biostudies-literaturePainter JNCancer Research UKWellcome Trust1159-1169https://www.ebi.ac.uk/biostudies/studies/S-EPMC4908177biostudies-literatureUnknown98(6)A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromosome 14q32.33. To prioritize the functional SNP(s) and target gene(s) at this locus, we employed an in silico fine-mapping approach using genotyped and imputed SNP data for 6,608 endometrial cancer cases and 37,925 controls of European ancestry. Association and functional analyses provide evidence that the best candidate causal SNP is rs2494737. Multiple experimental analyses show that SNP rs2494737 maps to a silencer element located within AKT1, a member of the PI3K/AKT/MTOR intracellular signaling pathway activated in endometrial tumors. The rs2494737 risk A allele creates a YY1 transcription factor-binding site American journal of human geneticsA Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding.PMC490817716565090532/Z/09/ZWaddell NThompson DJDarabi HHoivik EAPollock PMFrench JDHillman KMSpurdle ABKaufmann STomlinson IEdwards SLCheng THTPearson JSivakumaran HKazakoff SScott RJO'Mara TAEaston DFPainter JNDunning AMSalvesen HBGoode ELfalseA Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding.A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromosome 14q32.33. To prioritize the functional SNP(s) and target gene(s) at this locus, we employed an in silico fine-mapping approach using genotyped and imputed SNP data for 6,608 endometrial cancer cases and 37,925 controls of European ancestry. Association and functional analyses provide evidence that the best candidate causal SNP is rs2494737. Multiple experimental analyses show that SNP rs2494737 maps to a silencer element located within AKT1, a member of the PI3K/AKT/MTOR intracellular signaling pathway activated in endometrial tumors. The rs2494737 risk A allele creates a YY1 transcription factor-binding site 2016-01-01T00:00:00Z2016 Jun2026-05-30T08:30:30.75Z2024-11-20T17:14:06.941ZS-EPMC49081772725905110.1016/j.ajhg.2016.04.012