TP53 Splice Mutations Have Tumour-Independent Effects on Genomic Stability and Prognosis: An In Silico Study.

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• The tumor suppressor TP53 (tumor protein p53) is crucial for cell cycle regulation, DNA repair, and apoptosis.
• TP53 mutations are common in cancer, but splice site variants remain poorly understood.
• Splice site mutations constitute approximately 7% of all TP53 variants.

Purpose of the Study:

• To characterize the frequency, molecular impact, transcriptional effects, genomic instability, and clinical outcomes of TP53 splice site mutations.
• To fill a critical knowledge gap regarding the biological and clinical significance of these variants.

Main Methods:

• Analysis of 25,058 TP53 variants (18,562 somatic, 6496 germline).
• Characterization of variant distributions, molecular impact, and transcriptional effects.
• Assessment of genomic instability and correlation with clinical outcomes.

Main Results:

• TP53 splice mutations exhibit distinct germline and somatic patterns, often linked to copy number alterations and altered TP53 expression.
• Transcriptomic profiling revealed two distinct phenotypes: global suppression or mixed regulation of p53 target genes.
• Elevated genomic instability in a subset of splice-mutant tumors correlated with increased relapse risk, while others showed divergent clinical outcomes.

Conclusions:

• TP53 splice site mutations have a defined biological and clinical spectrum.
• These mutations can serve as prognostic biomarkers.
• TP53 splice variants represent potential therapeutic targets in precision oncology.