Skip to main content
SpringerLink
Log in

Progesterone receptor PROGINS and +331G/A polymorphisms confer susceptibility to ovarian cancer: a meta-analysis based on 17 studies

  • Research Article
  • Published:
Tumor Biology

Abstract

Progesterone and its receptor, progesterone receptor (PGR), have been widely studied for their roles in the onset and development of ovarian cancer. Although numerous epidemiological studies have focused on the association of PGR PROGINS and +331G/A polymorphisms with ovarian cancer susceptibility, presently, available results remain controversial, in part due to low sample sizes. Thus, a meta-analysis is required to evaluate this association. A literature search of PubMed, Embase, Web of Science, CNKI, and CBM databases was performed to retrieve eligible studies published before August 15, 2013. Summary odds ratios (ORs) with 95 % confidence intervals (CIs) were used to evaluate the strength of this association. All analyses were done using STATA 12.0 software (Stata Corp., College Station, TX, USA). Seventeen case–control studies with a total of 6,365 cases and 9,998 controls were identified. While no statistically significant association between the PROGINS allele and ovarian cancer risk was found in an overall analysis, a stratified analysis revealed that for Caucasians, never-oral contraceptive (OC) users, and serous tumor patients, there were statistically significant ORs for ovarian cancer risk associated with the mutated PROGINS allele. No significant association, however, between the +331G/A polymorphism and ovarian cancer susceptibility was observed in the overall analyses and subgroup analyses based on ethnicity and histological type. This meta-analysis provides evidence that the PROGINS allele occurs more frequently in ovarian cancer patients and especially in non-OC users and serous cancer patients, indicating that PROGINS may be a risk modifier. No significant association between the +331G/A polymorphism and ovarian cancer was found, even in stratified analyses by ethnicity and histological type. More detailed and well-designed studies are still needed to confirm the role of the PROGINS allele in ovarian cancer development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.

    Article  PubMed  Google Scholar 

  2. Lowe KA, Chia VM, Taylor A, O'Malley C, Kelsh M, et al. An international assessment of ovarian cancer incidence and mortality. Gynecol Oncol. 2013;130:107–14.

    Article  PubMed  Google Scholar 

  3. Boyd J, Rubin SC. Hereditary ovarian cancer: molecular genetics and clinical implications. Gynecol Oncol. 1997;64:196–206.

    Article  PubMed  CAS  Google Scholar 

  4. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71.

    Article  PubMed  CAS  Google Scholar 

  5. Wooster R, Weber BL. Breast and ovarian cancer. N Engl J Med. 2003;348:2339–47.

    Article  PubMed  CAS  Google Scholar 

  6. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case–control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol. 1992;136:1184–203.

    PubMed  CAS  Google Scholar 

  7. King RJ. Biology of female sex hormone action in relation to contraceptive agents and neoplasia. Contraception. 1991;43:527–42.

    Article  PubMed  CAS  Google Scholar 

  8. Ivarsson K, Sundfeldt K, Brannstrom M, Janson PO. Production of steroids by human ovarian surface epithelial cells in culture: possible role of progesterone as growth inhibitor. Gynecol Oncol. 2001;82:116–21.

    Article  PubMed  CAS  Google Scholar 

  9. Rodriguez GC, Nagarsheth NP, Lee KL, Bentley RC, Walmer DK, et al. Progestin-induced apoptosis in the macaque ovarian epithelium: differential regulation of transforming growth factor-beta. J Natl Cancer Inst. 2002;94:50–60.

    Article  PubMed  CAS  Google Scholar 

  10. Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 1995;9:2266–78.

    Article  PubMed  CAS  Google Scholar 

  11. Mattei MG, Krust A, Stropp U, Mattei JF, Chambon P. Assignment of the human progesterone receptor to the q22 band of chromosome 11. Hum Genet. 1988;78:96–7.

    Article  PubMed  CAS  Google Scholar 

  12. Wen DX, Xu YF, Mais DE, Goldman ME, McDonnell DP. The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells. Mol Cell Biol. 1994;14:8356–64.

    PubMed Central  PubMed  CAS  Google Scholar 

  13. McKenna NJ, Kieback DG, Carney DN, Fanning M, McLinden J, et al. A germline TaqI restriction fragment length polymorphism in the progesterone receptor gene in ovarian carcinoma. Br J Cancer. 1995;71:451–5.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  14. Spurdle AB, Webb PM, Purdie DM, Chen X, Green A, et al. No significant association between progesterone receptor exon 4 Val660Leu G/T polymorphism and risk of ovarian cancer. Carcinogenesis. 2001;22:717–21.

    Article  PubMed  CAS  Google Scholar 

  15. Lancaster JM, Wenham RM, Halabi S, Calingaert B, Marks JR, et al. No relationship between ovarian cancer risk and progesterone receptor gene polymorphism in a population-based, case–control study in North Carolina. Cancer Epidemiol, Biomark Prev Publ Am Assoc Cancer Res, Cosponsored Am Soc Prev Oncol. 2003;12:226–7.

    CAS  Google Scholar 

  16. Berchuck A, Schildkraut JM, Wenham RM, Calingaert B, Ali S, et al. Progesterone receptor promoter +331A polymorphism is associated with a reduced risk of endometrioid and clear cell ovarian cancers. Cancer Epidemiol, Biomark Prev Publ Am Assoc Cancer Res, Cosponsored Am Soc Prev Oncol. 2004;13:2141–7.

    CAS  Google Scholar 

  17. Risch HA, Bale AE, Beck PA, Zheng W. PGR +331 A/G and increased risk of epithelial ovarian cancer. Cancer Epidemiol, Biomark Prev Publ Am Assoc Cancer Res, Cosponsored Am Soc Prev Oncol. 2006;15:1738–41.

    Article  CAS  Google Scholar 

  18. Quaye L, Tyrer J, Ramus SJ, Song H, Wozniak E, et al. Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer. PloS One. 2009;4:e5983.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Chaudhary S, Panda AK, Mishra DR, Mishra SK. Association of +331G/A PGR polymorphism with susceptibility to female reproductive cancer: evidence from a meta-analysis. PloS One. 2013;8:e53308.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  20. da Costa BR, Cevallos M, Altman DG, Rutjes AW, Egger M. Uses and misuses of the strobe statement: bibliographic study. BMJ Open. 2011;1:e000048.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.

    Article  PubMed  Google Scholar 

  22. Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol. 2005;28:123–37.

    Article  PubMed  Google Scholar 

  23. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295:676–80.

    Article  PubMed  CAS  Google Scholar 

  24. Manolitsas TP, Englefield P, Eccles DM, Campbell IG. No association of a 306-bp insertion polymorphism in the progesterone receptor gene with ovarian and breast cancer. Br J Cancer. 1997;75:1398–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Runnebaum IB, Wang-Gohrke S, Vesprini D, Kreienberg R, Lynch H, et al. Progesterone receptor variant increases ovarian cancer risk in BRCA1 and BRCA2 mutation carriers who were never exposed to oral contraceptives. Pharmacogenetics. 2001;11:635–8.

    Article  PubMed  CAS  Google Scholar 

  26. Tong D, Fabjani G, Heinze G, Obermair A, Leodolter S, et al. Analysis of the human progesterone receptor gene polymorphism PROGINS in Austrian ovarian carcinoma patients. Int J Cancer [Journal International du Cancer]. 2001;95:394–7.

    Article  CAS  Google Scholar 

  27. Agoulnik IU, Tong XW, Fischer DC, Korner K, Atkinson NE, et al. A germline variation in the progesterone receptor gene increases transcriptional activity and may modify ovarian cancer risk. J Clin Endocrinol Metab. 2004;89:6340–7.

    Article  PubMed  CAS  Google Scholar 

  28. Pearce CL, Hirschhorn JN, Wu AH, Burtt NP, Stram DO, et al. Clarifying the PROGINS allele association in ovarian and breast cancer risk: a haplotype-based analysis. J Natl Cancer Inst. 2005;97:51–9.

    Article  PubMed  CAS  Google Scholar 

  29. Terry KL, De Vivo I, Titus-Ernstoff L, Sluss PM, Cramer DW. Genetic variation in the progesterone receptor gene and ovarian cancer risk. Am J Epidemiol. 2005;161:442–51.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Romano A, Lindsey PJ, Fischer DC, Delvoux B, Paulussen AD, et al. Two functionally relevant polymorphisms in the human progesterone receptor gene (+331 G/A and PROGINS) and the predisposition for breast and/or ovarian cancer. Gynecol Oncol. 2006;101:287–95.

    Article  PubMed  CAS  Google Scholar 

  31. Delort L, Chalabi N, Satih S, Rabiau N, Kwiatkowski F, et al. Association between genetic polymorphisms and ovarian cancer risk. Anticancer Res. 2008;28:3079–81.

    PubMed  CAS  Google Scholar 

  32. Leite DB, Junqueira MG, de Carvalho CV, Massad-Costa AM, Goncalves WJ, et al. Progesterone receptor (PROGINS) polymorphism and the risk of ovarian cancer. Steroids. 2008;73:676–80.

    Article  PubMed  CAS  Google Scholar 

  33. Ludwig AH, Murawska M, Panek G, Timorek A, Kupryjanczyk J. Androgen, progesterone, and FSH receptor polymorphisms in ovarian cancer risk and outcome. Endocr-Relat Cancer. 2009;16:1005–16.

    Article  PubMed  CAS  Google Scholar 

  34. Lancaster JM, Berchuck A, Carney ME, Wiseman R, Taylor JA. Progesterone receptor gene polymorphism and risk for breast and ovarian cancer. Br J Cancer. 1998;78:277.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. Rosenberg L, Palmer JR, Zauber AG, Warshauer ME, Lewis Jr JL, et al. A case–control study of oral contraceptive use and invasive epithelial ovarian cancer. Am J Epidemiol. 1994;139:654–61.

    PubMed  CAS  Google Scholar 

  36. Risch HA. Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst. 1998;90:1774–86.

    Article  PubMed  CAS  Google Scholar 

  37. Narod SA, Risch H, Moslehi R, Dorum A, Neuhausen S, et al. Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary ovarian cancer clinical study group. New Engl J Med. 1998;339:424–8.

    Article  PubMed  CAS  Google Scholar 

  38. De Vivo I, Huggins GS, Hankinson SE, Lescault PJ, Boezen M, et al. A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci U S A. 2002;99:12263–8.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  39. Fujimoto J, Ichigo S, Hirose R, Sakaguchi H, Tamaya T. Clinical implication of expression of progesterone receptor form A and B mRNAs in secondary spreading of gynecologic cancers. J Steroid Biochem Mol Biol. 1997;62:449–54.

    Article  PubMed  CAS  Google Scholar 

Download references

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, Renji Hospital, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1630, Shanghai, 200127, People’s Republic of China

    Ting Liu, Lilan Chen, Xiangjun Sun, You Wang, Shu Li, Xia Yin, Xinran Wang & Wen Di

  2. Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, People’s Republic of China

    Ting Liu, Lilan Chen, Xiangjun Sun, Shu Li, Xia Yin, Xinran Wang, Chenhuan Ding, He Li & Wen Di

  3. Department of Obstetrics and Gynecology, Affiliated Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Wuxi, People’s Republic of China

    You Wang

  4. Department of Chinese Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1630, Shanghai, 200127, People’s Republic of China

    Chenhuan Ding & He Li

Authors
  1. Ting Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lilan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiangjun Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. You Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xia Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xinran Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chenhuan Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. He Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wen Di
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to He Li or Wen Di.

Additional information

Ting Liu and Lilan Chen have contributed equally to this work and are co-first authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, T., Chen, L., Sun, X. et al. Progesterone receptor PROGINS and +331G/A polymorphisms confer susceptibility to ovarian cancer: a meta-analysis based on 17 studies. Tumor Biol. 35, 2427–2436 (2014). https://doi.org/10.1007/s13277-013-1322-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-013-1322-x

Keywords

Search

Navigation