Cancer Genetics

Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer

  1. Maria Notaridou1,†,
  2. Lydia Quaye1,†,
  3. Dimitra Dafou2,†,
  4. Chris Jones1,
  5. Honglin Song3,
  6. Estrid Høgdall4,
  7. Susanne K. Kjaer4,
  8. Lise Christensen5,
  9. Claus Høgdall6,
  10. Jan Blaakaer7,
  11. Valerie McGuire8,
  12. Anna H. Wu9,
  13. David J. Van Den Berg9,
  14. Malcolm C. Pike9,
  15. Aleksandra Gentry-Maharaj1,
  16. Eva Wozniak1,
  17. Tanya Sher1,
  18. Ian J. Jacobs1,‡,
  19. Jonathan Tyrer3,
  20. Joellen M. Schildkraut10,
  21. Patricia G. Moorman10,
  22. Edwin S. Iversen11,
  23. Anna Jakubowska12,
  24. Krzysztof Mędrek12,
  25. Jan Lubiński12,
  26. Roberta B. Ness13,
  27. Kirsten B. Moysich14,
  28. Galina Lurie15,
  29. Lynne R. Wilkens15,
  30. Michael E. Carney15,
  31. Shan Wang-Gohrke16,
  32. Jennifer A. Doherty17,
  33. Mary Anne Rossing17,
  34. Matthias W. Beckmann18,
  35. Falk C. Thiel18,
  36. Arif B. Ekici19,
  37. Xiaoqing Chen20,
  38. Jonathan Beesley20,
  39. The Australian Ovarian Cancer Study Group/Australian Cancer Study (Ovarian Cancer)20,21,
  40. Jacek Gronwald12,
  41. Peter A. Fasching18,22,
  42. Jenny Chang-Claude23,
  43. Marc T. Goodman15,
  44. Georgia Chenevix-Trench20,
  45. Andrew Berchuck24,
  46. C. Leigh Pearce9,
  47. Alice S. Whittemore8,
  48. Usha Menon1,
  49. Paul D.P. Pharoah3,
  50. Simon A. Gayther1,*,
  51. Susan J. Ramus1,
  52. on behalf of the Ovarian Cancer Association Consortium24

Article first published online: 15 JUL 2010

DOI: 10.1002/ijc.25554

Issue

International Journal of Cancer

International Journal of Cancer

Volume 128, Issue 9, pages 2063–2074, 1 May 2011

Additional Information

How to Cite

Notaridou, M., Quaye, L., Dafou, D., Jones, C., Song, H., Høgdall, E., Kjaer, S. K., Christensen, L., Høgdall, C., Blaakaer, J., McGuire, V., Wu, A. H., Van Den Berg, D. J., Pike, M. C., Gentry-Maharaj, A., Wozniak, E., Sher, T., Jacobs, I. J., Tyrer, J., Schildkraut, J. M., Moorman, P. G., Iversen, E. S., Jakubowska, A., Mędrek, K., Lubiński, J., Ness, R. B., Moysich, K. B., Lurie, G., Wilkens, L. R., Carney, M. E., Wang-Gohrke, S., Doherty, J. A., Rossing, M. A., Beckmann, M. W., Thiel, F. C., Ekici, A. B., Chen, X., Beesley, J., The Australian Ovarian Cancer Study Group/Australian Cancer Study (Ovarian Cancer), Gronwald, J., Fasching, P. A., Chang-Claude, J., Goodman, M. T., Chenevix-Trench, G., Berchuck, A., Pearce, C. L., Whittemore, A. S., Menon, U., Pharoah, P. D., Gayther, S. A., Ramus, S. J. and on behalf of the Ovarian Cancer Association Consortium (2011), Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer. International Journal of Cancer, 128: 2063–2074. doi: 10.1002/ijc.25554

Author Information

  1. 1

    Gynaecological Oncology Unit, UCL EGA Institute for Women's Health, University College London, United Kingdom

  2. 2

    Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, United Kingdom

  3. 3

    CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom

  4. 4

    Department of Viruses, Hormones and Cancer, Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark

  5. 5

    Department of Pathology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark

  6. 6

    The Gynaecologic Clinic, The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Denmark

  7. 7

    Department of Gynaecology and Obstetrics, Aarhus University Hospital, Skejby, Aarhus, Denmark

  8. 8

    Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA

  9. 9

    University of Southern California, Keck School of Medicine, Department of Preventive Medicine, Los Angeles, CA

  10. 10

    Department of Community and Family Medicine, Duke University Medical Center, Durham, NC

  11. 11

    Department of Statistical Science, Duke University, Medical Center, Durham, NC

  12. 12

    Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland

  13. 13

    University of Texas, School of Public Health, Houston, TX

  14. 14

    Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY

  15. 15

    Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI

  16. 16

    Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany

  17. 17

    Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington

  18. 18

    Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany

  19. 19

    Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany

  20. 20

    Genetics and Population Health, The Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Australia

  21. 21

    Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia

  22. 22

    Division of Hematology and Oncology, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, CA

  23. 23

    Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany

  24. 24

    Department of Obstetrics and Gynecology/Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC, 27710

  1. †

    M.N., L.Q., and D.D. contributed equally to this work.

  2. ‡

    Professor Ian J. Jacobs is a consultant to Beckton Dickinson in the field of ovarian cancer.

*Gynaecological Oncology Unit, UCL EGA Institute for Women's Health, University College London, Gower Street, London, WC1E 6BT, United Kingdom

Publication History

  1. Issue published online: 8 MAR 2011
  2. Article first published online: 15 JUL 2010
  3. Accepted manuscript online: 15 JUL 2010 12:00AM EST
  4. Manuscript Accepted: 24 JUN 2010
  5. Manuscript Revised: 26 MAY 2010
  6. Manuscript Received: 26 MAR 2010

Funded by

  • Cancer Research UK project grant. Grant Number: C8804/A7058
  • National Cancer Institute the Danish Cancer Society (MALOVA). Grant Number: RO1 CA61107
  • The Roswell Park Alliance and the National Cancer Institute (GEOCS study). Grant Number: CA71766 and Core Grant CA16056
  • NIH grant (the DOVE study). Grant Number: RO1 CA87538
  • NCI grants and Department of Defence grant (The HOPE project). Grant Number: K07-CA80668 and R01CA095023, and DAMD17-02-1-0669
  • California Cancer Research Program. Grant Numbers: 00-01389V-20170, 2110200
  • U.S. Public Health Service and California Department of Health Services sub-contract as part of its statewide cancer reporting program (University of Southern California). Grant Numbers: CA14089, CA17054, CA61132, CA63464, N01-PC-67010 and R03-CA113148 and sub-contract 050-E8709
  • U.S. Public Health Service grant and contracts from the Department of Health and Human Services, National Institutes of Health (HAW study). Grant Number: R01-CA-58598, and contracts N01-CN67001 and NO1-PC-035137

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Keywords:

  • risk of ovarian cancer;
  • polymorphism;
  • association studies

Abstract

Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty-three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer [HetOR = 1.42 (1.15–1.74) and the HomOR = 1.63 (1.10–1.42), p-trend = 0.0002] and [HetOR = 0.97 (0.80–1.17), HomOR = 0.74 (0.58–0.93), p-trend = 0.009], respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele-specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele-specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer.

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