title: Gene regulatory mechanisms underpinning prostate cancer susceptibility.
abstract: Molecular characterization of genome-wide association study (GWAS) loci can uncover key genes and biological mechanisms underpinning complex traits and diseases. Here we present deep, high-throughput characterization of gene regulatory mechanisms underlying prostate cancer risk loci. Our methodology integrates data from 295 prostate cancer chromatin immunoprecipitation and sequencing experiments with genotype and gene expression data from 602 prostate tumor samples. The analysis identifies new gene regulatory mechanisms affected by risk locus SNPs, including widespread disruption of ternary androgen receptor (AR)-FOXA1 and AR-HOXB13 complexes and competitive binding mechanisms. We identify 57 expression quantitative trait loci at 35 risk loci, which we validate through analysis of allele-specific expression. We further validate predicted regulatory SNPs and target genes in prostate cancer cell line models. Finally, our integrated analysis can be accessed through an interactive visualization tool. This analysis elucidates how genome sequence variation affects disease predisposition via gene regulatory mechanisms and identifies relevant genes for downstream biomarker and drug development.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Whitington
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.|Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.|Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Ross-Adams
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.|Department of Urology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Lamb
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.|Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.|Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Svezia
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0002-9810-3838
authors.initials: D
authors.lastname: Klevebring
authors.affiliation: Prostate Cancer Research Group, Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.|Department of Molecular Oncology, Institute of Cancer Research, Oslo University Hospital, Oslo, Norway.|Prostate Cancer UK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Robert
authors.identifier: http://orcid.org/0000-0002-8949-2587
authors.initials: R
authors.lastname: Karlsson
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.|Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Halim
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dunning
authors.affiliation: Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.|Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Egevad
authors.affiliation: Department of Pathology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Warren
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
authors.forename: David E
authors.identifier: http://orcid.org/0000-0002-6033-5086
authors.initials: DE
authors.lastname: Neal
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Grönberg
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lindberg
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.|Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Gong-Hong
authors.initials: GH
authors.lastname: Wei
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wiklund
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D040641:Quantitative Trait Loci; D012097:Repressor Proteins / Q000378:metabolism; D012307:Risk Factors; D017422:Sequence Analysis, DNA
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D012097:Repressor Proteins