title: Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer.
abstract: Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs.
  
  
  
  Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia.
  
  
  
  This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.
authors.affiliation: Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, Faculty of Medicine, University of Oslo, Oslo, Norway.|NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.|European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Verena
authors.initials: V
authors.lastname: Zuber
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bettella
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Aree
authors.initials: A
authors.lastname: Witoelar
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.|PCUK Movember Centre of Excellence, CCRCB, Queen's University, Belfast, UK.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
authors.affiliation: Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, Faculty of Medicine, University of Oslo, Oslo, Norway. alfonsourbanucci@gmail.com.|Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. alfonsourbanucci@gmail.com.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Urbanucci
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D002874:Chromosome Mapping; D019295:Computational Biology / Q000379:methods; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D040641:Quantitative Trait Loci; D011944:Receptors, Androgen / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D006657:Histones; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins
keywords: BRD4; Chromatin; Functional annotation; Genome-wide association studies; Prostate cancer risk; Risk loci; SNPs; breast cancer risk; schizophrenia; super-enhancer