Letter | Published:

Five endometrial cancer risk loci identified through genome-wide association analysis

Nature Genetics volume 48, pages 667674 (2016) | Download Citation


We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r2 = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

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We thank the many individuals who participated in this study and the numerous institutions and their staff that supported recruitment, detailed in full in the Supplementary Note.

The iCOGS endometrial cancer analysis was supported by an NHMRC project grant (1031333) to A.B.S., D.F.E. and A.M.D. A.B.S., P.M.W., G.W.M. and D.R.N. are supported by the NHMRC Fellowship scheme. A.M.D. was supported by the Joseph Mitchell Trust. I.T. is supported by Cancer Research UK and the Oxford Comprehensive Biomedical Research Centre. T.H.T.C. is supported by the Rhodes Trust and the Nuffield Department of Medicine. Funding for iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 and C8197/A16565), the US National Institutes of Health (R01 CA128978, U19 CA148537, U19 CA148065 and U19 CA148112), the US Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Susan G. Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund.

ANECS recruitment was supported by project grants from the NHMRC (339435), Cancer Council Queensland (4196615) and Cancer Council Tasmania (403031 and 457636). SEARCH recruitment was funded by a programme grant from Cancer Research UK (C490/A10124). Stage 1 and stage 2 case genotyping was supported by the NHMRC (552402 and 1031333). Control data were generated by the WTCCC, and a full list of the investigators who contributed to the generation of the data is available from the WTCCC website. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by UK Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02; funding for this project was provided by the Wellcome Trust under award 085475. NSECG was supported by the European Union's Framework Programme 7 CHIBCHA grant and Wellcome Trust Centre for Human Genetics Core Grant 090532/Z/09Z, and CORGI was funded by Cancer Research UK. Recruitment of the QIMR Berghofer controls was supported by the NHMRC. The University of Newcastle, the Gladys M. Brawn Senior Research Fellowship scheme, the Vincent Fairfax Family Foundation, the Hunter Medical Research Institute and the Hunter Area Pathology Service all contributed toward the costs of establishing HCS.

The Bavarian Endometrial Cancer Study (BECS) was partly funded by the ELAN fund of the University of Erlangen. The Hannover–Jena Endometrial Cancer Study was partly supported by the Rudolf Bartling Foundation. The Leuven Endometrium Study (LES) was supported by the Verelst Foundation for Endometrial Cancer. The Mayo Endometrial Cancer Study (MECS) and Mayo controls (MAY) were supported by grants from the National Cancer Institute of the US Public Health Service (R01 CA122443, P30 CA15083 and P50 CA136393), the Fred C. and Katherine B. Andersen Foundation, the Mayo Foundation and the Ovarian Cancer Research Fund with support of the Smith family, in memory of Kathryn Sladek Smith. MoMaTEC received financial support from a Helse Vest Grant, the University of Bergen, the Melzer Foundation, the Norwegian Cancer Society (Harald Andersens legat), the Research Council of Norway and Haukeland University Hospital. The Newcastle Endometrial Cancer Study (NECS) acknowledges contributions from the University of Newcastle, the NBN Children's Cancer Research Group, Jennie Thomas and the Hunter Medical Research Institute. RENDOCAS was supported through the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institutet (20110222, 20110483, 20110141 and DF 07015), Swedish Labor Market Insurance (100069) and the Swedish Cancer Society (11 0439). The Cancer Hormone Replacement Epidemiology in Sweden study (CAHRES; formerly called the Singapore and Swedish Breast/Endometrial Cancer study, SASBAC) was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institutes of Health and the Susan G. Komen Breast Cancer Foundation.

BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/A12014). OCAC is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07) and the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge.

Additional funding for individual control groups is detailed in the Supplementary Note.

Author information

Author notes

    • Timothy H T Cheng
    •  & Deborah J Thompson

    These authors contributed equally to this work.


  1. Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Timothy H T Cheng
    • , Susanne Flach
    • , Annabelle Lewis
    • , Luke Freeman-Mills
    • , David Church
    • , Maggie Gorman
    • , Lynn Martin
    • , Claire Palles
    •  & Ian Tomlinson
  2. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Deborah J Thompson
    • , Joe Dennis
    • , Manjeet K Bolla
    • , Kyriaki Michailidou
    • , Qin Wang
    •  & Douglas F Easton
  3. Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Tracy A O'Mara
    • , Jodie N Painter
    • , Dylan M Glubb
    • , Juliet D French
    • , Penelope M Webb
    • , Anjali K Henders
    • , Nicholas G Martin
    • , Grant W Montgomery
    • , Dale R Nyholt
    • , Stacey L Edwards
    •  & Amanda B Spurdle
  4. Department of Clinical Genetics, St George's, University of London, London, UK.

    • Shirley Hodgson
  5. Hunter Medical Research Institute, John Hunter Hospital, Newcastle, New South Wales, Australia.

    • John Attia
    • , Elizabeth G Holliday
    • , Rodney J Scott
    •  & Katie Ashton
  6. Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.

    • John Attia
    • , Elizabeth G Holliday
    •  & Mark McEvoy
  7. Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia.

    • Rodney J Scott
  8. Centre for Information-Based Medicine, University of Newcastle, Newcastle, New South Wales, Australia.

    • Rodney J Scott
    •  & Katie Ashton
  9. School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.

    • Rodney J Scott
    •  & Katie Ashton
  10. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.

    • Dale R Nyholt
  11. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.

    • Shahana Ahmed
    • , Catherine S Healey
    • , Mitul Shah
    • , Jonathan P Tyrer
    • , Paul D P Pharoah
    • , Alison M Dunning
    •  & Douglas F Easton
  12. Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA.

    • Peter A Fasching
  13. Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.

    • Peter A Fasching
    • , Matthias W Beckmann
    •  & Alexander Hein
  14. Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.

    • Arif B Ekici
  15. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Per Hall
    • , Kamila Czene
    • , Hatef Darabi
    •  & Jingmei Li
  16. Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.

    • Thilo Dörk
  17. Department of Gynaecology, Jena University Hospital, Friedrich Schiller University, Jena, Germany.

    • Matthias Dürst
    •  & Ingo Runnebaum
  18. Clinics of Gynaecology and Obstetrics, Hannover Medical School, Hannover, Germany.

    • Peter Hillemanns
  19. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University Hospitals, KU Leuven, University of Leuven, Leuven, Belgium.

    • Frederic Amant
    • , Stefanie Schrauwen
    •  & Jeroen Depreeuw
  20. Vesalius Research Center, VIB, Leuven, Belgium.

    • Hui Zhao
    • , Diether Lambrechts
    •  & Jeroen Depreeuw
  21. Laboratory for Translational Genetics, Department of Oncology, University Hospitals Leuven, Leuven, Belgium.

    • Hui Zhao
    • , Diether Lambrechts
    •  & Jeroen Depreeuw
  22. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota, USA.

    • Sean C Dowdy
  23. Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

    • Ellen L Goode
    • , Stacey J Winham
    • , Junwen Wang
    •  & Fergus J Couch
  24. Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas, USA.

    • Brooke L Fridley
  25. Centre for Cancerbiomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.

    • Tormund S Njølstad
    • , Helga B Salvesen
    • , Jone Trovik
    •  & Henrica M J Werner
  26. Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.

    • Tormund S Njølstad
    • , Helga B Salvesen
    • , Jone Trovik
    •  & Henrica M J Werner
  27. School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.

    • Geoffrey Otton
    •  & Tony Proietto
  28. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

    • Tao Liu
    • , Emma Tham
    •  & Annika Lindblom
  29. Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

    • Miriam Mints
  30. Department of Clinical Genetics, Karolinska University Hospital Solna, Stockholm, Sweden.

    • Emma Tham
  31. Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.

    • Mulin Jun Li
    •  & Shun H Yip
  32. Department of Biomedical Informatics, Arizona State University, Scottsdale, Arizona, USA.

    • Junwen Wang
  33. Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Malcolm Dunlop
  34. MRC Human Genetics Unit, Western General Hospital Edinburgh, Edinburgh, UK.

    • Malcolm Dunlop
  35. Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.

    • Richard Houlston
    •  & Anthony J Swerdlow
  36. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

    • John L Hopper
    •  & Graham G Giles
  37. London School of Hygiene and Tropical Medicine, London, UK.

    • Julian Peto
  38. Division of Breast Cancer Research, Institute of Cancer Research, London, UK.

    • Anthony J Swerdlow
  39. Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany.

    • Barbara Burwinkel
  40. Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Barbara Burwinkel
  41. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Hermann Brenner
  42. Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.

    • Hermann Brenner
  43. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Hermann Brenner
    •  & Hiltrud Brauch
  44. Division of Tumor Genetics, Department of Obstetrics and Gynecology, Technical University of Munich, Munich, Germany.

    • Alfons Meindl
  45. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.

    • Hiltrud Brauch
  46. University of Tübingen, Tübingen, Germany.

    • Hiltrud Brauch
  47. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Jenny Chang-Claude
  48. University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Jenny Chang-Claude
  49. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

    • Fergus J Couch
    •  & Julie M Cunningham
  50. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.

    • Graham G Giles
  51. Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

    • Graham G Giles
  52. Department of Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo, Norway.

    • Vessela N Kristensen
  53. K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

    • Vessela N Kristensen
  54. Department of Clinical Molecular Oncology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway.

    • Vessela N Kristensen
  55. Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.

    • Angela Cox


  1. National Study of Endometrial Cancer Genetics Group (NSECG)

    A list of members appears in the Supplementary Note.

  2. The Australian National Endometrial Cancer Study Group (ANECS)

    A list of members appears in the Supplementary Note.


    A list of members appears in the Supplementary Note.

  4. CHIBCHA Consortium

    A list of members appears in the Supplementary Note.

  5. AOCS Group

    A list of members appears in the Supplementary Note.


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A.B.S., D.F.E., A.M.D., G.W.M. and P.M.W. obtained funding for the study. A.B.S. and D.F.E. designed the study. T.H.T.C., D.J.T., T.A.O'M., J.N.P., D.M.G., I.T. and A.B.S. drafted the manuscript. T.H.T.C. and D.J.T. conducted statistical analyses and genotype imputation. T.A.O'M., D.M.G., M.J.L., S.H.Y. and J.W. conducted bioinformatic analyses. T.A.O'M. conducted eQTL analyses. S.F., A. Lewis, J.D.F., L.F.-M., D.C. and S.L.E. performed functional assays. T.H.T.C., T.A.O'M. and J.N.P. performed additional genotyping by KASPar and Fluidigm. T.A.O'M. coordinated the overall stage 2 genotyping and associated data management. J. Dennis, J.P.T. and K.M. coordinated quality control and data cleaning for the iCOGS control data sets. A.B.S. and T.A.O'M. coordinated the ANECS stage 1 genotyping. A.M.D., S.A. and C.S.H. coordinated the SEARCH stage 1 genotyping. I.T. and CHIBCHA funded and implemented the NSECG GWAS. I.T., L.M., M.G. and S.H. coordinated NSECG and collation of CORGI control GWAS data. A.B.S. and P.M.W. coordinated ANECS. R.J.S., M. McEvoy, J.A. and E.G.H. coordinated collation of GWAS data for HCS. N.G.M., G.W.M., D.R.N. and A.K.H. coordinated collation of GWAS data for the QIMR controls. P.D.P.P., D.F.E. and M.S. coordinated SEARCH. M.K.B. and Q.W. provided data management support for BCAC. The following authors designed and coordinated the baseline studies and/or extraction of questionnaire and clinical information for studies: P.A.F., M.W.B., A.H., A.B.E., T.D., P. Hillemanns, M. Dürst, I.R., D.L., S.S., H.Z., F.A., J. Depreeuw, S.C.D., E.L.G., B.L.F., S.J.W., H.B.S., J.T., T.S.N., H.M.J.W., R.J.S., K.A., T.P., G.O., T.L., M. Mints, E.T., P. Hall, K.C., J.L., H.D., M. Dunlop, R.H., C.P., J.L.H., J.P., A.J.S., B.B., H. Brenner, A.M., H. Brauch, A. Lindblom, J.C.-C., F.J.C., G.G.G., V.N.K., A.C. and J.M.C. All authors provided critical review of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Douglas F Easton or Ian Tomlinson or Amanda B Spurdle.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–7 and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 1

    Endometrial cancer case and control sample sets.

  2. 2.

    Supplementary Table 2

    Meta-analysis after regional imputation for risk loci with P < 1 × 10−5 identified by meta-analysis of GWAS and iCOGS data sets.

  3. 3.

    Supplementary Table 3

    Overall meta-analysis including additional genotyping from phase 2.

  4. 4.

    Supplementary Table 4

    Genotyping concordance rates for different platforms in quality control duplicates.

  5. 5.

    Supplementary Table 5

    Endometrial tissue eQTLs: association between GWAS risk locus genotypes and transcript levels of nearby genes.

  6. 6.

    Supplementary Table 6

    Functional annotation of SNPs in LD with GWAS risk loci (r2 >0.7 in 1000 Genomes Project EUR) from HaploReg, RegulomeDB and ENCODE.

  7. 7.

    Supplementary Table 7

    Pairwise t-test P values for 13q22 luciferase assays.

  8. 8.

    Supplementary Table 8

    Primers and oligonucleotides used in experimental procedures.

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