Characterization of p53 p.T253I as a pathogenic mutation underlying Li-Fraumeni Syndrome

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Pediatric adrenocortical carcinoma (ACC) can be associated with Li-Fraumeni Syndrome (LFS).
• Germline TP53 mutations are a common cause of LFS.
• The TP53 c.758C>T (p.T253I) mutation was identified in a pediatric ACC patient.

Purpose of the Study:

• To investigate the functional impact of the novel TP53 p.T253I mutation.
• To determine if the p.T253I mutation is associated with Li-Fraumeni Syndrome.
• To characterize the pathogenicity of the p.T253I variant.

Main Methods:

• Stable transduction of p53-/- HEK293 cells with wild-type (WT) or mutant p53 (T253I, C176Y, R213X) tagged with GFP.
• Analysis of p53 and MDM2 protein levels.
• Assessment of DNA damage response, DNA binding, and transactivation capacity.

Main Results:

• The p.T253I mutation led to increased p53 protein levels and decreased MDM2 levels, indicating impaired regulation.
• T253I p53 exhibited reduced DNA damage responsiveness.
• Diminished DNA binding and transactivation capabilities were observed for T253I p53 compared to WT p53.

Conclusions:

• The TP53 p.T253I variant represents a pathogenic mutation.
• This mutation impairs critical tumor suppressor functions of p53.
• The p.T253I mutation may predispose individuals to LFS-associated tumors.