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<p>Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in the <i>TP53</i> tumour suppressor gene, which encodes the multifunctional transcription factor p53. p53 is the most commonly mutated protein in human cancer, with the majority occurring within the DNA-binding domain, often disrupting transcriptional activity and resulting in a loss-of-function. Here, we characterise the novel p53<sub>N263Tfs*7</sub> truncated mutant, identified as a germline mutation from a patient with LFS who developed breast cancer. Functional assays revealed a partial loss-of-function across key cellular processes, including proliferation, cell death, cell motility, and transcriptional transactivation. This mutant lacked a dominant-negative effect, distinguishing it from common DNA-binding domain missense mutations. Our findings demonstrate that oncogenesis in LFS can be driven by partial impairment of functional p53, rather than dominant-negative or gain-of-function mutations alone. This underscores the clinical significance of recognising subtle <i>TP53</i> variants for the refined molecular classification and clinical prediction of cancer risk in <i>TP53</i> mutation carriers.</p>

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Characterisation of a novel p53 mutation (p53N263Tfs*7) associated with li-fraumeni syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Francesca M. Wright,
  • Mariela Vasileva-Slaveva,
  • Angel Yordanov,
  • Ivan Ivanov,
  • Zornitsa Gorcheva,
  • Andrea Mohr,
  • Gareth S. A. Wright,
  • Greg N. Brooke,
  • Metodi V. Metodiev

摘要

Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in the TP53 tumour suppressor gene, which encodes the multifunctional transcription factor p53. p53 is the most commonly mutated protein in human cancer, with the majority occurring within the DNA-binding domain, often disrupting transcriptional activity and resulting in a loss-of-function. Here, we characterise the novel p53N263Tfs*7 truncated mutant, identified as a germline mutation from a patient with LFS who developed breast cancer. Functional assays revealed a partial loss-of-function across key cellular processes, including proliferation, cell death, cell motility, and transcriptional transactivation. This mutant lacked a dominant-negative effect, distinguishing it from common DNA-binding domain missense mutations. Our findings demonstrate that oncogenesis in LFS can be driven by partial impairment of functional p53, rather than dominant-negative or gain-of-function mutations alone. This underscores the clinical significance of recognising subtle TP53 variants for the refined molecular classification and clinical prediction of cancer risk in TP53 mutation carriers.