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

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27 Citations (Scopus)
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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
Number of pages13
JournalOncotarget
Early online date09 Oct 2016
DOIs
Publication statusEarly online date - 09 Oct 2016

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