Kim Meejeong, Lee Miseon, Lee Ahwon, Choi Byung-Ock, Park Woo-Chan, Kim Sung Hun, Lee Jieun, Kang Jun
Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Cancer Research Institute, The Catholic University of Korea, Seoul, Korea.
Histopathology. 2025 Aug;87(2):299-309. doi: 10.1111/his.15453. Epub 2025 Mar 31.
Immunohistochemical (IHC) staining of p53 is a potential marker for TP53 mutations in various cancers. However, criteria for predicting TP53 mutations in triple-negative breast cancer (TNBC) using p53 IHC staining are not yet established. We aim to correlate p53 IHC expression patterns with TP53 mutation status in TNBC.
A total of 113 TNBC cases were analysed for p53 IHC staining 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 patterns were categorized as nuclear overexpression (n = 58), null pattern (n = 40), wildtype (n = 15), cytoplasmic (n = 5), and subclonal (n = 5). The cutoff for predictive p53 nuclear overexpression was determined to be 80%, which strongly correlated with TP53 mutations. Notably, p53 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. P53 overexpression was significantly linked to missense mutations within the DNA-binding domain (DBD) exhibiting gain-of-function (GOF) or dominant-negative effect (DNE). Cases exhibiting cytoplasmic expression correlated with nonsense or frameshift mutations in the DBD, nuclear localization signal (NLS), or splice sites. Cases with subclonal p53 staining patterns were 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.
p53的免疫组织化学（IHC）染色是多种癌症中TP53突变的潜在标志物。然而，使用p53 IHC染色预测三阴性乳腺癌（TNBC）中TP53突变的标准尚未确立。我们旨在将p53 IHC表达模式与TNBC中的TP53突变状态相关联。
共对113例TNBC病例进行p53 IHC染色模式分析，并使用全外显子测序检测体细胞TP53突变。利用美国国立癌症研究所（NCI）的TP53数据库确定TP53突变的功能特性。p53 IHC模式分为核过表达（n = 58）、无表达模式（n = 40）、野生型（n = 15）、胞质型（n = 5）和亚克隆型（n = 5）。预测p53核过表达的临界值确定为80%，这与TP53突变密切相关。值得注意的是，p53过表达对错义或框内突变的阳性预测值（PPV）为83%，而无表达模式对检测无义、移码或剪接突变的PPV为85%。p53过表达与DNA结合域（DBD）内表现出功能获得（GOF）或显性负效应（DNE）的错义突变显著相关。表现为胞质表达的病例与DBD、核定位信号（NLS）或剪接位点的无义或移码突变相关。具有亚克隆p53染色模式的病例与TP53突变有关。
我们的数据提出了用于解释TNBC中p53免疫染色模式的新定义标准，有可能实现对TP53突变类型及其功能影响的预测。
