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

The tumour suppressor TP53 (tumor protein p53) is a master regulator of cell cycle, DNA repair, and apoptosis, and its mutation is a hallmark of cancer, with individual mutations exerting distinct effects on tumour biology. Despite accounting for ~7% of all TP53 variants, splice site mutations remain the least studied class, and their functional and clinical consequences are poorly understood. We analyzed 25,058 TP53 variants (18,562 somatic; 6496 germline) to characterize the frequency, molecular impact, transcriptional effects, genomic instability, and clinical outcomes of splice mutations. These alterations showed distinct distributions and substitution patterns between germline and somatic contexts and were frequently associated with copy number alterations, reduced TP53 mRNA, and variable protein expression. Transcriptomic profiling identified two transcriptional phenotypes: one with global suppression of canonical p53 target genes and another with mixed activation and repression independent of tumour type. Genomic instability was elevated in a subset of splice-mutant tumours, correlating with increased relapse risk, while other splice mutations showed lower instability but divergent clinical outcomes, including unexpectedly poor prognoses. Our findings fill a critical knowledge gap, defining the biological and clinical spectrum of TP53 splice site mutations and highlighting their potential as prognostic biomarkers and therapeutic targets in precision oncology.