Skip to main content

Advertisement

SpringerLink
Log in

MDM2 Gene rs2279744 Polymorphism and Breast Cancer Risk: Evidence from Meta-Analysis and Meta-Regression Analysis

  • Original Article
  • Published:
Indian Journal of Gynecologic Oncology Aims and scope Submit manuscript

Abstract

Background

Several case–control studies have previously assessed the association of mouse double minute 2 homolog (MDM2) gene rs2279744 polymorphisms, and the risk of breast cancer (BC) that has resulted in incongruous conclusions. In order to clarify the conflicting outcomes obtained from different individual association studies, here we performed the most updated meta-analysis of rs2279744 polymorphism and risk of BC.

Methods

A comprehensive systematic search of literature, including ISI Web of Science, Scopus, and PubMed/MEDLINE, was carried out prior to March 2023, and the pooled odds ratio (OR) and their corresponding 95% confidence interval (CI) were calculated to determine the overall association power in the pooled population.

Results

Literature search led to retrieving of 39 studies, containing 22,764 cases and 22,444 healthy controls. The pooled analysis indicated that the dominant model (OR = 1.04, 95% CI = 1–1.09, P = 0.03), recessive model (OR = 1.13, 95% CI = 1.01–1.26, P = 0.2), allelic model (OR = 1.07, 95% CI = 1.02–1.12, P = 0.009), and GG genotype (OR = 1.18, 95% CI = 1.04–1.34, P = 0.008) were significantly associated with increased risk of BC. This polymorphism was also associated with increased risk of BC in Asians (dominant, allelic, and heterozygote models) but not Caucasians.

Conclusions

The current meta-analysis suggests that MDM2 gene rs2279744 polymorphism is a predisposing genetic factor in BC, particularly in Asians.

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
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Wendt C, Margolin S. Identifying breast cancer susceptibility genes—a review of the genetic background in familial breast cancer. Acta Oncol. 2019;58(2):135–46.

    Article  CAS  PubMed  Google Scholar 

  2. Yadav P, et al. Clinical significance of TP53 (R72P) and MDM2 (T309G) polymorphisms in breast cancer patients. Clin Transl Oncol. 2016;18(7):728–34.

    Article  MathSciNet  CAS  PubMed  Google Scholar 

  3. Xu Y, et al. Global trends and forecasts of breast cancer incidence and deaths. Sci Data. 2023;10(1):334.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sung H, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.

    Article  PubMed  Google Scholar 

  5. Arnold M, et al. Current and future burden of breast cancer: global statistics for 2020 and 2040. Breast. 2022;66:15–23.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Xu H, Xu B. Breast cancer: epidemiology, risk factors and screening. Chin J Cancer Res. 2023;35(6):565.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Iacoviello L, et al. Epidemiology of breast cancer, a paradigm of the “common soil” hypothesis. In: Seminars in Cancer biology. Elsevier; 2020.

  8. Miedl H, et al. Association of the MDM2 SNP285 and SNP309 genetic variants with the risk, age at onset and prognosis of breast cancer in Central European women: a hospital-based case-control study. Int J Mol Sci. 2019;20(3):509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sha M, Huang X, Yin Q. MiR-548b-3p inhibits proliferation and migration of breast cancer cells by targeting MDM2. Eur Rev Med Pharmacol Sci. 2020;24(6):3105–12.

    PubMed  Google Scholar 

  10. Levav-Cohen Y, Haupt S, Haupt Y. Mdm2 in growth signaling and cancer: mini review. Growth Factors. 2005;23(3):183–92.

    Article  CAS  PubMed  Google Scholar 

  11. Agrawal A, et al. Regulation of the p14ARF-Mdm2-p53 pathway: an overview in breast cancer. Exp Mol Pathol. 2006;81(2):115–22.

    Article  MathSciNet  CAS  PubMed  Google Scholar 

  12. Razi B, et al. Association between MTHFR gene polymorphism and susceptibility to autism spectrum disorders: systematic review and meta-analysis. Res Autism Spectr Disord. 2020;70:101473.

    Article  Google Scholar 

  13. Fouchécourt S, et al. Apoptosis of Sertoli cells after conditional ablation of murine double minute 2 (Mdm2) gene is p53-dependent and results in male sterility. Cell Death Differ. 2016;23(3):521–30.

    Article  PubMed  Google Scholar 

  14. Momand J, et al. The MDM2 gene amplification database. Nucleic Acids Res. 1998;26(15):3453–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ladanyi M, et al. MDM2 gene amplification in metastatic osteosarcoma. Can Res. 1993;53(1):16–8.

    CAS  Google Scholar 

  16. Li X, et al. Competitive ubiquitination activates the tumor suppressor p53. Cell Death Differ. 2020;27:1807–18.

    Article  CAS  PubMed  Google Scholar 

  17. Liu B, et al. MDM2-mediated degradation of WRN promotes cellular senescence in a p53-independent manner. Oncogene. 2019;38(14):2501–15.

    Article  CAS  PubMed  Google Scholar 

  18. Eslami MM, et al. Factor V Leiden 1691G> a mutation and the risk of recurrent pregnancy loss (RPL): systematic review and meta-analysis. Thromb J. 2020;18(1):1–16.

    Article  Google Scholar 

  19. Surekha D, et al. Codon 72 and G13964C intron 6 polymorphisms of TP53 in relation to development and progression of breast cancer in India. Asian Pac J Cancer Prev. 2011;12(8):1893–988.

    CAS  PubMed  Google Scholar 

  20. Mitra S, et al. Association of specific genotype and haplotype of p53 gene with cervical cancer in India. J Clin Pathol. 2005;58(1):26–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jain N, et al. Infection of human papillomavirus type 18 and p53 codon 72 polymorphism in lung cancer patients from India. Chest. 2005;128(6):3999–4007.

    Article  CAS  PubMed  Google Scholar 

  22. Addala L, et al. P5 3 codon 72 gene polymorphism and risk of Oral squamous cell carcinoma in South Indian population: a case-control study. J Cancer Sci Ther. 2012;4:188–92.

    Article  CAS  ADS  Google Scholar 

  23. Bond GL, et al. MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Can Res. 2006;66(10):5104–10.

    Article  CAS  Google Scholar 

  24. Bond GL, et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119(5):591–602.

    Article  CAS  PubMed  Google Scholar 

  25. Moher D, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–9.

    Article  PubMed  Google Scholar 

  26. Stang A. Critical evaluation of the Newcastle–Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5.

    Article  PubMed  Google Scholar 

  27. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22(4):719–48.

    CAS  PubMed  Google Scholar 

  28. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.

    Article  CAS  PubMed  Google Scholar 

  29. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.

    Article  CAS  PubMed  Google Scholar 

  30. Egger M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Akisik E, Yazici H, Dalay N. ARLTS1, MDM2 and RAD51 gene variations are associated with familial breast cancer. Mol Biol Rep. 2011;38(1):343–8.

    Article  CAS  PubMed  Google Scholar 

  32. Paulin FE, et al. MDM2 SNP309 is associated with high grade node positive breast tumours and is in linkage disequilibrium with a novel MDM2 intron 1 polymorphism. BMC Cancer. 2008;8(1):281.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Copson ER, et al. Influence of the MDM2 single nucleotide polymorphism SNP309 on tumour development in BRCA1 mutation carriers. BMC Cancer. 2006;6(1):80.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Campbell IG, Eccles DM, Choong DY. No association of the MDM2 SNP309 polymorphism with risk of breast or ovarian cancer. Cancer Lett. 2006;240(2):195–7.

    Article  CAS  PubMed  Google Scholar 

  35. Krekac D, et al. MDM2SNP309 does not associate with elevated MDM2 protein expression or breast cancer risk. Oncology. 2008;74(1–2):84–7.

    Article  CAS  PubMed  Google Scholar 

  36. Knappskog S, et al. The MDM2 promoter SNP285C/309G haplotype diminishes Sp1 transcription factor binding and reduces risk for breast and ovarian cancer in Caucasians. Cancer Cell. 2011;19(2):273–82.

    Article  CAS  PubMed  Google Scholar 

  37. Gansmo LB, et al. Influence of MDM2 SNP309 and SNP285 status on the risk of cancer in the breast, prostate, lung and colon. Int J Cancer. 2015;137(1):96–103.

    Article  CAS  PubMed  Google Scholar 

  38. Yilmaz M, et al. Significant association of the MDM2 T309G polymorphism with breast cancer risk in a Turkish population. Asian Pac j Cancer Prev APJCP. 2018;19(4):1059.

    CAS  PubMed  Google Scholar 

  39. Petenkaya A, et al. Lack of association between the MDM2-SNP309 polymorphism and breast cancer risk. Anticancer Res. 2006;26(6C):4975–7.

    CAS  PubMed  Google Scholar 

  40. Piotrowski P, et al. Murine double minute clone 2 309T/G and 285G/C promoter single nucleotide polymorphism as a risk factor for breast cancer: a Polish experience. Int J Biol Markers. 2012;27(2):105–10.

    Article  Google Scholar 

  41. Sinilnikova OM, et al. The TP53 Arg72Pro and MDM2 309G> T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2009;101(8):1456–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wasielewski M, et al. MDM2 SNP309 accelerates familial breast carcinogenesis independently of estrogen signaling. Breast Cancer Res Treat. 2007;104(2):153–7.

    Article  CAS  PubMed  Google Scholar 

  43. Wilkening S, et al. The single nucleotide polymorphism IVS1+ 309 in mouse double minute 2 does not affect risk of familial breast cancer. Can Res. 2006;66(2):646–8.

    Article  CAS  Google Scholar 

  44. Yarden RI, et al. MDM2 SNP309 accelerates breast and ovarian carcinogenesis in BRCA1 and BRCA2 carriers of Jewish-Ashkenazi descent. Breast Cancer Res Treat. 2008;111(3):497–504.

    Article  CAS  PubMed  Google Scholar 

  45. Alshatwi AA, et al. A single-nucleotide polymorphism in the TP53 and MDM-2 gene modifies breast cancer risk in an ethnic Arab population. Fundam Clin Pharmacol. 2012;26(3):438–43.

    Article  CAS  PubMed  Google Scholar 

  46. Afshari ZT, et al. Lack of an association between a functional polymorphism in the MDM2 promoter and breast cancer in women in northeast Iran. Rep Biochem mol biol. 2017;6(1):112.

    CAS  Google Scholar 

  47. Sun Y-F, et al. Results based on 124 cases of breast cancer and 97 controls from Taiwan suggest that the single nucleotide polymorphism (SNP309) in the MDM2 gene promoter is associated with earlier onset and increased risk of breast cancer. BMC Cancer. 2009;9(1):13.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Isakova J, et al. The association of polymorphic markers Arg399Gln of XRCC1 gene, Arg72Pro of TP53 gene and T309G of MDM2 gene with breast cancer in Kyrgyz females. BMC Cancer. 2017;17(1):758.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Singh V, et al. Association of polymorphism in MDM-2 and p53 genes with breast cancer risk in Indian women. Ann Epidemiol. 2008;18(1):48–57.

    Article  MathSciNet  PubMed  Google Scholar 

  50. Leu J-D, et al. Involvement of p53 R72P polymorphism in the association of MDM2-SNP309 with breast cancer. Oncol Rep. 2011;25(6):1755–63.

    CAS  PubMed  Google Scholar 

  51. Lum SS, et al. MDM2 SNP309 G allele increases risk but the T allele is associated with earlier onset age of sporadic breast cancers in the Chinese population. Carcinogenesis. 2008;29(4):754–61.

    Article  CAS  PubMed  Google Scholar 

  52. Koh W-P, et al. Combined effects of MDM2 SNP309 and TP53 R72P polymorphisms, and soy isoflavones on breast cancer risk among Chinese women in Singapore. Breast Cancer Res Treat. 2011;130(3):1011–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Isakova J, et al. Gene-to-gene interactions and the association of TP53, XRCC1, TNFα, HMMR, MDM2 and PALB2 with breast cancer in Kyrgyz females. Breast Cancer. 2020;27(5):938–46.

    Article  CAS  PubMed  Google Scholar 

  54. Boersma BJ, et al. Association of breast cancer outcome with status of p53 and MDM2 SNP309. J Natl Cancer Inst. 2006;98(13):911–9.

    Article  CAS  PubMed  Google Scholar 

  55. Cox DG, et al. The p53 Arg72Pro and MDM2-309 polymorphisms and risk of breast cancer in the nurses’ health studies. Cancer Causes Control. 2007;18(6):621–5.

    Article  MathSciNet  PubMed  Google Scholar 

  56. Macedo GS, et al. p53 signaling pathway polymorphisms, cancer risk and tumor phenotype in TP53 R337H mutation carriers. Fam Cancer. 2018;17(2):269–74.

    Article  CAS  PubMed  Google Scholar 

  57. Márquez-Rosales M, et al. Association of the rs2279744 promoter polymorphism in the MDM2 gene with breast cancer in a Mexican population (DSD) reulting in female sex reversal in 46XY males. Hered Genet. 2016;5(165):2.

    Google Scholar 

  58. Millikan RC, et al. No association between the MDM2− 309 T/G promoter polymorphism and breast cancer in African-Americans or Whites. Cancer Epidemiol Prev Biomark. 2006;15(1):175–7.

    Article  CAS  Google Scholar 

  59. Lilly CM. Diversity of asthma: evolving concepts of pathophysiology and lessons from genetics. J Allergy Clin Immunol. 2005;115(4):S526–31.

    Article  CAS  PubMed  Google Scholar 

  60. Zhang J, Zhang Y, Zhang Z. Association of rs2279744 and rs117039649 promoter polymorphism with the risk of gynecological cancer: a meta-analysis of case—control studies. Medicine. 2018;97(2):e9554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gao J, et al. Association between MDM2 rs2279744 polymorphism and breast cancer susceptibility: a meta-analysis based on 9,788 cases and 11,195 controls. Ther Clin Risk Manag. 2014;10:269.

    PubMed  PubMed Central  ADS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Mohammad Masoud Eslami, Saman Masoudifar & Bahman Razi

  2. Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Payam Mohammadi

  3. Department of Hematology and Blood Transfusion, School of Allied Medical Science, Iran University of Medical Sciences, Tehran, Iran

    Amir Samii

  4. Department of Nursing, Faculty of Nursing and Midwifery, Mashhad Branch of Islamic Azad University, Mashhad, Iran

    Javad Gholampour

  5. Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Tannaz Jamialahmadi

  6. Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Amirhossein Sahebkar

  7. Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Amirhossein Sahebkar

Authors
  1. Mohammad Masoud Eslami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Payam Mohammadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amir Samii
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Saman Masoudifar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bahman Razi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Javad Gholampour
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tannaz Jamialahmadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Amirhossein Sahebkar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Bahman Razi or Amirhossein Sahebkar.

Ethics declarations

Conflict of interest

The authors have no competing interests to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eslami, M.M., Mohammadi, P., Samii, A. et al. MDM2 Gene rs2279744 Polymorphism and Breast Cancer Risk: Evidence from Meta-Analysis and Meta-Regression Analysis. Indian J Gynecol Oncolog 22, 49 (2024). https://doi.org/10.1007/s40944-024-00819-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s40944-024-00819-8

Keywords

Search

Navigation