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

Helen Ross-Adams, Stephen Ball, Kate Lawrenson, Silvia Halim, Roslin Russell, Claire Wells, Siri H. Strand, Torben F. Ørntoft, Melissa Larson, Sebastian Armasu, Charles E. Massie, Mohammad Asim, Martin M. Mortensen, Michael Borre, Kathryn Woodfine, Anne Y. Warren, Alastair D. Lamb, Jonathan Kay, Hayley Whitaker, Antonio Ramos-MontoyaAdele Murrell, Karina D. Sørensen, Brooke L. Fridley, Ellen L. Goode, Simon A. Gayther, John Masters, David E. Neal, Ian G. Mills

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)74734-74746
Number of pages13
JournalOncotarget
Volume7
Issue number46
DOIs
StatePublished - 2016

Keywords

  • Cancer
  • EQTL
  • HNF1B
  • Ovarian
  • Prostate

ASJC Scopus subject areas

  • Oncology

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    Ross-Adams, H., Ball, S., Lawrenson, K., Halim, S., Russell, R., Wells, C., Strand, S. H., Ørntoft, T. F., Larson, M., Armasu, S., Massie, C. E., Asim, M., Mortensen, M. M., Borre, M., Woodfine, K., Warren, A. Y., Lamb, A. D., Kay, J., Whitaker, H., ... Mills, I. G. (2016). HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer. Oncotarget, 7(46), 74734-74746. https://doi.org/10.18632/oncotarget.12543