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p53 signaling pathway polymorphisms, cancer risk and tumor phenotype in TP53 R337H mutation carriers

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Abstract

Li-Fraumeni and Li-Fraumeni-like syndrome (LFS/LFL) are clinically heterogeneous cancer predisposition syndromes characterized by diagnosis of early-onset and often multiple cancers with variable tumor patterns and incomplete penetrance. To date, the genetic modifiers described in LFS/LFL have been shown to map to either TP53 or its main negative regulator, MDM2. Additionally, all studies were focused on families with different TP53 germline mutations. Hence, in this study we explored the effect of the most studied polymorphisms of p53 pathway genes on clinical manifestations of individuals carrying the founder TP53 mutation R337H (n = 136) and controls (n = 186). Cancer-affected carriers had been diagnosed either with adrenocortical carcinoma (ACC, n = 29) or breast cancer (BC, n = 43). Allelic discrimation using TaqMan assay was used for genotyping MDM2 SNP 309 (rs2279744) as well as MDM4 (rs1563828) and USP7 (rs1529916) polymorphisms. We found significantly higher MDM2 SNP 309 GG genotype and G allele frequencies in the LFS cohort than in controls. Furthermore, median age at first diagnosis was earlier in MDM2 SNP309 GG carriers when compared to other genotypes for both cancers (ACC: age 1 vs. 2 years; BC: age 35 vs. 43 years, respectively), although not statistically different. The allelic and genotypic frequencies for all SNPs did not differ between cancer affected and unaffected carriers, neither between patients with ACC or BC. In conclusion, our results suggest that MDM2 SNP 309 may contribute to the LFL phenotype and also to an earlier age at diagnosis of ACC and BC cancer in carriers of the R337H founder mutation.

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References

  1. Li FP, Fraumeni JF, Mulvihill JJ et al (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48(18):5358–5362

    CAS  PubMed  Google Scholar 

  2. Li FP, Fraumeni JF (1969) Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 71(4):747–752

    Article  CAS  PubMed  Google Scholar 

  3. Li FP, Fraumeni JF (1969) Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst 43(6):1365–1373

    CAS  PubMed  Google Scholar 

  4. Malkin D, Li FP, Strong LC et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250(4985):1233–1238

    Article  CAS  PubMed  Google Scholar 

  5. Palmero EI, Schüler-Faccini L, Caleffi M et al (2008) Detection of R337H, a germline TP53 mutation predisposing to multiple cancers, in asymptomatic women participating in a breast cancer screening program in Southern Brazil. Cancer Lett 261(1):21–25. doi:10.1016/j.canlet200710.044

    Article  CAS  PubMed  Google Scholar 

  6. Custódio G, Parise GA, Kiesel Filho N et al (2013) Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J Clin Oncol 31(20):2619–2626. doi:10.1200/JCO.2012.46.3711

    Article  PubMed  PubMed Central  Google Scholar 

  7. Achatz MI, Olivier M, Le Calvez F et al (2007) The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. Cancer Lett 245(1–2):96–102. doi:10.1016/j.canlet200512.039

    Article  CAS  PubMed  Google Scholar 

  8. Ribeiro RC, Sandrini F, Figueiredo B et al (2001) An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA 98(16):9330–9335. doi:10.1073/pnas.161479898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Giacomazzi J, Selistre SG, Rossi C et al (2013) Li-Fraumeni and Li-Fraumeni-like syndrome among children diagnosed with pediatric cancer in Southern Brazil. Cancer 119(24):4341–4349. doi:10.1002/cncr.28346

    Article  CAS  PubMed  Google Scholar 

  10. 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(1):12–16. doi:10.1038/nsb730

    Article  CAS  PubMed  Google Scholar 

  11. Malkin D (2011) Li-fraumeni syndrome. Genes Cancer 2(4):475–484. doi:10.1177/1947601911413466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137(3):413–431. doi:10.1016/j.cell200904.037

    Article  CAS  PubMed  Google Scholar 

  13. Marcel V, Palmero EI, Falagan-Lotsch P et al (2009) TP53 PIN3 and MDM2 SNP309 polymorphisms as genetic modifiers in the Li-Fraumeni syndrome: impact on age at first diagnosis. J Med Genet 46(11):766–772 doi:10.1136/jmg.2009.066704

    Article  CAS  PubMed  Google Scholar 

  14. Bougeard G, Baert-Desurmont S, Tournier I et al (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. doi:10.1136/jmg.2005.037952

    Article  CAS  PubMed  Google Scholar 

  15. Caleffi M, Ribeiro RA, Duarte Filho DL et al (2009) A model to optimize public health care and downstage breast cancer in limited-resource populations in southern Brazil. (Porto Alegre Breast Health Intervention Cohort). BMC Public Health 9:83. doi:10.1186/1471-2458-9-83

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lee JT, Gu W (2010) The multiple levels of regulation by p53 ubiquitination. Cell Death Differ 17(1):86–92. doi:10.1038/cdd.2009.77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Brooks CL, Li M, Hu M, Shi Y, Gu W (2007) The p53–Mdm2–HAUSP complex is involved in p53 stabilization by HAUSP. Oncogene 26(51):7262–7266. doi:10.1038/sj.onc.1210531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li M, Brooks CL, Kon N, Gu W (2004) A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol Cell 13(6):879–886

    Article  CAS  PubMed  Google Scholar 

  19. Perry ME (2010) The regulation of the p53-mediated stress response by MDM2 and MDM4. Cold Spring Harb Perspect Biol 2(1):a000968. doi:10.1101/cshperspect.a000968

    Article  PubMed  PubMed Central  Google Scholar 

  20. Renaux-Petel M, Sesboüé R, Baert-Desurmont S et al (2014) The MDM2 285G-309G haplotype is associated with an earlier age of tumour 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 

  21. Pinto C, Veiga I, Pinheiro M et al (2009) TP53 germline mutations in Portugal and genetic modifiers of age at cancer onset. Fam Cancer 8(4):383–390. doi:10.1007/s10689-009-9251-y

    Article  CAS  PubMed  Google Scholar 

  22. Tabori U, Nanda S, Druker H, Lees J, Malkin D (2007) Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Cancer Res 67(4):1415–1418. doi:10.1158/0008-5472.CAN-06-3682

    Article  CAS  PubMed  Google Scholar 

  23. Ruijs MW, Schmidt MK, Nevanlinna H et al (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. doi:10.1038/sj.ejhg.5201715

    Article  CAS  PubMed  Google Scholar 

  24. Wu CC, Krahe R, Lozano G et al (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(6):663–673. doi:10.1007/s00439-011-0957-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to Patricia Silva, Diego Paskulin and Cristina Brinckmann Netto for their valuable contributions and support. The authors also wish to thank Flávia Giusti and Rafael Bringhenti from Unidade de Patologia Experimental, Centro de Pesquisa Experimental. This work was supported by fellowships from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and funded in part by Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS-PPSUS) (Grant # 09/0103-0), FAPERGS-PRONEX (Grant #10/0051-9), Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE-HCPA) and CNPQ (Grant #478430/2012-4).

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Authors and Affiliations

  1. Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil

    Gabriel S. Macedo, Igor Araujo Vieira, Fernanda Salles Luiz Vianna, Barbara Alemar, Ana Paula Carneiro Brandalize & Patricia Ashton-Prolla

  2. Genomic Medicine Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil

    Gabriel S. Macedo, Igor Araujo Vieira, Fernanda Salles Luiz Vianna, Barbara Alemar, Ana Paula Carneiro Brandalize & Patricia Ashton-Prolla

  3. Hospital Tacchini, Bento Gonçalves, Rio Grande do Sul, Brazil

    Juliana Giacomazzi

  4. Hospital Moinhos de Vento, Porto Alegre, Rio Grande do Sul, Brazil

    Maira Caleffi

  5. Department of Genetics, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil

    Patricia Ashton-Prolla

  6. Molecular Oncology Research Center, Hospital do Câncer de Barretos, Barretos, São Paulo, Brazil

    Sahlua Miguel Volc, Henrique de Campos Reis Galvão & Edenir Inez Palmero

  7. Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center dr., Rockville, MD, 20850, USA

    Maria Isabel Achatz

  8. Medical Genetics Service, HCPA, Porto Alegre, Rio Grande do Sul, Brazil

    Patricia Ashton-Prolla

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  1. Gabriel S. Macedo
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  2. Igor Araujo Vieira
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  11. Maria Isabel Achatz
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Correspondence to Gabriel S. Macedo.

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Macedo, G.S., Vieira, I.A., Vianna, F.S.L. et al. p53 signaling pathway polymorphisms, cancer risk and tumor phenotype in TP53 R337H mutation carriers. Familial Cancer 17, 269–274 (2018). https://doi.org/10.1007/s10689-017-0028-4

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