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 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.
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Jodie N
JN
Painter
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Susanne
S
Kaufmann
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Tracy A
TA
O'Mara
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Kristine M
KM
Hillman
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Haran
H
Sivakumaran
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
Hatef
H
Darabi
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Timothy H T
THT
Cheng
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
John
J
Pearson
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Stephen
S
Kazakoff
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Nicola
N
Waddell
Centre for Cancer Biomarkers, Department of Clinical Science, The University of Bergen, N5020 Bergen, Norway; Department of Obstetrics and Gynecology, Haukeland University Hospital, N5021 Bergen, Norway.
Erling A
EA
Hoivik
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Ellen L
EL
Goode
Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW 2305, Australia; Pathology North (Newcastle) John Hunter Hospital, Newcastle, NSW 2305, Australia; Centre for Information Based Medicine, University of Newcastle, NSW 2308, Australia; School of Biomedical Sciences and Pharmacy, University of Newcastle, NSW 2308, Australia.
Rodney J
RJ
Scott
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Ian
I
Tomlinson
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
Alison M
AM
Dunning
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
Douglas F
DF
Easton
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Juliet D
JD
French
Centre for Cancer Biomarkers, Department of Clinical Science, The University of Bergen, N5020 Bergen, Norway; Department of Obstetrics and Gynecology, Haukeland University Hospital, N5021 Bergen, Norway.
Helga B
HB
Salvesen
Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology at the Translation Research Institute, Brisbane 4102, Australia.
Pamela M
PM
Pollock
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
Deborah J
DJ
Thompson
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Amanda B
AB
Spurdle
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia. Electronic address: stacey.edwards@qimrberghofer.edu.au.
Stacey L
SL
Edwards
D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D015398:Signal Transduction; D014594:Uterine Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt