Correlating p53 immunostaining patterns with somatic TP53 mutation and functional properties of mutant p53 in triple-negative breast cancer

Abstract

Immunohistochemical (IHC) staining pattern of p53 has been recognized as a potential surrogate marker for TP53 mutations across diverse cancer types. Nevertheless, interpretative criteria for p53 IHC expression as a predictive tool for TP53 mutation in triple-negative breast cancer (TNBC) have not been established yet. A total of 113 TNBC cases were analyzed for p53 IHC pattern and somatic TP53 mutation using whole exome sequencing. Functional properties of TP53 mutations were determined using the National Cancer Institute (NCI) TP53 database. P53 IHC staining patterns fell into three distinct categories: nuclear overexpression (n = 58), absence of staining indicating null pattern (n = 40), and wild-type expression (n = 15). The cutoff for predictive p53 nuclear overexpression was determined to be 80%. This threshold correlated strongly with TP53 mutations. Notably, nuclear overexpression had a positive predictive value (PPV) of 83% for missense or in-frame mutations, while the null pattern showed a PPV of 85% for detecting nonsense, frameshift, or splicing mutations. Furthermore, p53 overexpression was significantly linked to missense mutations within the DNA-binding domain (DBD) exhibiting gain-of-functon(GOF) or dominant-negative effect (DNE). Cases exhibiting both nuclear overexpression and cytoplasmic expression (n = 5) were correlated with nonsense or frameshift mutations affecting the DBD, NLS, or splice sites. Subclonal p53 staining patterns observed in 7 cases were found to be associated with TP53 mutations. Our study proposes newly defined criteria for interpreting p53 immunostaining patterns in TNBC, potentially allowing for the prediction of TP53 mutation types and their functional implications.