The p53 gene is a tumour suppressor gene located on the short arm of chromosome 17 (17p13.1). The p53 (phospho-)protein (p53), 53 kDa, is expressed in the nuclei of all normal cells, but usually not immunohistochemically detectable due to a very short half-life (10-20 min.). p53 is called the guardian of the genome. By binding to DNA, the normal p53 negatively regulates cell growth and division. In case of DNA damage, p53 arrests the cell cycle until repair has taken place. In case repair is not possible, p53 induces apoptosis. p53 acts a two checkpoints in the cell cycle, between G1 and S, and between G2 and M, respectively.
Normal (wild type - WT) p53 is accumulated in damages cells, e.g., in virus infections, where the protein is bound (e.g., to protein E6 of human papilloma virus) and prevented from break down. Also the over-expression of mdm2 protein arrests the p53 turnover. In such cases the protein may be immunohistochemically stainable not only in the nuclei but also in the cytoplasm. p53 binding decreases its control with cell proliferation and increases genetic instability, leading to neoplastic transformation.
A combination of genetic events that affects both alleles (e.g., deletion of one allele and point mutation of the other) causes loss of WT p53. Mutated p53 shows impaired DNA-binding and, consequently, release from cell cycle checkpoint control following DNA damage, thereby increasing genomic instability and promoting gene amplification. Mutated p53 has a prolonged half-life or is stabilized resulting in immunohistochemically stainable accumulation.
Changes in the p53 gene is one of the most common genetic changes associated with cancer, being implicated in a wide range of tumour types. In many types, more than half of the tumours are p53+. Often p53 positivity is correlated with high grade lesions (e.g., carcinoma of breast, prostate and bladder, malignant lymphoma) and poor prognosis. A few tumour types are characterised by strong p53 expression in most cases, e.g., uterine papillary serous carcinoma.
Analysis of p53 in dysplastic and neoplastic states is a powerful tool to provide molecular information on the oncogenic process. Marked p53 accumulation (at least 20-50% of the cells stained) largely reflects an underlying mutation. In many tumour types (e.g., malignant lymphomas), p53 appear to have prognostic significance , but the data are often conflicting. In dysplastic lesions, e.g., in Barrett's esophagus, p53 expression increases the risk of carcinoma. p53 may be helpful in differentiating between certain reactive and neoplastic lesions, e.g., reactive urothelial changes (patchy and weak) v. urothelial neoplasia (~60% pos.); reactive mesothelial proliferation (~10% pos.) v. malignant mesothelioma (~60% pos.). p53 has been advocated to distinguish between reactive astrocytosis and astrocytoma. However, some inflammatory lesions, like progressive multifocal leukoencephalopathy may also give rise to p53 positive astrocytes. In classification of uterine carcinoma, p53 should be included in the panel. p53 positivity is a parameter in the identification of tubal intraepithelial carcinoma associated with pelvic serous carcinoma.
Tonsil and appendix are the most recommendable external positive and negative tissue controls. As a guideline for an accurate p53 IHC test more than 20% of germinal centre B-cells must show a weak to moderate nuclear staining reaction, while less than 10% of the mantle zone B-cells should be demonstrated in tonsil. In appendix, dispersed epithelial cells in the basal parts of the crypts must show a weak to moderate nuclear staining reaction, while the luminal epithelial cells must be negative.
In addition, it has to be emphasized, that stromal cells, lymphocytes and endothelial cells in the clinical samples are essential as internal positive tissue controls especially for carcinomas with TP53 mutations causing absence and loss of p53 expression in the tumour cells.
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