Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Genome-wide association study identifies a common variant associated with risk of endometrial cancer


Endometrial cancer is the most common malignancy of the female genital tract in developed countries. To identify genetic variants associated with endometrial cancer risk, we performed a genome-wide association study involving 1,265 individuals with endometrial cancer (cases) from Australia and the UK and 5,190 controls from the Wellcome Trust Case Control Consortium. We compared genotype frequencies in cases and controls for 519,655 SNPs. Forty seven SNPs that showed evidence of association with endometrial cancer in stage 1 were genotyped in 3,957 additional cases and 6,886 controls. We identified an endometrial cancer susceptibility locus close to HNF1B at 17q12 (rs4430796, P = 7.1 × 10−10) that is also associated with risk of prostate cancer and is inversely associated with risk of type 2 diabetes.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Forest plot showing the association between rs4430796 and endometrial cancer for each component of the study.


  1. 1

    Ferlay, J. et al. GLOBOCAN 2008, cancer incidence and mortality worldwide. in CancerBase No. 10, Vol. 2010 (International Agency for Research on Cancer Lyon, France, 2010).

  2. 2

    Varol, N. et al. Ten-year review of hysterectomy morbidity and mortality: can we change direction? Aust. N. Z. J. Obstet. Gynaecol. 41, 295–302 (2001).

    CAS  Article  Google Scholar 

  3. 3

    Hindorff, L.A., Junkins, H.A., Hall, P.N., Mehta, J.P. & Manolio, T.A. A Catalog of Published Genome-Wide Association Studies. Vol. 2010 (National Human Genome Research Institute, Bethesda, Maryland, USA, 2010).

  4. 4

    Goldgar, D.E., Easton, D.F., Cannon-Albright, L.A. & Skolnick, M.H. Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J. Natl. Cancer Inst. 86, 1600–1608 (1994).

    CAS  Article  Google Scholar 

  5. 5

    Hemminki, K., Vaittinen, P. & Kyyronen, P. Age-specific familial risks in common cancers of the offspring. Int. J. Cancer 78, 172–175 (1998).

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  PubMed  Google Scholar 

  7. 7

    Lucenteforte, E. et al. Family history of cancer and the risk of endometrial cancer. Eur. J. Cancer Prev. 18, 95–99 (2009).

    Article  Google Scholar 

  8. 8

    Haidopoulos, D. et al. Risk factors in women 40 years of age and younger with endometrial carcinoma. Acta Obstet. Gynecol. Scand. 89, 1326–1330 (2010).

    Article  Google Scholar 

  9. 9

    Hampel, H. et al. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res. 66, 7810–7817 (2006).

    CAS  Article  Google Scholar 

  10. 10

    Setiawan, V.W. 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).

    CAS  Article  Google Scholar 

  11. 11

    Low, Y.L. et al. Multi-variant pathway association analysis reveals the importance of genetic determinants of estrogen metabolism in breast and endometrial cancer susceptibility. PLoS Genet. 6, e1001012 (2010).

    Article  Google Scholar 

  12. 12

    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).

  13. 13

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

    CAS  Article  Google Scholar 

  14. 14

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

    CAS  Article  Google Scholar 

  15. 15

    Gudmundsson, J. et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat. Genet. 39, 977–983 (2007).

    CAS  Article  Google Scholar 

  16. 16

    Thomas, G. et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat. Genet. 40, 310–315 (2008).

    CAS  Article  Google Scholar 

  17. 17

    Elliott,, K.S. et al. Evaluation of association of HNF1B variants with diverse cancers: collaborative analysis of data from 19 genome-wide association studies. PLoS ONE 5, e10858 (2010).

    Article  Google Scholar 

  18. 18

    Voight, B.F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010).

    CAS  Article  Google Scholar 

  19. 19

    Kasper, J.S., Liu, Y. & Giovannucci, E. Diabetes mellitus and risk of prostate cancer in the health professionals follow-up study. Int. J. Cancer 124, 1398–1403 (2009).

    CAS  Article  Google Scholar 

  20. 20

    Stevens, V.L. et al. HNF1B and JAZF1 genes, diabetes, and prostate cancer risk. Prostate 70, 601–607 (2010).

    CAS  Article  Google Scholar 

  21. 21

    Hemminki, K., Li, X., Sundquist, J. & Sundquist, K. Risk of cancer following hospitalization for type 2 diabetes. Oncologist 15, 548–555 (2010).

    Article  Google Scholar 

  22. 22

    Hjartåker, A., Langseth, H. & Weiderpass, E. Obesity and diabetes epidemics: cancer repercussions. Adv. Exp. Med. Biol. 630, 72–93 (2008).

    Article  Google Scholar 

  23. 23

    Noto, H., Osame, K., Sasazuki, T. & Noda, M. Substantially increased risk of cancer in patients with diabetes mellitus: a systematic review and meta-analysis of epidemiologic evidence in Japan. J. Diabetes Complications 24, 345–353 (2010).

    Article  Google Scholar 

  24. 24

    Rosato, V. et al. Metabolic syndrome and endometrial cancer risk. Ann. Oncol. published online, doi:10.1093/annonc/mdq464 (11 October 2010).

  25. 25

    Bach, I. & Yaniv, M. More potent transcriptional activators or a transdominant inhibitor of the HNF1 homeoprotein family are generated by alternative RNA processing. EMBO J. 12, 4229–4242 (1993).

    CAS  Article  Google Scholar 

  26. 26

    Bernardini, L. et al. Recurrent microdeletion at 17q12 as a cause of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome: two case reports. Orphanet J. Rare Dis. 4, 25 (2009).

    Article  Google Scholar 

  27. 27

    Oram, R.A. et al. Mutations in the hepatocyte nuclear factor-1β (HNF1B) gene are common with combined uterine and renal malformations but are not found with isolated uterine malformations. Am. J. Obstet. Gynecol. 203, 364 e1–364.e5 (2010).

    Article  Google Scholar 

  28. 28

    Kato, N. & Motoyama, T. Expression of hepatocyte nuclear factor-1β in human urogenital tract during the embryonic stage. Anal. Quant. Cytol. Histol. 31, 34–40 (2009).

    PubMed  Google Scholar 

  29. 29

    Kim, L. et al. Clear cell carcinoma of the pancreas: histopathologic features and a unique biomarker: hepatocyte nuclear factor-1β. Mod. Pathol. 21, 1075–1083 (2008).

    CAS  Article  Google Scholar 

  30. 30

    Kato, N., Sasou, S. & Motoyama, T. Expression of hepatocyte nuclear factor-1β (HNF-1β) in clear cell tumors and endometriosis of the ovary. Mod. Pathol. 19, 83–89 (2006).

    CAS  Article  Google Scholar 

  31. 31

    Kato, N. & Motoyama, T. Hepatocyte nuclear factor-1β (HNF-1β) in human urogenital organs: its expression and role in embryogenesis and tumorigenesis. Histol. Histopathol. 24, 1479–1486 (2009).

    CAS  PubMed  Google Scholar 

  32. 32

    Tsuchiya, A. et al. Expression profiling in ovarian clear cell carcinoma: identification of hepatocyte nuclear factor-1 β as a molecular marker and a possible molecular target for therapy of ovarian clear cell carcinoma. Am. J. Pathol. 163, 2503–2512 (2003).

    CAS  Article  Google Scholar 

  33. 33

    Mahata, P. Biomarkers for epithelial ovarian cancers. Genome Inform. 17, 184–193 (2006).

    CAS  PubMed  Google Scholar 

  34. 34

    Harries, L.W., Perry, J.R., McCullagh, P. & Crundwell, M. Alterations in LMTK2, MSMB and HNF1B gene expression are associated with the development of prostate cancer. BMC Cancer 10, 315 (2010).

    Article  Google Scholar 

  35. 35

    Liu, H., Wang, B. & Han, C. Meta-analysis of genome-wide and replication association studies on prostate cancer. Prostate 71, 209–224 (2011).

    Article  Google Scholar 

  36. 36

    Higgins, J.P., Thompson, S.G., Deeks, J.J. & Altman, D.G. Measuring inconsistency in meta-analyses. Br. Med. J. 327, 557–560 (2003).

    Article  Google Scholar 

  37. 37

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

    CAS  Article  Google Scholar 

  38. 38

    Turnbull, C. et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nat. Genet. 42, 504–507 (2010).

    CAS  Article  Google Scholar 

  39. 39

    Durbin, R.M. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

    CAS  Article  Google Scholar 

  40. 40

    Aulchenko, Y.S., Ripke, S., Isaacs, A. & van Duijn, C.M. GenABEL: an R library for genome-wide association analysis. Bioinformatics 23, 1294–1296 (2007).

    CAS  Article  Google Scholar 

  41. 41

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

    Article  Google Scholar 

  42. 42

    Aulchenko, Y.S., Struchalin, M.V. & van Duijn, C.M. ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics 11, 134 (2010).

    Article  Google Scholar 

  43. 43

    Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).

    CAS  Article  Google Scholar 

  44. 44

    Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    CAS  Article  Google Scholar 

Download references


This work was supported by the National Health and Medical Research Council (NHMRC; ID 552402), the Wellcome Trust and by Cancer Research UK grants C1287/A10118, C490/A1021, C8197/A10865 and C8197/A10123. A.B.S. and P.M.W. are NHMRC Senior Research Fellows, and G.M. is an NHMRC Senior Principle Research Fellow. T.O. is supported by an Australian Postgraduate Award, an Institute of Health and Biomedical Innovation PhD Top-Up and a Smart State PhD Award. L.C.W. is a John Gavin Postdoctoral Fellow (Genesis Oncology Trust, New Zealand). D.F.E. is a Principal Research Fellow of Cancer Research UK. A.M.D. is supported by the Joseph Mitchell Trust. I.T. is supported by Cancer Research UK and the Oxford Comprehensive Biomedical Research Centre. P.A.F. was partly funded by the Dr. Mildred Scheel Stiftung of the Deutsche Krebshilfe (German Cancer Aid).

This study makes use of data generated by the Wellcome Trust Case Control Consortium (WTCCC) 2. 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 the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. Funding for this project was provided by the Wellcome Trust under award 085475.

We thank the study participants and collaborators and the research teams involved in the design and implementation of the individual studies included (see Supplementary Note for full list of collaborators and specific acknowledgments). Australian National Endometrial Cancer Study (ANECS) recruitment was supported by project grants from the National Health and Medical Research Council of Australia (ID#339435), The Cancer Council Queensland (ID#4196615) and Cancer Council Tasmania (ID#403031 and ID#457636). The Bavarian Endometrial Cancer Study (BECS) was partly funded by the Erlanger Leistungsbezogene Anschubfinanzierung und Nachwuchsförderung Fond (ELAN fund) of the University of Erlangen. The Leuven Endometrium Study (LES) was supported by the Verelst Foundation for endometrial cancer. Molecular Markers in Treatment of Endometrial Cancer (MoMaTEC) received financial support from a Helse Vest Grant, the University of Bergen, 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 National Broadcasting Network (NBN) Children's Cancer Research Group, Jennie Thomas and the Hunter Medical Research Institute. The National Study of Endometrial Cancer Genetics (NSECG) Group was supported principally by Cancer Research UK and by funds from the Oxford Comprehensive Biomedical Research Centre, with core infrastructure support to the Wellcome Trust Centre for Human Genetics, Oxford provided by grant 075491/Z/04. The Polish Endometrial Cancer Study (PECS) was funded by the intramural research program at the US National Cancer Institute, Division of Cancer Epidemiology and Genetics in the Hormonal and Reproductive Epidemiology Branch. 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 (NIH) and the Susan G. Komen Breast Cancer Foundation. The Shanghai Endometrial Cancer Genetic Study (SECGS) was supported by grants from the National Cancer Institute of the United States Public Health Service (RO1 CA 092585 and R01 CA90899, R01 CA64277). SEARCH is funded by a program grant from Cancer Research UK (C490/A10124).

Author information





A.B.S., D.F.E., G.M. and P.M.W. obtained funding for the study. A.B.S. and D.F.E. designed the study. A.B.S. and D.J.T. drafted the manuscript. P.F. and K.M. conducted preliminary analysis, and D.F.E. and D.J.T. conducted the final statistical analyses. A.B.S. and P.M.W. coordinated the ANECS. P.D.P. and D.F.E. coordinated Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH). A.B.S., K.F. and T.O. coordinated the ANECS stage 1 genotyping. A.M.D., S.A. and C.S.H. coordinated the SEARCH stage 1 genotyping. L.C.W., S.B.M. and E.T.D. conducted analyses to assess correlations between genotype and gene expression. J.M. provided data management and bioinformatics support. T.O. and K.F. coordinated the ANECS and other Brisbane-based stage 2 genotyping and assisted with data management. S.A., C.S.H. and A.M.D. coordinated the stage 2 genotyping of the SEARCH samples. M.S. coordinated overall management of data for SEARCH samples. D.L., P.H., K.C., J. Liu, J. Li, I.T., K.H., M.G.-C., N.W., H.Y., S.C., X.-O.S. and J. Long coordinated the stage 2 genotyping, or extraction of existing genotype data, for the LES, SASBAC, NSECG, PECS and SECGS samples. The following authors coordinated the baseline studies and/or extraction of questionnaire and clinical information for studies included in stage 2 analysis: BECS (P.A.F., M.W.B., A.H. and A.B.E.); LES (D.L., L.C., I.V. and F.A.); MoMaTEC (H.B.S., J.T., H.H. and T.S.N.); NECS (R.J.S., K.A., T.P. and G.O.); NSECG (I.T., K.H., M.G. and S.H.); PECS (M.G.-C., H.Y. and N.W.); SASBAC (P.H., K.C., and J. Li); SECGS (X.-O.S. and W.Z. (principal investigators), J. Long (principal study geneticist) and Y.-B.X. (site principal investigator at the Shanghai Cancer Institute)). All authors provided critical review of the manuscript.

Corresponding author

Correspondence to Amanda B Spurdle.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1 and 2 and Supplementary Tables 1–7. (PDF 232 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing