title: A genome wide meta-analysis study for identification of common variation associated with breast cancer prognosis.
abstract: OBJECTIVE
  Genome wide association studies (GWAs) of breast cancer mortality have identified few potential associations. The concordance between these studies is unclear. In this study, we used a meta-analysis of two prognostic GWAs and a replication cohort to identify the strongest associations and to evaluate the loci suggested in previous studies. We attempt to identify those SNPs which could impact overall survival irrespective of the age of onset.
  
  
  METHODS
  To facilitate the meta-analysis and to refine the association signals, SNPs were imputed using data from the 1000 genomes project. Cox-proportional hazard models were used to estimate hazard ratios (HR) in 536 patients from the POSH cohort (Prospective study of Outcomes in Sporadic versus Hereditary breast cancer) and 805 patients from the HEBCS cohort (Helsinki Breast Cancer Study). These hazard ratios were combined using a Mantel-Haenszel fixed effects meta-analysis and a p-value threshold of 5×10(-8) was used to determine significance. Replication was performed in 1523 additional patients from the POSH study.
  
  
  RESULTS
  Although no SNPs achieved genome wide significance, three SNPs have significant association in the replication cohort and combined p-values less than 5.6×10(-6). These SNPs are; rs421379 which is 556 kb upstream of ARRDC3 (HR = 1.49, 95% confidence interval (CI) = 1.27-1.75, P = 1.1×10(-6)), rs12358475 which is between ECHDC3 and PROSER2 (HR = 0.75, CI = 0.67-0.85, P = 1.8×10(-6)), and rs1728400 which is between LINC00917 and FOXF1.
  
  
  CONCLUSIONS
  In a genome wide meta-analysis of two independent cohorts from UK and Finland, we identified potential associations at three distinct loci. Phenotypic heterogeneity and relatively small sample sizes may explain the lack of genome wide significant findings. However, the replication at three SNPs in the validation cohort shows promise for future studies in larger cohorts. We did not find strong evidence for concordance between the few associations highlighted by previous GWAs of breast cancer survival and this study.
authors.affiliation: Genetic Epidemiology and Bioinformatics Research Group, Human Genetics, Faculty of Medicine, University of Southampton, Southampton General Hospital, Hants, United Kingdom.
authors.forename: Sajjad
authors.initials: S
authors.lastname: Rafiq
authors.affiliation: Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Sofia
authors.initials: S
authors.lastname: Khan
authors.affiliation: Genetic Epidemiology and Bioinformatics Research Group, Human Genetics, Faculty of Medicine, University of Southampton, Southampton General Hospital, Hants, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Tapper
authors.affiliation: Genetic Epidemiology and Bioinformatics Research Group, Human Genetics, Faculty of Medicine, University of Southampton, Southampton General Hospital, Hants, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Collins
authors.affiliation: Genetic Epidemiology and Bioinformatics Research Group, Human Genetics, Faculty of Medicine, University of Southampton, Southampton General Hospital, Hants, United Kingdom.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Upstill-Goddard
authors.affiliation: Clinical Trials Unit, Faculty of Medicine, University of Southampton, Hants, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: Gerty
authors.affiliation: Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.affiliation: Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.affiliation: Cancer Sciences Division, University of Southampton, School of Medicine, Southampton General Hospital, Hants, United Kingdom.
authors.forename: Diana
authors.initials: D
authors.lastname: Eccles
mesh_terms: D000328:Adult; D000368:Aged; D019390:Arrestins / Q000235:genetics; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis
chemical_list: C508469:ARRDC3 protein, human; D019390:Arrestins; C098521:FOXF1 protein, human; D051858:Forkhead Transcription Factors