In-frame germline TP53 variant impairs p53 oligomerization and predisposes to cancer

Area of Science:

• Genetics
• Molecular Biology
• Oncology

Background:

• Germline loss-of-function variants in the TP53 gene are responsible for Li-Fraumeni syndrome (LFS), a hereditary cancer predisposition syndrome.
• LFS is characterized by an increased risk of developing various cancers at an early age, including sarcomas, adrenocortical carcinoma, and breast cancer.
• While mutations in the DNA binding domain of p53 are common, alterations in the oligomerization domain can also lead to LFS with varying penetrance.

Purpose of the Study:

• To identify and functionally characterize a novel germline TP53 variant associated with Li-Fraumeni syndrome.
• To investigate the impact of the identified variant on p53 protein function, including transcriptional activity and tetramer formation.
• To assess the cellular response of the variant to MDM2 inhibition.

Main Methods:

• Identification of a novel germline in-frame deletion TP53 variant (c.1015_1023del, p.E339_F341del) through family-based genetic analysis.
• Functional assays in human cells and a yeast model to evaluate the variant's impact on p53 transcriptional activity.
• Assessment of p53 tetramer formation and cellular sensitivity to MDM2 inhibition using nutlin-3.

Main Results:

• The novel TP53 variant p.E339_F341del, a deletion in the oligomerization domain, was identified in a family with early-onset breast cancer and other malignancies.
• Functional testing revealed that the p.E339_F341del variant significantly impairs the transcriptional activity of p53 in both human and yeast systems.
• The impaired transcriptional activity correlated with defects in p53 tetramer formation and rendered cells insensitive to MDM2 inhibition by nutlin-3.

Conclusions:

• The germline TP53 variant c.1015_1023del (p.E339_F341del) encodes a transcriptionally inactive p53 protein.
• This variant promotes Li-Fraumeni syndrome with a high-penetrant cancer phenotype, highlighting the importance of the p53 oligomerization domain in tumor suppression.
• The findings contribute to a deeper understanding of LFS pathogenesis and the functional consequences of TP53 alterations.