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

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

来源：Oncotarget, 2016, 7(46): 74734-74746.

DOI：10.18632/oncotarget.12543

• HNF1B
• eQTL
• prostate
• ovarian
• cancer

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.

• 出版日期2016-11-15