseo de la Castellana, 261, 28046, Madrid, Spain. zamorapilar@gmail.com.
authors.forename: M Pilar
authors.initials: MP
authors.lastname: Zamora
authors.affiliation: Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Avenida Doctores Fernández Vega, 107, 33012, Oviedo, Spain. jiarias@msn.com.
authors.forename: Jose Ignacio Arias
authors.initials: JI
authors.lastname: Perez
authors.affiliation: Servicio de Anatomía Patológica, Hospital Monte Naranco, Avenida Doctores Fernández Vega, 107, 33012, Oviedo, Spain. tiva@hca.es.
authors.forename: Primitiva
authors.initials: P
authors.lastname: Menéndez
authors.affiliation: Department of Genetics and Pathology, Pomeranian Medical University, ul. Rybacka 1, Szczecin, Poland. aniaj@sci.pam.szczecin.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Jakubowska
authors.affiliation: Department of Genetics and Pathology, Pomeranian Medical University, ul. Rybacka 1, Szczecin, Poland. lubinski@sci.pam.szczecin.pl.
authors.forename: Jan
authors.initials: J
authors.lastname: Lubinski
authors.affiliation: Department of Genetics and Pathology, Pomeranian Medical University, ul. Rybacka 1, Szczecin, Poland. jgron@sci.pum.edu.pl.
authors.forename: Jacek
authors.initials: J
authors.lastname: Gronwald
authors.affiliation: Department of Genetics and Pathology, Pomeranian Medical University, ul. Rybacka 1, Szczecin, Poland. k.durda@onet.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Durda
authors.affiliation: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. u.hamann@dkfz-heidelberg.de.
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
authors.affiliation: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. m.kabisch@dkfz-heidelberg.de.
authors.forename: Maria
authors.initials: M
authors.lastname: Kabisch
authors.affiliation: Frauenklinik der Stadtklinik Baden-Baden, Balger Strasse 50, 76532, Baden-Baden, Germany. hu.ulmer@klinikum-mittelbaden.de.
authors.forename: Hans Ulrich
authors.initials: HU
authors.lastname: Ulmer
authors.affiliation: Institute of Pathology, Städtisches Klinikum Karlsruhe, Moltkestrasse 90, 76133, Karlsruhe, Germany. Thomas.Ruediger@klinikum-karlsruhe.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rüdiger
authors.affiliation: Department of Oncology - Pathology, Karolinska Institutet, Tomtebodavägen 23b, Stockholm, 171 65, Sweden. Sara.Margolin@karolinska.se.
authors.forename: Sara
authors.initials: S
authors.lastname: Margolin
authors.affiliation: Faculty of Medicine (Faculty Division Ahus), University of Oslo (UiO), Problemveien 7, Oslo, 0313, Norway. Vessela.N.Kristensen@rr-research.no.|Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Montebello, 0379, Oslo, Norway. Vessela.N.Kristensen@rr-research.no.
authors.forename: Vessela
authors.initials: V
authors.lastname: Kristensen
authors.affiliation: Faculty of Medicine (Faculty Division Ahus), University of Oslo (UiO), Problemveien 7, Oslo, 0313, Norway. silje.nordgard@gmail.com.|Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Montebello, 0379, Oslo, Norway. silje.nordgard@gmail.com.
authors.forename: Siljie
authors.initials: S
authors.lastname: Nord
authors.affiliation: Genomic Medicine, Manchester Academic Health Science Centre, University of Manchester, Central Manchester Foundation Trust, St. Mary's Hospital, Oxford Road, Manchester, M13 9WL, UK. Gareth.Evans@cmft.nhs.uk.
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Evans
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, 2 Wort's Causeway, Cambridge, CB1 8RN, UK. ja344@medschl.cam.ac.uk.|Cambridge Experimental Cancer Medicine Centre, Robinson Way, Cambridge, CB2 0RE, UK. ja344@medschl.cam.ac.uk.|Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals, Hills Road, Cambridge, CB2 0QQ, UK. ja344@medschl.cam.ac.uk.
authors.forename: Jean
authors.initials: J
authors.lastname: Abraham
authors.affiliation: Cambridge Experimental Cancer Medicine Centre, Robinson Way, Cambridge, CB2 0RE, UK. hme22@cam.ac.uk.|Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals, Hills Road, Cambridge, CB2 0QQ, UK. hme22@cam.ac.uk.
authors.forename: Helena
authors.initials: H
authors.lastname: Earl
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Campus, Coventry, CV4 7AL, UK. christopher.poole@warwick.ac.uk.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Poole
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Campus, Coventry, CV4 7AL, UK. l.hiller@warwick.ac.uk.
authors.forename: Louise
authors.initials: L
authors.lastname: Hiller
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Campus, Coventry, CV4 7AL, UK. j.a.dunn@warwick.ac.uk.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Dunn
authors.affiliation: Cancer Research UK Clinical Trials Unit, Institute for Cancer Studies, the University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK. s.j.bowden@bham.ac.uk.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bowden
authors.affiliation: Early Detection Research Group, Division of Cancer Prevention National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892, USA. royang@mail.nih.gov.
authors.forename: Rose
authors.initials: R
authors.lastname: Yang
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. d.campa@dkfz-heidelberg.de.|Department of Biology, University of Pisa, Lungarno Pacinotti 43, 56126, Pisa, Italy. d.campa@dkfz-heidelberg.de.
authors.forename: Daniele
authors.initials: D
authors.lastname: Campa
authors.affiliation: Epidemiology Research Program, American Cancer Society, 250 Williams Street, Atlanta, GA, 30303, USA. Ryan.diver@cancer.org.
authors.forename: W Ryan
authors.initials: WR
authors.lastname: Diver
authors.affiliation: Epidemiology Research Program, American Cancer Society, 250 Williams Street, Atlanta, GA, 30303, USA. Susan.gapstur@cancer.org.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Gapstur
authors.affiliation: Epidemiology Research Program, American Cancer Society, 250 Williams Street, Atlanta, GA, 30303, USA. Mia.gaudet@cancer.org.
authors.forename: Mia M
authors.initials: MM
authors.lastname: Gaudet
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA. shankinson@schoolph.umass.edu.|Division of Biostatistics and Epidemiology, University of Massachusetts-Amherst School of Public Health and Health Sciences, 715 N Pleasant Street, Amherst, MA, 01002, USA. shankinson@schoolph.umass.edu.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA. shankinson@schoolph.umass.edu.
authors.forename: Susan
authors.initials: S
authors.lastname: Hankinson
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD, 20892, USA. hooverr@exchange.nih.gov.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Hoover
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. a.huesing@dkfz.de.
authors.forename: Anika
authors.initials: A
authors.lastname: Hüsing
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. r.kaaks@dkfz.de.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD, 20892, USA. Mitchell.machiela@nih.gov.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Machiela
authors.affiliation: Department of Nutrition, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA, 02115, USA. wwillett@hsph.harvard.edu.
authors.forename: Walter
authors.initials: W
authors.lastname: Willett
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. m.barrdahl@Dkfz-Heidelberg.de.
authors.forename: Myrto
authors.initials: M
authors.lastname: Barrdahl
authors.affiliation: Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. f.canzian@dkfz-heidelberg.de.
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
authors.affiliation: Breast Cancer Functional Genomics Laboratory, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, CB2 0RE, UK. Suet-Feung.Chin@cruk.cam.ac.uk.
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.affiliation: Cambridge Experimental Cancer Medicine Centre, Robinson Way, Cambridge, CB2 0RE, UK. carlos.caldas@cruk.cam.ac.uk.|Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals, Hills Road, Cambridge, CB2 0QQ, UK. carlos.caldas@cruk.cam.ac.uk.|Breast Cancer Functional Genomics Laboratory, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, CB2 0RE, UK. carlos.caldas@cruk.cam.ac.uk.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA. dhunter@hsph.harvard.edu.|Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA. dhunter@hsph.harvard.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA. slindstr@hsph.harvard.edu.|Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA. slindstr@hsph.harvard.edu.
authors.forename: Sara
authors.initials: S
authors.lastname: Lindstrom
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK. Montse.GarciaClosas@icr.ac.uk.|Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK. Montse.GarciaClosas@icr.ac.uk.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. couch.fergus@mayo.edu.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Department of Genetics, Qimr Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia. Georgia.Trench@qimrberghofer.edu.au.
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.affiliation: School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine and Cancer Center of Eastern Finland, University of Eastern Finland, Yliopistonranta 1C, 70210, Kuopio, Finland. arto.mannermaa@uef.fi.|Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Puijonlaaksontie 2, 70210, Kuopio, Finland. arto.mannermaa@uef.fi.
authors.forename: Arto
authors.initials: A
authors.lastname: Mannermaa
authors.affiliation: Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, M5G 1X5, Canada. andrulis@lunenfeld.ca.|Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. andrulis@lunenfeld.ca.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, Stockholm, 17177, Sweden. Per.Hall@ki.se.
authors.forename: Per
authors.initials: P
authors.lastname: Hall
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. j.chang-claude@dkfz-heidelberg.de.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Wort's Causeway, Cambridge, CB1 8RN, UK. dfe20@medschl.cam.ac.uk.|Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, 2 Wort's Causeway, Cambridge, CB1 8RN, UK. dfe20@medschl.cam.ac.uk.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.affiliation: Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730, Herlev, Copenhagen, Denmark. stig.egil.bojesen@regionh.dk.|Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730, Herlev, Copenhagen, Denmark. stig.egil.bojesen@regionh.dk.|Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2220, Copenhagen, Denmark. stig.egil.bojesen@regionh.dk.
authors.forename: Stig E
authors.initials: SE
authors.lastname: Bojesen
authors.affiliation: CRUK/YCR Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK. a.cox@shef.ac.uk.
authors.forename: Angela
authors.initials: A
authors.lastname: Cox
authors.affiliation: Institute of Human Genetics; University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Emn, Universitaetsstrasse 21-23, 91054, Erlangen, Germany. peter.fasching@uk-erlangen.de.|David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA, 90095, USA. peter.fasching@uk-erlangen.de.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Wort's Causeway, Cambridge, CB1 8RN, UK. pp10001@medschl.cam.ac.uk.|Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, 2 Wort's Causeway, Cambridge, CB1 8RN, UK. pp10001@medschl.cam.ac.uk.
authors.forename: Paul Dp
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Netherlands Cancer Institute, Antoni Van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. mk.schmidt@nki.nl.
authors.forename: Marjanka K
authors.initials: MK
authors.lastname: Schmidt
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005854:Germ Cells / Q000378:metabolism*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis