A 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...
| Váldodahkkit: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Materiálatiipa: | Journal article |
| Giella: | English |
| Almmustuhtton: |
Cell Press
2016
|
| _version_ | 1826278775804919808 |
|---|---|
| author | Painter, J Kaufmann, S O'Mara, T Hillman, K Sivakumaran, H Darabi, H Cheng, T Pearson, J Kazakoff, S Waddell, N Hoivik, E Goode, E Scott, R Tomlinson, I Dunning, A Easton, D French, J Salvesen, H Pollock, P Thompson, D Spurdle, A Edwards, S |
| author_facet | Painter, J Kaufmann, S O'Mara, T Hillman, K Sivakumaran, H Darabi, H Cheng, T Pearson, J Kazakoff, S Waddell, N Hoivik, E Goode, E Scott, R Tomlinson, I Dunning, A Easton, D French, J Salvesen, H Pollock, P Thompson, D Spurdle, A Edwards, S |
| author_sort | Painter, J |
| collection | OXFORD |
| description | 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 and abrogates the silencer activity in luciferase assays, an effect mimicked by transfection of YY1 siRNA. Our findings suggest YY1 is a positive regulator of AKT1, mediating the stimulatory effects of rs2494737 increasing endometrial cancer risk. Identification of an endometrial cancer risk allele within a member of the PI3K/AKT signaling pathway, more commonly activated in tumors by somatic alterations, raises the possibility that well tolerated inhibitors targeting this pathway could be candidates for evaluation as chemopreventive agents in individuals at high risk of developing endometrial cancer. |
| first_indexed | 2024-03-06T23:49:00Z |
| format | Journal article |
| id | oxford-uuid:71f3059c-dc3f-43d0-9b01-7fe1af4f784e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:49:00Z |
| publishDate | 2016 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:71f3059c-dc3f-43d0-9b01-7fe1af4f784e2022-03-26T19:47:01ZA common variant at the 14q32 endometrial cancer risk locus activates AKT1 through YY1 bindingJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:71f3059c-dc3f-43d0-9b01-7fe1af4f784eEnglishSymplectic Elements at OxfordCell Press2016Painter, JKaufmann, SO'Mara, THillman, KSivakumaran, HDarabi, HCheng, TPearson, JKazakoff, SWaddell, NHoivik, EGoode, EScott, RTomlinson, IDunning, AEaston, DFrench, JSalvesen, HPollock, PThompson, DSpurdle, AEdwards, SA 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 and abrogates the silencer activity in luciferase assays, an effect mimicked by transfection of YY1 siRNA. Our findings suggest YY1 is a positive regulator of AKT1, mediating the stimulatory effects of rs2494737 increasing endometrial cancer risk. Identification of an endometrial cancer risk allele within a member of the PI3K/AKT signaling pathway, more commonly activated in tumors by somatic alterations, raises the possibility that well tolerated inhibitors targeting this pathway could be candidates for evaluation as chemopreventive agents in individuals at high risk of developing endometrial cancer. |
| spellingShingle | Painter, J Kaufmann, S O'Mara, T Hillman, K Sivakumaran, H Darabi, H Cheng, T Pearson, J Kazakoff, S Waddell, N Hoivik, E Goode, E Scott, R Tomlinson, I Dunning, A Easton, D French, J Salvesen, H Pollock, P Thompson, D Spurdle, A Edwards, S A common variant at the 14q32 endometrial cancer risk locus activates AKT1 through YY1 binding |
| title | A common variant at the 14q32 endometrial cancer risk locus activates AKT1 through YY1 binding |
| title_full | A common variant at the 14q32 endometrial cancer risk locus activates AKT1 through YY1 binding |
| title_fullStr | A common variant at the 14q32 endometrial cancer risk locus activates AKT1 through YY1 binding |
| title_full_unstemmed | A common variant at the 14q32 endometrial cancer risk locus activates AKT1 through YY1 binding |
| title_short | A common variant at the 14q32 endometrial cancer risk locus activates AKT1 through YY1 binding |
| title_sort | common variant at the 14q32 endometrial cancer risk locus activates akt1 through yy1 binding |
| work_keys_str_mv | AT painterj acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT kaufmanns acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT omarat acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT hillmank acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT sivakumaranh acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT darabih acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT chengt acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT pearsonj acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT kazakoffs acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT waddelln acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT hoivike acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT goodee acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT scottr acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT tomlinsoni acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT dunninga acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT eastond acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT frenchj acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT salvesenh acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT pollockp acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT thompsond acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT spurdlea acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT edwardss acommonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT painterj commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT kaufmanns commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT omarat commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT hillmank commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT sivakumaranh commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT darabih commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT chengt commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT pearsonj commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT kazakoffs commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT waddelln commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT hoivike commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT goodee commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT scottr commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT tomlinsoni commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT dunninga commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT eastond commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT frenchj commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT salvesenh commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT pollockp commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT thompsond commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT spurdlea commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding AT edwardss commonvariantatthe14q32endometrialcancerrisklocusactivatesakt1throughyy1binding |