p53

(p53 protein)
Assessments
Characteristics
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.
Neoplasms
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.
Application
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.
Controls
Tonsil and colon are the most recommendable positive and negative tissue controls. In tonsil, 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 colon, 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.
Selected references
Beenken SW, Bland KI. Biomarkers for breast cancer. Minerva Chir. 2002 Aug;57(4):437-48. Campling BG, el-Deiry WS. Clinical implications of p53 mutations in lung cancer. Methods Mol Med. 2003;75:53-77. Flejou JF. Barrett's oesophagus: from metaplasia to dysplasia and cancer. Gut. 2005 Mar;54 Suppl 1:i6-12. Hensel M, Schneeweiss A, Sinn HP, Egerer G, Solomayer E, Haas R, Bastert G, Ho AD. P53 is the strongest predictor of survival in high-risk primary breast cancer patients undergoing high-dose chemotherapy with autologous blood stem cell support. Int J Cancer. 2002 Jul 20;100(3):290-6. Kurtkaya-Yapicier O, Scheithauer BW, Hebrink D, James CD. p53 in nonneoplastic central nervous system lesions: an immunohistochemical and genetic sequencing study. Neurosurgery. 2002 Nov;51(5):1246-54; discussion 1254-5. Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, Garber JE, Cramer DW, Crum CP. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol. 2006 Feb;30(2):230-6. Munro AJ, Lain S, Lane DP. P53 abnormalities and outcomes in colorectal cancer: a systematic review. Br J Cancer. 2005 Feb 14;92(3):434-44. Rudolph P, Alm P, Olsson H, Heidebrecht HJ, Ferno M, Baldetorp B, Parwaresch R. Concurrent overexpression of p53 and c-erbB-2 correlates with accelerated cycling and concomitant poor prognosis in node-negative breast cancer. Hum Pathol. 2001 Mar;32(3):311-9. Tanaka N, Sugihara K, Odajima T, Mimura M, Kimijima Y, Ichinose S. Oral squamous cell carcinoma: electron microscopic and immunohistochemical characteristics. Med Electron Microsc. 2002 Sep;35(3):127-38.
13.06.13 - MV/LE