p53

p53 is a tumour suppressor gene located on the short arm of chromosome 17. The gene product is a 53-kDa nuclear phosphoprotein involved in transcription regulation and cell growth. Mutations of p53 are the most commonly detected genetic abnormality in human neoplasia¹⁰. Mutations induce a conformal change in the protein, rendering it stablised. For this reason, nuclear overexpression of p53 by immunohistochemistry correlates with p53 mutations. However, in some cases, p53 positivity occurs without detectable mutations^12,13. Lower levels of immunoreactivity may result from stabilisaton of wild type p53 by other mechanisms. Conversely, mutations may occur without detectable levels of p53 protein¹³. In one study of non-Hodgkin lymphoma, point mutations of p53 were only observed in cases that were negative for p21^{WAF1 18}.

Immunostaining for p53 requires appropriate antigen retrieval²¹: immunoreactivity is lost in slides stored at room temperature but is restored by microwave heating²². Different antibodies appear to recognise different epitopes. A range of antibodies (PAb 1801, DO1, DO7, BP53.12 and 421) have been shown to recognise nuclear p53 but only BP53.12 and 421 recognise cytoplasmic p53¹⁹. PAb 1801 and DO7 have been recommended for routine use²⁰.

Immunohistochemical expression

lung carcinoma: 33% of cases¹, 6/19 bronchioloalveolar carcinomas²

	squamous carcinoma	14/257
	adenocarcinoma	28/467
	adenosquamous carcinoma	1/37
	large cell carcinoma	7/117

malignant phyllodes tumours are positive, while benign phyllodes tumours and fibroadenomas are negative.³

• gastric carcinoma: 23/80⁵

• overexpressed in 24/28 cholangiocarcinomas³

• ovarian caner, particularly of serous type. Mutations of p53 have been reported in 8% of low grade and 51% of high grade serous carcinomas of the ovary⁸.

• Cervical high-grade intraepithelial neoplasia with low expression of both p53 and retinoblastoma protein (p53 <15% of nuclei, pRb < 40% of nuclei) is highly likely to persist, in contrast to those cases where one of these cell regulators is strongly expressed⁹.

Diagnostic utility

• concurrent p53 and c-erbB-2 overexpression are indicators of poor prognosis in node-negative breast carcinoma⁶.

• p53 expression is associated with a worse survival in stage I non-small cell carcinoma of lung⁷.

• Overexpression of p53 correlates with recurrence and poor survival in transitonal cell carcinoma of the bladder²³.

• p53 positive follicular lymphomas may be at risk for progression and in this subset aggressive therapy may be warranted¹¹.

• Mutations of p53 may be one mechanism involved in the development of variant forms of mantle cell lymphoma and p53 mutations in mantle cell lymphoma may predict a poor prognosis^14,15,16.

• p53 expression has been found to be a marker of failure to respond to chemotherapy and of poor prognosis in high grade B-cell lymphomas^10,17.

• Differentiation of reactive mesothelial cells (negative) from malignant cells (positive) in effusions.

• Differentiation of type I and type II endometrial carcinoma

References

¹ Greenblatt, M. S., Bennett, W. P., Hollstein, M., Harris, C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis Cancer Res 1994;54:4855-4878.

² McDonald, J. W., Pilgram, T. K. Nuclear expression of p53, p21 and cyclin D1 is increased in bronchioloalveolar carcinoma Histopathology 1999;34:439-446.3Histopathology 1999;34:439-446.

³ Millar, E. K., eretov, J., Marr, P., Sarris, M., Clarke, R. A., Kearsley, J. H., Lee, C. S. Malignant phyllodes tumours of the breast display increased stromal p53 protein expression. Histopathology 1999;34:491-6.

⁴ Arora, D. S., Ramsdale, J., Lodge, J. P., Wyatt, J. I. p53 but not bcl-2 is expressed by most cholangiocarcinomas: a study of 28 cases Histopathology 1999;34:497-501.

⁵ Kume, T., Oshima, K., Shinohara, T., Takeo, H., Yamashita, Y., Shirakusa, T., Kikuchi, M. Low rate of apoptosis and overexpression of bcl-2 in Epstein-Barr virus- associated gastric carcinoma Histopathology 1999;34:502-509.

⁶ Rudolph, P., Alm, P., Olsson, H., Heidebrecht, H. J., 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. Human Pathol 2001;32:311-319.

⁷ Han, H., Landreneau, R. J., Santucci, T. S., Tung, M. Y., Macherey, R. S., Shackney, S. E., Sturgis, C. D., Raab., S. S., Silverman, J. F. Prognostic value of immunohistochemical expressions of p53, HER-2/neu, and bcl-2 in stage I non-small-cell lung cancer. Human Pathol 2002;3:105-110.

⁸ Singer G, Stohr R, Cope L, et al. Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation. Am J Surg Pathol 2005; 29:218-24

⁹ Baak JP, Kruse AJ, Garland SM, et al. Combined p53 and retinoblastoma protein detection identifies persistent and regressive cervical high-grade squamous intraepithelial lesions. Am J Surg Pathol 2005; 29:1062-6

¹⁰ Piris MA, Villuendas R, Martinez JC, et al. p53 expression in non-Hodgkin's lymphomas: a marker of p53 inactivation? Leuk Lymphoma 1995; 17:35-42

¹¹ Sander CA, Yano T, Clark HM, et al. p53 mutation is associated with progression in follicular lymphomas. Blood 1993; 82:1994-2004

¹² Adamson DJ, Thompson WD, Dawson AA, et al. p53 mutation and expression in lymphoma. Br J Cancer 1995; 72:150-4

¹³ Villuendas R, Piris MA, Algara P, et al. The expression of p53 protein in non-Hodgkin's lymphomas is not always dependent on p53 gene mutations. Blood 1993; 82:3151-6 FULL TEXT

¹⁴ Greiner TC, Moynihan MJ, Chan WC, et al. p53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis. Blood 1996; 87:4302-10 FULL TEXT

¹⁵ Hernandez L, Fest T, Cazorla M, et al. p53 gene mutations and protein overexpression are associated with aggressive variants of mantle cell lymphomas. Blood 1996; 87:3351-9 FULL TEXT

¹⁶ Zoldan MC, Inghirami G, Masuda Y, et al. Large-cell variants of mantle cell lymphoma: cytologic characteristics and p53 anomalies may predict poor outcome. Br J Haematol 1996; 93:475-86

¹⁷ Navaratnam S, Williams GJ, Rubinger M, et al. Expression of p53 predicts treatment failure in aggressive non-Hodgkin's lymphomas. Leuk Lymphoma 1998; 29:139-44

¹⁸ Chilosi M, Doglioni C, Magalini A, et al. p21/WAF1 cyclin-kinase inhibitor expression in non-Hodgkin's lymphomas: a potential marker of p53 tumor-suppressor gene function. Blood 1996; 88:4012-20 FULL TEXT

¹⁹ Danks MK, Whipple DO, McPake CR, et al. Differences in epitope accessibility of p53 monoclonal antibodies suggest at least three conformations or states of protein binding of p53 protein in human tumor cell lines. Cell Death Differ 1998; 5:678-86

²⁰ Horne GM, Anderson JJ, Tiniakos DG, et al. p53 protein as a prognostic indicator in breast carcinoma: a comparison of four antibodies for immunohistochemistry. Br J Cancer 1996; 73:29-35

²¹ Imam SA, Young L, Chaiwun B, et al. Comparison of two microwave based antigen-retrieval solutions in unmasking epitopes in formalin-fixed tissue for immunostaining. Anticancer Res 1995; 15:1153-8

²² Shin HJ, Kalapurakal SK, Lee JJ, et al. Comparison of p53 immunoreactivity in fresh-cut versus stored slides with and without microwave heating. Mod Pathol 1997; 10:224-30

²³ Esrig D, Elmajian D, Groshen S, et al. Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 1994; 331:1259-64 FULL TEXT

This page last revised 30.11.2008.

©SMUHT/PW Bishop