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Functional evaluation of germline TP53 variants identified in Brazilian families at-risk for Li-Fraumeni syndrome.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
    • Publication Information:
      Original Publication: London : Nature Publishing Group, copyright 2011-
    • Subject Terms:
      Li-Fraumeni Syndrome*/genetics ; Tumor Suppressor Protein p53*/genetics ; Germ-Line Mutation* ; Genetic Predisposition to Disease* ; Mutation, Missense*; Humans ; Brazil ; Proto-Oncogene Proteins c-mdm2/genetics ; Female ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; Male ; Cell Cycle Proteins/genetics ; Cell Line, Tumor ; Transcriptional Activation/genetics ; GADD45 Proteins
    • Abstract:
      Germline TP53 pathogenic variants can lead to a cancer susceptibility syndrome known as Li-Fraumeni (LFS). Variants affecting its activity can drive tumorigenesis altering p53 pathways and their identification is crucial for assessing individual risk. This study explored the functional impact of TP53 missense variants on its transcription factor activity. We selected seven TP53 missense variants (c.129G > C, c.320A > G, c.417G > T, c.460G > A, c,522G > T, c.589G > A and c.997C > T) identified in Brazilian families at-risk for LFS. Variants were created through site-directed mutagenesis and transfected into SK-OV-3 cells to assess their transcription activation capabilities. Variants K139N and V197M displayed significantly reduced transactivation activity in a TP53-dependent luciferase reporter assay. Additionally, K139N negatively impacted CDKN1A and MDM2 expression and had a limited effect on GADD45A and PMAIP1 upon irradiation-induced DNA damage. Variant V197M demonstrated functional impact in all target genes evaluated and loss of Ser15 phosphorylation. K139N and V197M variants presented a reduction of p21 levels after irradiation. Our data show that K139N and V197M negatively impact p53 functions, supporting their classification as pathogenic variants. This underscores the significance of conducting functional studies on germline TP53 missense variants classified as variants of uncertain significance to ensure proper management of LFS-related cancer risks.
      (© 2024. The Author(s).)
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    • Grant Information:
      Productivity Fellowships Conselho Nacional de Desenvolvimento Científico e Tecnológico; Productivity Fellowships Conselho Nacional de Desenvolvimento Científico e Tecnológico; Productivity Fellowships Conselho Nacional de Desenvolvimento Científico e Tecnológico; 2018/25118-8 Fundação de Amparo à Pesquisa do Estado de São Paulo; 2018/25118-8 Fundação de Amparo à Pesquisa do Estado de São Paulo; 25000.056766/2015-64 Ministério da Saúde
    • Contributed Indexing:
      Keywords: TP53; DNA repair; Functional analysis; Li–Fraumeni syndrome; Transcription factor; Variants of uncertain significance
    • Accession Number:
      0 (Tumor Suppressor Protein p53)
      0 (TP53 protein, human)
      EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
      EC 2.3.2.27 (MDM2 protein, human)
      0 (Cyclin-Dependent Kinase Inhibitor p21)
      0 (GADD45A protein, human)
      0 (CDKN1A protein, human)
      0 (Cell Cycle Proteins)
      0 (GADD45 Proteins)
    • Publication Date:
      Date Created: 20240726 Date Completed: 20240728 Latest Revision: 20240814
    • Publication Date:
      20250114
    • Accession Number:
      PMC11282216
    • Accession Number:
      10.1038/s41598-024-67810-3
    • Accession Number:
      39060302