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Further evidence for pathogenicity of the TP53 tetramerization domain mutation p.Arg342Pro in Li–Fraumeni syndrome

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Abstract

Li–Fraumeni syndrome (LFS) is a rare genetic disease with a highly significant predisposition to multiple early-onset neoplasms. These neoplasms include adrenocortical carcinoma, sarcoma, leukemia and CNS tumors in children and sarcoma, breast cancer and lung cancer in adults. LFS is inherited in an autosomal dominant manner. In most patients germline mutations in the tumor suppressor gene TP53 are found. As the majority of known mutations affect the DNA-binding domain of the p53 protein, there are only a few case reports showing the clinical presentation of mutations outside of this mutational hotspot. Here we present a family with a typical LFS pedigree with patients suffering from early-onset lung cancer, bilateral breast cancer and osteosarcoma. TP53 sequence analysis of the index patient revealed the germline mutation c.1025G > C in a heterozygous state, resulting in an amino acid exchange from arginine to proline (p.Arg342Pro) in the tetramerization domain of p53. Using DNA from an old bedside blood typing test, the same mutation was found in the mother of the index patient, who had died of breast cancer 29 years ago. In conclusion, we provide evidence for the co-segregation of a TP53 tetramerization domain mutation and cancer phenotypes, but also report pre-symptomatic mutation carriers within the family. We review published recommendations for clinical management and surveillance of high-risk members in Li–Fraumeni kindreds.

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References

  1. Nichols KE, Malkin D, Garber JE et al (2001) Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev 10:83–87

    CAS  PubMed  Google Scholar 

  2. Kast K, Krause M, Schuler M et al (2012) Late onset Li–Fraumeni syndrome with bilateral breast cancer and other malignancies: case report and review of the literature. BMC Cancer 12:217. doi:10.1186/1471-2407-12-217

    Article  PubMed Central  PubMed  Google Scholar 

  3. Cavalier ME, Davis MM, Croop JM (2005) Germline p53 mutation presenting as synchronous tumors. J Pediatr Hematol Oncol 27:441–443

    Article  PubMed  Google Scholar 

  4. Hisada M, Garber JE, Fung CY et al (1998) Multiple primary cancers in families with Li–Fraumeni syndrome. J Natl Cancer Inst 90:606–611

    Article  CAS  PubMed  Google Scholar 

  5. Birch JM, Alston RD, McNally RJ et al (2001) Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 20:4621–4628. doi:10.1038/sj.onc.1204621

    Article  CAS  PubMed  Google Scholar 

  6. Li FP, Fraumeni JF (1982) Prospective study of a family cancer syndrome. JAMA 247:2692–2694

    Article  CAS  PubMed  Google Scholar 

  7. Chompret A, Abel A, Stoppa-Lyonnet D et al (2001) Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 38:43–47

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Tinat J, Bougeard G, Baert-Desurmont S et al (2009) 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 27:e108–e109. doi:10.1200/JCO.2009.22.7967; author reply e110

    Article  PubMed  Google Scholar 

  9. Varley JM (2003) Germline TP53 mutations and Li–Fraumeni syndrome. Hum Mutat 21:313–320. doi:10.1002/humu.10185

    Article  CAS  PubMed  Google Scholar 

  10. Soussi T, Béroud C (2001) Assessing TP53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer 1:233–240. doi:10.1038/35106009

    Article  CAS  PubMed  Google Scholar 

  11. Olivier M, Goldgar DE, Sodha N et al (2003) Li–Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 63:6643–6650

    CAS  PubMed  Google Scholar 

  12. Kato S, Han S-Y, Liu W et al (2003) Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci USA 100:8424–8429. doi:10.1073/pnas.1431692100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Rollenhagen C, Chène P (1998) Characterization of p53 mutants identified in human tumors with a missense mutation in the tetramerization domain. Int J Cancer 78:372–376. doi:10.1002/(SICI)1097-0215(19981029)78:3<372:AID-IJC19>3.0.CO;2-8

    Article  CAS  PubMed  Google Scholar 

  14. Kamada R, Nomura T, Anderson CW, Sakaguchi K (2011) Cancer-associated p53 tetramerization domain mutants: quantitative analysis reveals a low threshold for tumor suppressor inactivation. J Biol Chem 286:252–258. doi:10.1074/jbc.M110.174698

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. DiGiammarino EL, Lee AS, Cadwell C et al (2002) A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol 9:12–16. doi:10.1038/nsb730

    Article  CAS  PubMed  Google Scholar 

  16. Fiszer-Maliszewska L, Kazanowska B, Padzik J (2009) p53 Tetramerization domain mutations: germline R342X and R342P, and somatic R337G identified in pediatric patients with Li–Fraumeni syndrome and a child with adrenocortical carcinoma. Fam Cancer 8:541–546. doi:10.1007/s10689-009-9284-2

    Article  CAS  PubMed  Google Scholar 

  17. Seidinger AL, Mastellaro MJ, Paschoal Fortes F et al (2011) Association of the highly prevalent TP53 R337H mutation with pediatric choroid plexus carcinoma and osteosarcoma in southeast Brazil. Cancer 117:2228–2235. doi:10.1002/cncr.25826

    Article  CAS  PubMed  Google Scholar 

  18. Varley JM, McGown G, Thorncroft M et al (1996) A previously undescribed mutation within the tetramerization domain of TP53 in a family with Li–Fraumeni syndrome. Oncogene 12:2437–2442

    CAS  PubMed  Google Scholar 

  19. Petitjean A, Mathe E, Kato S et al (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 28:622–629. doi:10.1002/humu.20495

    Article  CAS  PubMed  Google Scholar 

  20. Chène P (2001) The role of tetramerization in p53 function. Oncogene 20:2611–2617. doi:10.1038/sj.onc.1204373

    Article  PubMed  Google Scholar 

  21. Halazonetis TD, Kandil AN (1993) Conformational shifts propagate from the oligomerization domain of p53 to its tetrameric DNA binding domain and restore DNA binding to select p53 mutants. EMBO J 12:5057–5064

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Itahana Y, Ke H, Zhang Y (2009) p53 Oligomerization is essential for its C-terminal lysine acetylation. J Biol Chem 284:5158–5164. doi:10.1074/jbc.M805696200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Sakaguchi K, Herrera JE, Saito S et al (1998) DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev 12:2831–2841

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Maki CG (1999) Oligomerization is required for p53 to be efficiently ubiquitinated by MDM2. J Biol Chem 274:16531–16535

    Article  CAS  PubMed  Google Scholar 

  25. Warnock LJ, Knox A, Mee TR et al (2008) Influence of tetramerisation on site-specific post-translational modifications of p53: comparison of human and murine p53 tumor suppressor protein. Cancer Biol Ther 7:1481–1489

    Article  CAS  PubMed  Google Scholar 

  26. Malkin D (2011) Li–Fraumeni syndrome. Genes Cancer 2:475–484. doi:10.1177/1947601911413466

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Villani A, Tabori U, Schiffman J et al (2011) Biochemical and imaging surveillance in germline TP53 mutation carriers with Li–Fraumeni syndrome: a prospective observational study. Lancet Oncol 12:559–567. doi:10.1016/S1470-2045(11)70119-X

    Article  CAS  PubMed  Google Scholar 

  28. Fresneau B, Brugières L, Caron O, Moutel G (2013) Ethical issues in presymptomatic genetic testing for minors: a dilemma in Li–Fraumeni syndrome. J Genet Couns 22:315–322. doi:10.1007/s10897-012-9556-0

    Article  PubMed  Google Scholar 

  29. Evans DG, Lunt P, Clancy T, Eeles R (2010) Childhood predictive genetic testing for Li–Fraumeni syndrome. Fam Cancer 9:65–69. doi:10.1007/s10689-009-9245-9

    Article  CAS  PubMed  Google Scholar 

  30. Mai PL, Malkin D, Garber JE et al (2012) Li–Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet 205:479–487. doi:10.1016/j.cancergen.2012.06.008

    Article  PubMed Central  PubMed  Google Scholar 

  31. Masciari S, Van den Abbeele AD, Diller LR et al (2008) F18-fluorodeoxyglucose-positron emission tomography/computed tomography screening in Li–Fraumeni syndrome. JAMA 299:1315–1319. doi:10.1001/jama.299.11.1315

    Article  CAS  PubMed  Google Scholar 

  32. Lammens CRM, Aaronson NK, Wagner A et al (2010) Genetic testing in Li–Fraumeni syndrome: uptake and psychosocial consequences. J Clin Oncol 28:3008–3014. doi:10.1200/JCO.2009.27.2112

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank the patient’s family for consent to share their case with the scientific community. This study was supported by the FAZIT-STIFTUNG Gemeinnützige Verlagsgesellschaft mbH. We thank Prof. Dr. Susann Schweiger and Dr. Dennis Strand for careful and critical reading of the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

All patients gave their informed consent prior to their inclusion in that report. Molecular genetic testing was performed as a clinical service according to the ethical guidelines of the institution (University Medical Center Mainz).

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Authors and Affiliations

  1. Institute of Human Genetics, University Medical Centre of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany

    Anna Etzold, Julia C. Schröder, Oliver Bartsch, Ulrich Zechner & Danuta Galetzka

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  1. Anna Etzold
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  2. Julia C. Schröder
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  3. Oliver Bartsch
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  4. Ulrich Zechner
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  5. Danuta Galetzka
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Corresponding authors

Correspondence to Anna Etzold or Ulrich Zechner.

Additional information

Anna Etzold and Julia C. Schröder have contributed equally to this work.

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Etzold, A., Schröder, J.C., Bartsch, O. et al. Further evidence for pathogenicity of the TP53 tetramerization domain mutation p.Arg342Pro in Li–Fraumeni syndrome. Familial Cancer 14, 161–165 (2015). https://doi.org/10.1007/s10689-014-9754-z

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