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

Familial Cancer volume 17, pages 269–274 (2018)Cite this article

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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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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  8. Sahlua Miguel Volc
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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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  • DOI: https://doi.org/10.1007/s10689-017-0028-4

Keywords

  • P53
  • R337H
  • Polymorphism
  • Li-Fraumeni syndrome