SpringerLink
Log in

Evaluation of TP53 Pro72Arg and MDM2 SNP285–SNP309 polymorphisms in an Italian cohort of LFS suggestive patients lacking identifiable TP53 germline mutations

  • Original Article
  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

Li-Fraumeni syndrome (LFS) is a rare genetic cancer predisposition disease, partly determined by the presence of a TP53 germline mutation; lacking thereof, in presence of a typical LFS phenotype, defines a wide group of ‘LFS Suggestive’ patients. Alternative LFS susceptibility genes have been investigated without promising results, thus suggesting other genetic determinants involvement in cancer predisposition. Hence, this study explores the single and combined effects of cancer risk, age of onset and cancer type of three single nucleotide polymorphisms (SNPs)—TP53 Pro72Arg, MDM2 SNP285 and SNP309—already described as modifiers on TP53 mutation carriers but not properly investigated in LFS Suggestive patients. This case–control study examines 34 Italian LFS Suggestive lacking of germline TP53 mutations and 95 tumour-free subjects. A significant prevalence of homozygous MDM2 SNP309 G in the LFS Suggestive group (p < 0.0005) confirms its contribute to cancer susceptibility, also highlighted in LFS TP53 positive families. Conversely its anticipating role on tumour onset has not been confirmed, as in our results it was associated with the SNP309 T allele. A strong combined outcome with a ‘dosage’ effect has also been reported for TP53 P72 and MDM2 SNP309 G allele on cancer susceptibility (p < 0.0005). Whereas the MDM2 SNP285 C allele neutralizing effect on MDM2 SNP309 G variant is not evident in our population. Although it needs further evaluations, obtained results strengthen the role of MDM2 SNP309 as a genetic factor in hereditary predisposition to cancer, so improving LFS Suggestive patients management.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Malkin D (2011) Li-Fraumeni syndrome. genes. Cancer 2(4):475–484. doi:10.1177/1947601911413466

    CAS  Google Scholar 

  2. Reinhardt HC, Schumacher B (2012) The p53 network: cellular and systemic DNA damage responses in aging and cancer. Trends Genet 28(3):128–136. doi:10.1016/j.tig.2011.12.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Xu J, Qian J, Hu Y, Wang J, Zhou X, Chen H, Fang JY (2014) Heterogeneity of Li-Fraumeni syndrome links to unequal gain-of-function effects of p53 mutations. Sci Rep 4:4223. doi:10.1038/srep04223

    PubMed  PubMed Central  Google Scholar 

  4. Li FP, Fraumeni JF Jr, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48(18):5358–5362

    CAS  PubMed  Google Scholar 

  5. Chompret A, Abel A, Stoppa-Lyonnet D, Brugiéres L, Pagés S, Feunteun J, Bonaïti-Pellié C (2001) Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 38(1):43–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, Caron O, Bressac-de Paillerets B, Berthet P, Dugast C, Bonaïti-Pellié C, Stoppa-Lyonnet D, Frébourg T (2009) 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 27(26):e108-9;author reply e110. doi: 10.1200/JCO.2009.22.7967

  7. Bougeard G, Renaux-Petel M, Flaman JM et al (2015) Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol 33(21):2345–2352. doi:10.1200/JCO.2014.59.5728

    Article  CAS  PubMed  Google Scholar 

  8. Finkova A, Vazna A, Hrachovina O, Bendova S, Prochazkova K, Sedlacek Z (2009) The TP53 gene promoter is not methylated in families suggestive of Li-Fraumeni syndrome with no germline TP53 mutations. Cancer Genet Cytogene 193(1):63–66. doi:10.1016/j.cancergencyto.2009.04.014

    Article  CAS  Google Scholar 

  9. Houlston RS, Peto J (2004) The search for low-penetrance cancer susceptibility alleles. Oncogene 23(38):6471–6476

    Article  CAS  PubMed  Google Scholar 

  10. McBride K, Ballinger ML, Killick E et al (2014) Li-Fraumeni syndrome: cancer risk assesment and clinical management. Nat Rev Clin Oncol 11(5):260–271. doi:10.1038/nrclinonc.2014.41

    Article  CAS  PubMed  Google Scholar 

  11. Michael D, Oren M (2003) The p53-Mdm2 module and the ubiquitin system. Semin Cancer Biol 13(1):49–58

    Article  CAS  PubMed  Google Scholar 

  12. Renaux-Petel M, Sesboue R, Baert-Desurmont S, Vasseur S, Fourneaux S, Bessenay E, Frébourg T, Bougeard G (2014) The MDM2 285G-309G haplotype is associated with an earlier age of tumor onset in patients with Li Fraumeni Syndrome. Fam cancer 13(1):127–130. doi:10.1007/s10689-013-9667-2

    Article  CAS  PubMed  Google Scholar 

  13. Wu CC, Krahe R, Lozano G, Zhang B, Wilson CD, Jo EJ, Amos CI, Shete S, Strong LC (2011) Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome. Hum Genet 129:663–673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fang S, Krahe R, Lozano G, Han Y, Chen W, Post SM, Zhang B, Wilson CD, Bachinski LL, Strong LC, Amos CI (2010) Effects of MDM2, MDM4 and TP53 codon 72 polymorphisms on cancer risk in a cohort study of carriers of TP53 germline mutations. PLoS ONE 5:e10813

    Article  PubMed  PubMed Central  Google Scholar 

  15. Dumont P, Leu JI, Della Pietra AC III, George DL, Murphy M (2003) The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 33(3):357–365

    Article  CAS  PubMed  Google Scholar 

  16. Wan Y, Wu W, Yin Z, Guan P, Zhou B (2011) MDM2 SNP309, gene-gene interaction, and tumor susceptibility: an updated meta-analysis. BMC Cancer 11:208. doi:10.1186/1471-2407-11-208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Khan MH, Kalil A, Rashid H (2015) Evaluation of the p53 Arg72Pro polymorphism and its association with cancer risk: a HuGE review and meta-analysis. Genet Res (Camb) 97:e7. doi:10.1017/S0016672315000075

    Article  Google Scholar 

  18. Biderman L, Poyurovsky MV, Assia Y, Manley JL, Prives C (2012) MdmX is required for p53 interaction with and full induction of the Mdm2 promoter after cellular stress. Mol Cell Biol 32(7):1214–1225. doi:10.1128/MCB.06150-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ruijs MW, Schmidt MK, Nevanlinna H, Tommiska J, Aittomäki K, Pruntel R, Verhoef S, Van’t Veer LJ (2007) The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes. Eur J Hum Genet 15(1):110–114

    Article  CAS  PubMed  Google Scholar 

  20. Bond GL, Hu W, Levine AJ (2005) MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets 5(1):3–8

    Article  CAS  PubMed  Google Scholar 

  21. Jones SN, Hancock AR, Vogel H, Donehower LA, Bradley A (1998) Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc Natl Acad Sci USA 95(26):15608–15612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cordon-Cardo C, Latres E, Drobnjak M, Oliva MR, Pollack D, Woodruff JM, Marechal V, Chen J, Brennan MF, Levine AJ (1994) Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. Cancer Res 54(3):794–799

    CAS  PubMed  Google Scholar 

  23. Leach FS, Tokino T, Meltzer P, Burrell M, Oliner JD, Smith S, Hill DE, Sidransky D, Kinzler KW, Vogelstein B (1993) p53 Mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res 53(10):2231–2234

    CAS  PubMed  Google Scholar 

  24. Epistolato MC, Disciglio V, Livide G, Berchialla P, Mencarelli MA, Marozza A, Amenduni M, Hadjistilianou T, De Francesco S, Acquaviva A, Toti P, Cetta F, Ariani F, De Marchi M, Renieri A, Giachino D (2011) p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma. JMG 53:685–686. doi:10.3810/jhg.2011.82

    Google Scholar 

  25. Menin C, Scaini MC, De Salvo GL, Biscuola M, Quaggio M, Esposito G, Belluco C, Montagna M, Agata S, D’Andrea E, Nitti D, Amadori A, Bertorelle R (2006) Association between MDM2-SNP309 and age at colorectal cancer diagnosis according to p53 mutation status. J Natl Cancer Inst 98(4):285–288

    Article  CAS  PubMed  Google Scholar 

  26. Bond GL, Hu W, Levine A (2005) A single nucleotide polymorphism in the MDM2 gene: from a molecular and cellular explanation to clinical effect. Cancer Res 65(13):5481–5484

    Article  CAS  PubMed  Google Scholar 

  27. Bougeard G, Baert-Desurmont S, Tournier I, Vasseur S, Martin C, Brugieres L, Chompret A, Bressac-de Paillerets B, Stoppa-Lyonnet D, Bonaiti-Pellie C, Frebourg T (2006) Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. J Med Genet 43(6):531–533

    Article  CAS  PubMed  Google Scholar 

  28. Hu Z, ** G, Wang L, Chen F, Wang X, Shen H (2007) MDM2 promoter polymorphism SNP309 contributes to tumor susceptibility: evidence from 21 case-control studies. Cancer Epidemiol Biomarkers Prev 16(12):2717–2723

    Article  CAS  PubMed  Google Scholar 

  29. Castera L, Sabbagh A, Dehainault C, Michaux D, Mansuet-Lupo A et al (2010) MDM2 as a modifier gene in retinoblastoma. J Natl Cancer Inst 102(23):1805–1808. doi:10.1093/jnci/djq416

    Article  CAS  PubMed  Google Scholar 

  30. Knappskog S, Lønning PE (2011) Effects of the MDM2 promoter SNP285 and SNP309 on Sp1 transcription factor binding and cancer risk. Transcription 2(5):207–210. doi:10.4161/trns.2.5.16813

    Article  PubMed  PubMed Central  Google Scholar 

  31. Talseth BA, Meldrum C, Suchy J, Kurzawski G, Lubinski J, Scott RJ (2007) MDM2 SNP309 T>G alone or in combination with the TP53 R72P polymorphism does not appear to influence disease expression and age of diagnosis of colorectal cancer in HNPCC patients. Int J Cancer 120(3):563–565

    Article  CAS  PubMed  Google Scholar 

  32. Knappskogg S, Gansmo LB, Dibirova K et al (2014) Population distribution and ancestry of the cancer protective MDM2 SNP285. Oncotarget 5(18):8223–8234

    Article  Google Scholar 

  33. Knappskogg S, Bjørnslett M, Myklebust LM, Huijts PE et al (2011) The MDM2 PromoterSNP285C/309G Haplotype diminishesSp1 transcription factor binding and reduces risk for breast and ovarian cancer in Caucasians. Cancer Cell 19(2):273–282. doi:10.1016/j.ccr.2010.12.019

    Article  Google Scholar 

  34. Ryan BM, Calhoun M, Pine S, Bowman E, Robles A, Ambs S (2012) MDM2 SNP285 does not antagonize the effect of SNP309 in lung cancer. Int J Cancer 131(11):2710–2716. doi:10.1002/ijc.27573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Said Id, Malkin D (2015) A functional variant in miR-605 modifies the age of onset in Li-Fraumeni syndrome. Cancer Genet. 208(1–2):47–51

    Article  Google Scholar 

  36. Gansmo LB, Knappskog S, Romundstd P, Hveem K, Vatten L, Lonning PE (2015) Influence of MDM2 SNP309 and SNP285 status on the risk of cancer in the breast, prostate, lung and colon. Int J 137:96–103

    CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank all patients and parents for valuable contribution to the study, the BIOGEN Biobank for granting access to samples and their related clinical informations and Dr. Elettra Pignotti for her fundamental contribution to the statistical data analysis. A special acknowledgment goes to Dr Gareth Bond and his group (Ludwig Institute for Cancer Research, University of Oxford, UK) for their helpful suggestions on the manuscript and supporting the genoty** validation.

Author information

Authors and Affiliations

  1. Department of Medical Genetics and Skeletal Rare Diseases, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136, Bologna, Italy

    Francesca Ponti, Serena Corsini, Maria Gnoli, Elena Pedrini & Luca Sangiorgi

  2. CLIBI – Clinical Bioinformatics Lab, Istituto Ortopedico Rizzoli, Bologna, Italy

    Marina Mordenti

Authors
  1. Francesca Ponti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Serena Corsini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Gnoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elena Pedrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marina Mordenti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Luca Sangiorgi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luca Sangiorgi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ponti, F., Corsini, S., Gnoli, M. et al. Evaluation of TP53 Pro72Arg and MDM2 SNP285–SNP309 polymorphisms in an Italian cohort of LFS suggestive patients lacking identifiable TP53 germline mutations. Familial Cancer 15, 635–643 (2016). https://doi.org/10.1007/s10689-016-9895-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-016-9895-3

Keywords

Search

Navigation