An accurate assessment of p53's functional status is critical for cancer genomic medicine. However, there is a significant challenge in identifying tumors with non-mutational p53 inactivations that are not detectable through DNA sequencing. These undetected cases are often misclassified as p53-normal, leading to inaccurate prognosis and downstream association analyses. To address this issue, we built the support vector machine (SVM) models to systematically reassess p53's functional status in TP53 wild-type (TP53 WT) tumors from multiple The Cancer Genome Atlas (TCGA) cohorts. Cross-validation demonstrated the good performance of the SVM models with a mean area under curve (AUC) of 0.9822, precision of 0.9747, and recall of 0.9784. Our study revealed that a significant proportion (87%-99%) of TP53 WT tumors actually have compromised p53 function. Additional analyses uncovered that these genetically intact but functionally impaired (termed as predictively reduced function of p53 or TP53 WT-pRF) tumors exhibited genomic and pathophysiologic features akin to TP53 mutant tumors: heightened genomic instability and elevated levels of hypoxia. Clinically, patients with TP53 WT-pRF tumors experienced significantly shortened overall survival or progression-free survival compared to those with predictively normal function of p53 (TP53 WT-pN) tumors, and these patients also displayed increased sensitivity to platinum-based chemotherapy and radiation therapy.
