HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer
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Helen Ross-Adams1, Stephen Ball2, Kate Lawrenson3, Silvia Halim1, Roslin Russell1, Claire Wells4, Siri H. Strand5, Torben F. Ørntoft5, Melissa Larson6, Sebastian Armasu6, Charles E. Massie1, Mohammad Asim1, Martin M. Mortensen8, Michael Borre8, Kathryn Woodfine1, Anne Y. Warren9, Alastair D. Lamb1,10, Jonathan Kay1,15, Hayley Whitaker1,15, Antonio Ramos-Montoya1, Adele Murrell7, Karina D. Sørensen5, Brooke L. Fridley11, Ellen L. Goode6, Simon A. Gayther3, John Masters2, David E. Neal1,10,* and Ian G. Mills1,12,13,14,*
1 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
2 Prostate Cancer Research Centre, University College London, London, UK
3 Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
4 Division of Cancer Studies, King’s College London, London, UK
5 Department of Molecular Medicine, Aarhus University Hospital, Denmark
6 Mayo Clinic, SW, Rochester, MN, USA
7 Department of Biology and Biochemistry, University of Bath, Centre for Regenerative Medicine, Claverton Down, Bath, UK
8 Department of Urology, Aarhus University Hospital, Aarhus, Denmark
9 Department of Pathology, Addenbrooke’s Hospital, Cambridge, UK
10 Department of Urology, Addenbrooke’s Hospital, Cambridge, UK
11 Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA
12 Prostate Cancer Research Group, Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway
13 Departments of Cancer Prevention and Urology, Institute of Cancer Research and Department of Urology, Oslo University Hospital, Oslo, Norway
14 Prostate Cancer UK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK
15 Molecular Diagnostics and Therapeutics Group, University College London, London, UK
* These authors have contributed equally to this work
Ian G. Mills, email:
Keywords: HNF1B, eQTL, prostate, ovarian, cancer
Received: September 20, 2016 Accepted: September 26, 2016 Published: October 09, 2016
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.
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