Abstract

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 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.

    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.

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

  3. 3.

    , , , & A Catalog of Published Genome-Wide Association Studies. Vol. 2010 (National Human Genome Research Institute, Bethesda, Maryland, USA, 2010).

  4. 4.

    , , & Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J. Natl. Cancer Inst. 86, 1600–1608 (1994).

  5. 5.

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

  6. 6.

    & 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).

  7. 7.

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

  8. 8.

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

  9. 9.

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

  10. 10.

    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).

  11. 11.

    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).

  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.

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

  14. 14.

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

  15. 15.

    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).

  16. 16.

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

  17. 17.

    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).

  18. 18.

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

  19. 19.

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

  20. 20.

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

  21. 21.

    , , & Risk of cancer following hospitalization for type 2 diabetes. Oncologist 15, 548–555 (2010).

  22. 22.

    , & Obesity and diabetes epidemics: cancer repercussions. Adv. Exp. Med. Biol. 630, 72–93 (2008).

  23. 23.

    , , & 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).

  24. 24.

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

  25. 25.

    & 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).

  26. 26.

    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).

  27. 27.

    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).

  28. 28.

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

  29. 29.

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

  30. 30.

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

  31. 31.

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

  32. 32.

    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).

  33. 33.

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

  34. 34.

    , , & Alterations in LMTK2, MSMB and HNF1B gene expression are associated with the development of prostate cancer. BMC Cancer 10, 315 (2010).

  35. 35.

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

  36. 36.

    , , & Measuring inconsistency in meta-analyses. Br. Med. J. 327, 557–560 (2003).

  37. 37.

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

  38. 38.

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

  39. 39.

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

  40. 40.

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

  41. 41.

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

  42. 42.

    , & ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics 11, 134 (2010).

  43. 43.

    , , & Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).

  44. 44.

    , , & Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

Download references

Acknowledgements

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

Author notes

    • Shahana Ahmed
    • , Kaltin Ferguson
    • , Catherine S Healey
    •  & Tracy O'Mara

    These authors contributed equally to this work.

Affiliations

  1. Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • Amanda B Spurdle
    • , Kaltin Ferguson
    • , Tracy O'Mara
    • , Logan C Walker
    • , Paul Fahey
    • , Grant W Montgomery
    •  & Penelope M Webb
  2. Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.

    • Deborah J Thompson
    • , Jonathan Morrison
    • , Kyriaki Michailidou
    • , Paul D Pharoah
    •  & Douglas F Easton
  3. Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.

    • Shahana Ahmed
    • , Catherine S Healey
    • , Mitul Shah
    • , Paul D Pharoah
    • , Alison M Dunning
    •  & Douglas F Easton
  4. Hormone Dependent Cancer Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.

    • Tracy O'Mara
  5. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

    • Stephen B Montgomery
    •  & Emmanouil T Dermitzakis
  6. University of California at Los Angeles, David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, Los Angeles, California, USA.

    • Peter A Fasching
  7. Institute of Human Genetics, Friedrich Alexander University Erlangen Nürnberg, Erlangen, Germany.

    • Matthias W Beckmann
    •  & Arif B Ekici
  8. University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich Alexander University Erlangen Nürnberg, Erlangen, Germany.

    • Alexander Hein
  9. University Gynecologic Oncology Center, Comprehensive Cancer Centre, Erlangen Nürnberg, Erlangen, Germany.

    • Alexander Hein
  10. Vesalius Research Center, Vlaams Instituut voor Biotechnologie, Leuven, Belgium.

    • Diether Lambrechts
  11. Vesalius Research Center, University of Leuven, Leuven, Belgium.

    • Diether Lambrechts
  12. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.

    • Lieve Coenegrachts
    • , Ignace Vergote
    •  & Frederic Amant
  13. Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.

    • Helga B Salvesen
    • , Jone Trovik
    • , Tormund S Njolstad
    •  & Harald Helland
  14. Department of Clinical Medicine, The University of Bergen, Bergen, Norway.

    • Helga B Salvesen
    • , Jone Trovik
    •  & Tormund S Njolstad
  15. The Centre for Information Based Medicine and the Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, New South Wales (NSW), Australia.

    • Rodney J Scott
    •  & Katie Ashton
  16. The Hunter Medical Research Institute, John Hunter Hospital, NSW, Australia.

    • Rodney J Scott
    •  & Katie Ashton
  17. Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia.

    • Rodney J Scott
  18. Hunter Centre for Gynaecological, John Hunter Hospital, NSW, Australia.

    • Rodney J Scott
  19. School of Medicine and Public Health, Faculty of Health, University of Newcastle, NSW, Australia.

    • Tony Proietto
    •  & Geoffrey Otton
  20. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Ian Tomlinson
    • , Maggie Gorman
    •  & Kimberley Howarth
  21. Department of Clinical Genetics, St. George's Hospital Medical School, London, UK.

    • Shirley Hodgson
  22. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

    • Montserrat Garcia-Closas
    • , Nicolas Wentzensen
    • , Hannah Yang
    •  & Stephen Chanock
  23. Institute of Cancer Research, London, UK.

    • Montserrat Garcia-Closas
  24. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Per Hall
    • , Kamila Czene
    •  & Jingmei Li
  25. Human Genetics, Genome Institute of Singapore, Singapore.

    • Jianjun Liu
    •  & Jingmei Li
  26. Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Xiao-Ou Shu
    • , Wei Zheng
    •  & Jirong Long
  27. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.

    • Yong-Bing Xiang

Consortia

  1. The Australian National Endometrial Cancer Study Group

    1. Division of Genetics and Population Health, Queensland Institute of Medical Research

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

  2. National Study of Endometrial Cancer Genetics Group

    1. Wellcome Trust Centre for Human Genetics, University of Oxford

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

Authors

  1. Search for Amanda B Spurdle in:

  2. Search for Deborah J Thompson in:

  3. Search for Shahana Ahmed in:

  4. Search for Kaltin Ferguson in:

  5. Search for Catherine S Healey in:

  6. Search for Tracy O'Mara in:

  7. Search for Logan C Walker in:

  8. Search for Stephen B Montgomery in:

  9. Search for Emmanouil T Dermitzakis in:

  10. Search for Paul Fahey in:

  11. Search for Grant W Montgomery in:

  12. Search for Penelope M Webb in:

  13. Search for Peter A Fasching in:

  14. Search for Matthias W Beckmann in:

  15. Search for Arif B Ekici in:

  16. Search for Alexander Hein in:

  17. Search for Diether Lambrechts in:

  18. Search for Lieve Coenegrachts in:

  19. Search for Ignace Vergote in:

  20. Search for Frederic Amant in:

  21. Search for Helga B Salvesen in:

  22. Search for Jone Trovik in:

  23. Search for Tormund S Njolstad in:

  24. Search for Harald Helland in:

  25. Search for Rodney J Scott in:

  26. Search for Katie Ashton in:

  27. Search for Tony Proietto in:

  28. Search for Geoffrey Otton in:

  29. Search for Ian Tomlinson in:

  30. Search for Maggie Gorman in:

  31. Search for Kimberley Howarth in:

  32. Search for Shirley Hodgson in:

  33. Search for Montserrat Garcia-Closas in:

  34. Search for Nicolas Wentzensen in:

  35. Search for Hannah Yang in:

  36. Search for Stephen Chanock in:

  37. Search for Per Hall in:

  38. Search for Kamila Czene in:

  39. Search for Jianjun Liu in:

  40. Search for Jingmei Li in:

  41. Search for Xiao-Ou Shu in:

  42. Search for Wei Zheng in:

  43. Search for Jirong Long in:

  44. Search for Yong-Bing Xiang in:

  45. Search for Mitul Shah in:

  46. Search for Jonathan Morrison in:

  47. Search for Kyriaki Michailidou in:

  48. Search for Paul D Pharoah in:

  49. Search for Alison M Dunning in:

  50. Search for Douglas F Easton in:

Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Amanda B Spurdle.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Note, Supplementary Figures 1 and 2 and Supplementary Tables 1–7.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.812

Further reading