Karina Dalsgaard Sørensen

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Helen Ross-Adams, Department of Oncology, Cancer Research UK Cambridge Research Institute, University of Cambridge
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  • Stephen J. Ball, Prostate Cancer Research Centre, University College London, London, UK.
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  • Kate Lawrenson, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA.
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  • Silvia Halim, Department of Oncology, Cancer Research UK Cambridge Research Institute, University of Cambridge
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  • Roslin Russell, Department of Oncology, Cancer Research UK Cambridge Research Institute, University of Cambridge
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  • Claire Wells, Division of Cancer Studies, Cancer Epidemiology Group, King's College London
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  • Siri Strand
  • Torben F Ørntoft
  • Melissa C Larson, Molecular Medicine Program, Mayo Clinic, Rochester, USA.
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  • Sebastian M Armasu, Molecular Medicine Program, Mayo Clinic, Rochester, USA.
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  • Charles E Massie, Department of Oncology, Cancer Research UK Cambridge Research Institute, University of Cambridge
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  • Mohammad Asim, Department of Oncology, Cancer Research UK Cambridge Research Institute, University of Cambridge
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  • Martin M Mortensen
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  • Michael Borre
  • Kathryn Woodfine, Department of Oncology, Cancer Research UK Cambridge Research Institute, University of Cambridge
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  • Anne Y Warren, Department of Pathology, Addenbrooke's Hospital, Cambridge, UK.
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  • Alastair D Lamb, Department of Urology, Addenbrooke's Hospital, Cambridge, UK.
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  • Jonathan Kay, Molecular Diagnostics and Therapeutics Group, University College London, London, UK.
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  • Hayley Whitaker, Molecular Diagnostics and Therapeutics Group, University College London, London, UK.
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  • Antonio Ramos-Montoya, Department of Oncology, Cancer Research UK Cambridge Research Institute, University of Cambridge
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  • Adele Murrell, Department of Biology and Biochemistry, University of Bath, Centre for Regenerative Medicine, Claverton Down, Bath, UK.
  • ,
  • Karina D Sørensen
  • Brooke L Fridley, Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA.
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  • Ellen L Goode, Molecular Medicine Program, Mayo Clinic, Rochester, USA.
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  • Simon A Gayther, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA.
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  • John R Masters, Prostate Cancer Research Centre, University College London, London, UK.
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  • David E Neal, Department of Urology, Addenbrooke's Hospital, Cambridge, UK.
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  • Ian G Mills, Prostate Cancer UK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK.

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.

Original languageEnglish
JournalOncoTarget
Volume7
Issue46
Pages (from-to)74734-74746
Number of pages13
ISSN1949-2553
DOIs
Publication statusPublished - 15 Nov 2016

    Research areas

  • Journal Article

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