H Ross-Adams, S Ball, K Lawrenson, S Halim, R Russell, C Wells, SH Strand, TF Ørntoft, M Larson, S Armasu, CE Massie, M Asim, MM Mortensen, M Borre, K Woodfine, AY Warren, AD Lamb, J Kay, H Whitaker, A Ramos-Montoya, A Murrell, KD Sørensen, BL Fridley, EL Goode, SA Gayther, J Masters, DE Neal, IG Mills
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.