HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer.

Autor: Ross-Adams H; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Ball S; Prostate Cancer Research Centre, University College London, London, UK., Lawrenson K; Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA., Halim S; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Russell R; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Wells C; Division of Cancer Studies, King's College London, London, UK., Strand SH; Department of Molecular Medicine, Aarhus University Hospital, Denmark., Ørntoft TF; Department of Molecular Medicine, Aarhus University Hospital, Denmark., Larson M; Mayo Clinic, SW Rochester, MN, USA., Armasu S; Mayo Clinic, SW Rochester, MN, USA., Massie CE; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Asim M; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Mortensen MM; Department of Urology, Aarhus University Hospital, Aarhus, Denmark., Borre M; Department of Urology, Aarhus University Hospital, Aarhus, Denmark., Woodfine K; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Warren AY; Department of Pathology, Addenbrooke's Hospital, Cambridge, UK., Lamb AD; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.; Department of Urology, Addenbrooke's Hospital, Cambridge, UK., Kay J; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.; Molecular Diagnostics and Therapeutics Group, University College London, London, UK., Whitaker H; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.; Molecular Diagnostics and Therapeutics Group, University College London, London, UK., Ramos-Montoya A; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Murrell A; Department of Biology and Biochemistry, University of Bath, Centre for Regenerative Medicine, Claverton Down, Bath, UK., Sørensen KD; Department of Molecular Medicine, Aarhus University Hospital, Denmark., Fridley BL; Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA., Goode EL; Mayo Clinic, SW Rochester, MN, USA., Gayther SA; Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA., Masters J; Prostate Cancer Research Centre, University College London, London, UK., Neal DE; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.; Department of Urology, Addenbrooke's Hospital, Cambridge, UK., Mills IG; 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.
Jazyk: angličtina
Zdroj: Oncotarget [Oncotarget] 2016 Nov 15; Vol. 7 (46), pp. 74734-74746.
DOI: 10.18632/oncotarget.12543
Abstrakt: 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.
Databáze: MEDLINE