title: HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer.
abstract: Two independent regions within HNF1B are consistently identified in prostate and ovarian cancer genome-wide association studies (GWAS); their functional roles are unclear. We link prostate cancer (PC) risk SNPs rs11649743 and rs3760511 with elevated HNF1B gene expression and allele-specific epigenetic silencing, and outline a mechanism by which common risk variants could effect functional changes that increase disease risk: functional assays suggest that HNF1B is a pro-differentiation factor that suppresses epithelial-to-mesenchymal transition (EMT) in unmethylated, healthy tissues. This tumor-suppressor activity is lost when HNF1B is silenced by promoter methylation in the progression to PC. Epigenetic inactivation of HNF1B in ovarian cancer also associates with known risk SNPs, with a similar impact on EMT. This represents one of the first comprehensive studies into the pleiotropic role of a GWAS-associated transcription factor across distinct cancer types, and is the first to describe a conserved role for a multi-cancer genetic risk factor.
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Ross-Adams
authors.affiliation: Prostate Cancer Research Centre, University College London, London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Ball
authors.affiliation: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Lawrenson
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Halim
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: Roslin
authors.initials: R
authors.lastname: Russell
authors.affiliation: Division of Cancer Studies, King's College London, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Wells
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Denmark.
authors.forename: Siri H
authors.initials: SH
authors.lastname: Strand
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Denmark.
authors.forename: Torben F
authors.initials: TF
authors.lastname: Ørntoft
authors.affiliation: Mayo Clinic, SW Rochester, MN, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Larson
authors.affiliation: Mayo Clinic, SW Rochester, MN, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Armasu
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Massie
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Asim
authors.affiliation: Department of Urology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Mortensen
authors.affiliation: Department of Urology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Woodfine
authors.affiliation: Department of Pathology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Warren
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: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.|Molecular Diagnostics and Therapeutics Group, University College London, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kay
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.|Molecular Diagnostics and Therapeutics Group, University College London, London, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Whitaker
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ramos-Montoya
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Centre for Regenerative Medicine, Claverton Down, Bath, UK.
authors.forename: Adele
authors.initials: A
authors.lastname: Murrell
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Denmark.
authors.forename: Karina D
authors.initials: KD
authors.lastname: Sørensen
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.affiliation: Mayo Clinic, SW Rochester, MN, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Gayther
authors.affiliation: Prostate Cancer Research Centre, University College London, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Masters
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.|Department of Urology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.|Prostate Cancer Research Group, Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.|Departments of Cancer Prevention and Urology, Institute of Cancer Research and Department of Urology, Oslo University Hospital, Oslo, Norway.|Prostate Cancer UK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
mesh_terms: D000483:Alleles; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019175:DNA Methylation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012306:Risk
chemical_list: C496495:HNF1B protein, human; D051539:Hepatocyte Nuclear Factor 1-beta
keywords: HNF1B; cancer; eQTL; ovarian; prostate