Letter | Published:

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

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

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , & Cancer statistics, 2014. CA Cancer J. Clin. 64, 9–29 (2014).

  2. 2.

    et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur. J. Cancer 49, 1374–1403 (2013).

  3. 3.

    , & Cancer and Steroid Hormone Study Group. A population-based study of endometrial cancer and familial risk in younger women. Cancer Epidemiol. Biomarkers Prev. 5, 411–417 (1996).

  4. 4.

    , & Family history and risk of endometrial cancer: a systematic review and meta-analysis. Obstet. Gynecol. 125, 89–98 (2015).

  5. 5.

    , & Cancer risk in Lynch syndrome. Fam. Cancer 12, 229–240 (2013).

  6. 6.

    et al. DNA polymerase ɛ and δ exonuclease domain mutations in endometrial cancer. Hum. Mol. Genet. 22, 2820–2828 (2013).

  7. 7.

    et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat. Genet. 45, 136–144 (2013).

  8. 8.

    et al. Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk. Hum. Mol. Genet. 24, 1478–1492 (2015).

  9. 9.

    et al. CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer. Endocr. Relat. Cancer 23, 77–91 (2016).

  10. 10.

    et al. Genome-wide association study identifies a common variant associated with risk of endometrial cancer. Nat. Genet. 43, 451–454 (2011).

  11. 11.

    et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat. Genet. 40, 631–637 (2008).

  12. 12.

    et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat. Genet. 39, 984–988 (2007).

  13. 13.

    Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  14. 14.

    et al. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat. Genet. 45, 385–391, e1–e2 (2013).

  15. 15.

    et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat. Genet. 45, 353–361, e1–e2 (2013).

  16. 16.

    et al. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer. Nat. Genet. 45, 362–370, e1–e2 (2013).

  17. 17.

    , & Turning of COGS moves forward findings for hormonally mediated cancers. Nat. Genet. 45, 345–348 (2013).

  18. 18.

    et al. Genome-wide association study of endometrial cancer in E2C2. Hum. Genet. 133, 211–224 (2014).

  19. 19.

    et al. Two estrogen-related variants in CYP19A1 and endometrial cancer risk: a pooled analysis in the Epidemiology of Endometrial Cancer Consortium. Cancer Epidemiol. Biomarkers Prev. 18, 242–247 (2009).

  20. 20.

    GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).

  21. 21.

    Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature 497, 67–73 (2013).

  22. 22.

    & Integrative genomic analyses on HES/HEY family: Notch-independent HES1, HES3 transcription in undifferentiated ES cells, and Notch-dependent HES1, HES5, HEY1, HEY2, HEYL transcription in fetal tissues, adult tissues, or cancer. Int. J. Oncol. 31, 461–466 (2007).

  23. 23.

    , & ERAP140, a conserved tissue-specific nuclear receptor coactivator. Mol. Cell. Biol. 22, 3358–3372 (2002).

  24. 24.

    et al. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat. Genet. 40, 1307–1312 (2008).

  25. 25.

    et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat. Genet. 42, 978–984 (2010).

  26. 26.

    et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007).

  27. 27.

    et al. Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis. Hum. Mol. Genet. 23, 4729–4737 (2014).

  28. 28.

    et al. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat. Genet. 42, 874–879 (2010).

  29. 29.

    et al. Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat. Genet. 41, 1116–1121 (2009).

  30. 30.

    et al. Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility. Nat. Genet. 41, 1122–1126 (2009).

  31. 31.

    , , & The 8q24 gene desert: an oasis of non-coding transcriptional activity. Front. Genet. 3, 69 (2012).

  32. 32.

    et al. Candidate locus analysis of the TERTCLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk. Hum. Genet. 134, 231–245 (2015).

  33. 33.

    , & Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2α kinase. Eur. J. Biochem. 265, 754–762 (1999).

  34. 34.

    et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).

  35. 35.

    The phosphoinositide 3-kinase pathway. Science 296, 1655–1657 (2002).

  36. 36.

    & The PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer. Clin. Cancer Res. 18, 5856–5864 (2012).

  37. 37.

    et al. AKT1 pleckstrin homology domain E17K activating mutation in endometrial carcinoma. Gynecol. Oncol. 116, 88–91 (2010).

  38. 38.

    et al. Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proc. Natl. Acad. Sci. USA 106, 4834–4839 (2009).

  39. 39.

    et al. The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas. Br. J. Cancer 101, 145–148 (2009).

  40. 40.

    et al. Suppression of p53 activity by Siva1. Cell Death Differ. 16, 1493–1504 (2009).

  41. 41.

    et al. Siva1 inhibits p53 function by acting as an ARF E3 ubiquitin ligase. Nat. Commun. 4, 1551 (2013).

  42. 42.

    et al. Siva1 suppresses epithelial–mesenchymal transition and metastasis of tumor cells by inhibiting stathmin and stabilizing microtubules. Proc. Natl. Acad. Sci. USA 108, 12851–12856 (2011).

  43. 43.

    et al. Mycophenolic acid inhibits migration and invasion of gastric cancer cells via multiple molecular pathways. PLoS One 8, e81702 (2013).

  44. 44.

    et al. FBXW7 mutations typically found in human cancers are distinct from null alleles and disrupt lung development. J. Pathol. 224, 180–189 (2011).

  45. 45.

    et al. Global expression changes of constitutive and hormonally regulated genes during endometrial neoplastic transformation. Gynecol. Oncol. 83, 177–185 (2001).

  46. 46.

    , , , & Isolation and characterization of a gene encoding human Kruppel-like factor 5 (IKLF): binding to the CAAT/GT box of the mouse lactoferrin gene promoter. Nucleic Acids Res. 27, 4807–4815 (1999).

  47. 47.

    et al. The emerging role of Krüppel-like factors in endocrine-responsive cancers of female reproductive tissues. J. Endocrinol. 204, 223–231 (2010).

  48. 48.

    et al. Krüppel-like factor 5 mediates cellular transformation during oncogenic KRAS-induced intestinal tumorigenesis. Gastroenterology 134, 120–130 (2008).

  49. 49.

    et al. The Catalogue of Somatic Mutations in Cancer (COSMIC). Curr. Protoc. Hum. Genet. Chapter 10, Unit 10.11 (2008).

  50. 50.

    ENCODE Project Consortium. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799–816 (2007).

  51. 51.

    et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665–1680 (2014).

  52. 52.

    , & H3K4me2 reliably defines transcription factor binding regions in different cells. Genomics 103, 222–228 (2014).

  53. 53.

    et al. Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1. Sci. Rep. 5, 17369 (2015).

  54. 54.

    et al. Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer. Endocr. Relat. Cancer 22, 851–861 (2015).

  55. 55.

    & Cohort profile: 1958 British birth cohort (National Child Development Study). Int. J. Epidemiol. 35, 34–41 (2006).

  56. 56.

    et al. Cohort profile: the Hunter Community Study. Int. J. Epidemiol. 39, 1452–1463 (2010).

  57. 57.

    et al. Genetic and environmental contributions to size, color, shape, and other characteristics of melanocytic naevi in a sample of adolescent twins. Genet. Epidemiol. 16, 40–53 (1999).

  58. 58.

    et al. A genotype calling algorithm for the Illumina BeadArray platform. Bioinformatics 23, 2741–2746 (2007).

  59. 59.

    et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

  60. 60.

    et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

  61. 61.

    , , & GenABEL: an R library for genome-wide association analysis. Bioinformatics 23, 1294–1296 (2007).

  62. 62.

    & An R package for analysis of whole-genome association studies. Hum. Hered. 64, 45–51 (2007).

  63. 63.

    , & Genotype imputation with thousands of genomes. G3 (Bethesda) 1, 457–470 (2011).

  64. 64.

    , & Improved whole-chromosome phasing for disease and population genetic studies. Nat. Methods 10, 5–6 (2013).

  65. 65.

    et al. A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans. Nat. Commun. 5, 4871 (2014).

  66. 66.

    , , , & A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

  67. 67.

    et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).

  68. 68.

    & GWAMA: software for genome-wide association meta-analysis. BMC Bioinformatics 11, 288 (2010).

  69. 69.

    & Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).

  70. 70.

    , , & Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol. Methods 11, 193–206 (2006).

  71. 71.

    & HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 40, D930–D934 (2012).

  72. 72.

    et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 22, 1790–1797 (2012).

  73. 73.

    et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).

  74. 74.

    et al. Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits. Genome Res. 24, 1–13 (2014).

  75. 75.

    & Analysis of relative gene expression data using real-time quantitative PCR and the 2(−ΔΔCT) method. Methods 25, 402–408 (2001).

  76. 76.

    , , , & FAIRE (formaldehyde-assisted isolation of regulatory elements) isolates active regulatory elements from human chromatin. Genome Res. 17, 877–885 (2007).

  77. 77.

    et al. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation. Nat. Commun. 4, 4999 (2014).

  78. 78.

    et al. A polymorphic enhancer near GREM1 influences bowel cancer risk through differential CDX2 and TCF7L2 binding. Cell Rep. 8, 983–990 (2014).

Download references

Acknowledgements

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.

Affiliations

  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

Consortia

  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.

  3. RENDOCAS

    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.

Authors

  1. Search for Timothy H T Cheng in:

  2. Search for Deborah J Thompson in:

  3. Search for Tracy A O'Mara in:

  4. Search for Jodie N Painter in:

  5. Search for Dylan M Glubb in:

  6. Search for Susanne Flach in:

  7. Search for Annabelle Lewis in:

  8. Search for Juliet D French in:

  9. Search for Luke Freeman-Mills in:

  10. Search for David Church in:

  11. Search for Maggie Gorman in:

  12. Search for Lynn Martin in:

  13. Search for Shirley Hodgson in:

  14. Search for Penelope M Webb in:

  15. Search for John Attia in:

  16. Search for Elizabeth G Holliday in:

  17. Search for Mark McEvoy in:

  18. Search for Rodney J Scott in:

  19. Search for Anjali K Henders in:

  20. Search for Nicholas G Martin in:

  21. Search for Grant W Montgomery in:

  22. Search for Dale R Nyholt in:

  23. Search for Shahana Ahmed in:

  24. Search for Catherine S Healey in:

  25. Search for Mitul Shah in:

  26. Search for Joe Dennis in:

  27. Search for Peter A Fasching in:

  28. Search for Matthias W Beckmann in:

  29. Search for Alexander Hein in:

  30. Search for Arif B Ekici in:

  31. Search for Per Hall in:

  32. Search for Kamila Czene in:

  33. Search for Hatef Darabi in:

  34. Search for Jingmei Li in:

  35. Search for Thilo Dörk in:

  36. Search for Matthias Dürst in:

  37. Search for Peter Hillemanns in:

  38. Search for Ingo Runnebaum in:

  39. Search for Frederic Amant in:

  40. Search for Stefanie Schrauwen in:

  41. Search for Hui Zhao in:

  42. Search for Diether Lambrechts in:

  43. Search for Jeroen Depreeuw in:

  44. Search for Sean C Dowdy in:

  45. Search for Ellen L Goode in:

  46. Search for Brooke L Fridley in:

  47. Search for Stacey J Winham in:

  48. Search for Tormund S Njølstad in:

  49. Search for Helga B Salvesen in:

  50. Search for Jone Trovik in:

  51. Search for Henrica M J Werner in:

  52. Search for Katie Ashton in:

  53. Search for Geoffrey Otton in:

  54. Search for Tony Proietto in:

  55. Search for Tao Liu in:

  56. Search for Miriam Mints in:

  57. Search for Emma Tham in:

  58. Search for Mulin Jun Li in:

  59. Search for Shun H Yip in:

  60. Search for Junwen Wang in:

  61. Search for Manjeet K Bolla in:

  62. Search for Kyriaki Michailidou in:

  63. Search for Qin Wang in:

  64. Search for Jonathan P Tyrer in:

  65. Search for Malcolm Dunlop in:

  66. Search for Richard Houlston in:

  67. Search for Claire Palles in:

  68. Search for John L Hopper in:

  69. Search for Julian Peto in:

  70. Search for Anthony J Swerdlow in:

  71. Search for Barbara Burwinkel in:

  72. Search for Hermann Brenner in:

  73. Search for Alfons Meindl in:

  74. Search for Hiltrud Brauch in:

  75. Search for Annika Lindblom in:

  76. Search for Jenny Chang-Claude in:

  77. Search for Fergus J Couch in:

  78. Search for Graham G Giles in:

  79. Search for Vessela N Kristensen in:

  80. Search for Angela Cox in:

  81. Search for Julie M Cunningham in:

  82. Search for Paul D P Pharoah in:

  83. Search for Alison M Dunning in:

  84. Search for Stacey L Edwards in:

  85. Search for Douglas F Easton in:

  86. Search for Ian Tomlinson in:

  87. Search for Amanda B Spurdle in:

Contributions

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.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.3562

Further reading