Identify Non-mutational p53 Functional Deficiency in Human Cancers

Journal article

An accurate assessment of p53's functional statuses is critical for cancer genomic medicine. However, there is a significant challenge in identifying tumors with non-mutational p53 inactivation which is 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 statuses in TP53 wild-type (TP53WT) tumors from multiple The Cancer Genome Atlas (TCGA) cohorts. Cross-validation demonstrated the good performance of the SVM models with a mean area under the receiver operating characteristic curve (AUROC) of 0.9822, precision of 0.9747, and recall of 0.9784. Our study revealed that a significant proportion (87%-99%) of TP53WT tumors actually had compromised p53 function. Additional analyses uncovered that these genetically intact but functionally impaired (termed as predictively reduced function of p53 or TP53WT-pRF) tumors exhibited genomic and pathophysiologic features akin to TP53-mutant tumors: heightened genomic instability and elevated levels of hypoxia. Clinically, patients with TP53WT-pRF tumors experienced significantly shortened overall survival or progression-free survival compared to those with predictively normal function of p53 (TP53WT-pN) tumors, and these patients also displayed increased sensitivity to platinum-based chemotherapy and radiation therapy.

Authors: Li, Q; Zhang, Y; Luo, S; Zhang, Z; Oberg, AL

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Oxford University Press
• Journal: Genomics, Proteomics and Bioinformatics
• Volume: 22
• Issue: 5
• Pages: qzae064
• Publication date: 2024-09-26
• DOI: 10.1093/gpbjnl/qzae064
• EISSN: 2210-3244
• ISSN: 1672-0229
• Language: English
• Keywords: Mutation; Computational biology; Gene; Biology; Genetics; Cancer research