Published in
Impact Journals, Oncotarget, 46(7), p. 74734-74746, 2016
DOI: 10.18632/oncotarget.12543
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HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer
,
Torben F. Ørntoft,
Melissa Larson,
Sebastian Armasu,
Charles E. Massie ,
Martin M. Mortensen,
Mohammad Asim,
Kathryn Woodfine,
Michael Borre
and other authors.
Full text: Download
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.