Primary Motility  Disorders of the  Esophagus
 The Esophageal
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 The
 Esophagogastric  Junction
 Barrett's
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OESO©2015
 
Volume: Barrett's Esophagus
Chapter: Markers
 

Can the incidence of p53 mutations be overestimated on the basis of the level of expression of p53 protein?

S.C. Evans, A.G. Casson (Halifax)

To understand the reported discordance between p53 mutation rates and protein expression, one must consider the relationship between a gene (DNA) and its protein product.

The p53 gene spans 20 kilobases on the short arm of chromosome 17. It comprises 11 exons encoding a nuclear phosphoprotein of 393 aminoacid residues. p53 is the most frequently altered gene in human cancer [1]. It functions as a tumor suppressor gene, interacting with additional genes involved in cell-cycle regulation, and has a key role in controlling cellular proliferation, apoptosis (programmed cell death), DNA synthesis and repair [2-4]. Our original description [5] of p53 mutations in Barrett's epithelium and primary esophageal adenocarcinomas has now been confirmed by several other investigators [6-31]. Studying the nature and frequency of p53 mutations may reveal possible etiologic factors in the molecular pathogenesis of human cancer [32]. For esophageal carcinoma, there is recent evidence from our laboratory to support geneenvironment interactions as modifiers of individual risk from exogenous carcinogens [27]. Furthermore, p53 may have prognostic importance for patients with esophageal adenocarcinomas, as p53 mutations were recently found to be associated with reduced postoperative survival [22, 27, 30].

The p53 protein is normally present in cells at very low concentrations and accumulates by reacting to internal cues. In response to cell stress which might lead to DNA damage, p53 is activated by a conformational change and begins the transcription of genes that are involved in cell cycle arrest, allowing internal repair to take place [33]. p53 also acts as a transcription factor for several downstream genes, including MDM2 (murine double minute 2 gene). In normal cells, MDM2 protein binds p53 protein, and following transport out of the cell nucleus, tags it for ubiquitin-mediated proteolysis in a negative feedback loop.

Cell nuclear p53 protein accumulation (with consequent deregulation and loss of function) may therefore result from several interrelated mechanisms, including p53 gene mutations (thought to be the commonest mechanism) [3]; reduced transcription, or mutation, of MDM2; or a deficiency in the ubiquitin pathway preventing p53 destruction.

Other factors reported to interfere with p53 degradation are ARF, ATM, the SV40 large T antigen, and other, as yet unidentified, cellular proteins.

References

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2. Harris C. Structure and function of the p5

3. tumor suppressor gene:clues for rational cancer therapeutic strategies. J Natl Cancer Inst 1996;88:1442-1455. 3. Blagosklonny M. p53 from complexity to simplicity: mutant p53 stability, gain-of-function, and dominant-negative effect. FASEB J 2000;14:1901-1907.

4. Levrero M, De Laurenzi V, Costanzo A, Sabatini S, Gong J, Wang J, Melino G. The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J Cell Sci 2000;113:1661-1670.

5. Casson AG, Mukhopadhyay T, Cleary KR, Ro J, Levin B, Roth JA. p53 gene mutations in Barrett's epithelium and esophageal cancer. Cancer Res 1991;51:4495-4499.

6. Blount P, Ramel S, Raskind W, Haggitt R, Sanchez C, Dean P, Rabinovitch P, Reid B. 17p allelic deletions and p53 protein overexpression in Barrett's adenocarcinoma. Cancer Res 1991;51:5482-5486.

7. Bennett W, Hollstein M, He A, Zhu S, Resau J, Trump B, Metcalf R, Welsh J, Midgley C, Lane D, Harris C. Archival analysis of p53 genetic and protein alterations in Chinese esophageal cancer. Oncogene 1991;6:1779-1784.

8. Bennett W, Hollstein M, Metcalf R, Welsh J, He A, Zhu S, Kusters I, Resau J, Trump B, Lane D, Harris C. p53 mutation and protein accumulation during multistage human esophageal carcinogenesis. Cancer Res 1992;52:6092-6097.

9. Wagata T, Shibagaki I, Imamura M, Shimada Y, Toguchida J, Yandell D, Ikenaga M, Tobe T, Ishizaki M. Loss of 17p, mutation of the p53 gene, and overexpression of p53 protein in esophageal squamous cell carcinomas. Cancer Res 1993;53:846-850.

10. Flejou J, Potet F, Muzeau F, Le Pelletier F, Henin D. Overexpression of p53 protein in Barrett's syndrome with malignant transformation. J Clin Pathol 1993;46:330-333.

11. Younes M, Lebovitz R, Lechago L, Lechago J. p53 protein accumulation in Barrett's metaplasia, dysplasia, and carcinoma:a follow-up study. Gastroenterology 1993;105:1637-1642.

12. Hamelin R, Flejou J, Muzeau F, Potet F, Laurent-Puig P, Thomas G. TP53 gene mutation and p53 protein immunoreactivity in malignant and premalignant Barrett's esophagus. Gastroenterology 1994:107:1012-1018.

13. Neshat K, Sanchez C, Galipeau P, Blount P, Levine D, Joslyn G, Reid B. p53 mutations in Barrett's adenocarcinoma and high-grade dysplasia. Gastroenterology 1994;106:1589-1595.

14. Jones D, Davidson A, Summers C, Murray G, Quinlan D. Potential application of p53 as an intermediate biomarker in Barrett's esophagus. Ann Thorac Surg 1994;57:598-603.

15. Symmans P, Linehan J, Brito M, Filipe I. p53 expression in Barrett's oesophagus, dysplasia, and adenocarcinoma using antibody DO-7. J Pathol 1994;173:221-226.

16. Hardwick R, Sheperd N, Moorghen M, Newcomb P, Alderson P. Adenocarcinoma arising in Barrett's oesophagus: evidence for the participation of p53 dysfunction in the dysplasia/carcinoma sequence. Gut 1994;35:764-776.

17. Flejou J, Muzeau F, Potet F, Le Pelletier F, Henin D. Overexpression of p53 tumor suppressor gene product in esophageal and gastric carcinomas. Pathol Res Pract 1994;190:1141-1148.

18. Krishnadath K, van Blankenstein M, Tilanus H, Prognostic value of p53 in Barrett's oesophagus. Eur J Gastroenterol Hepatol 1995;7:81-84.

19. Krishnadath K, Tilanus H, van Blankenstein M, Bosman F, Mulder A. Accumulation of p53 protein in normal, dysplastic, and neoplastic Barrett's oesophagus. J Pathol 1995;175:175-180.

20. Galiana C, Loranzo J, Bancel B, Nakazawa H, Yamasaki H. High frequency of Ki-ras amplification and p53 gene mutations in adenocarconomas of the human esophagus. Mol Carcinogenesis 1995;14:286-293.

21. Duhaylongsod F, Gottfried M, Iglehart D, Vaughn A, Wolfe W. The significance of c-erb B-2 and p53 immunoreactivity in patients with adenocarcinoma of the esophagus. Ann Surg 1995;221:677-684.

22. Casson A, Kerkvliet N, O'Malley F. Prognostic value of p53 protein in esophageal adenocarcinoma. J Surg Oncol 1995;60:5-11.

23. Audrezet M, Robaszkiewicz M, Mercier B, Nousbaum J, Hardy E, Bail J, Volant A, Lozac P, Gouerou H, Ferec C. Molecular analysis of the TP53 gene in Barrett's adenocarcinoma. Hum Mutat 1996;7:109-113.

24. Schneider P, Casson A, Levin B, Garewal H, Hoelscher A, Becker K, Dittler H, Cleary K, Troster M, Siewert J, Roth J. Mutations of p53 in Barrett's esophagus and Barrett's cancer: a prospective study of ninety-eight cases. J Thorac Cardiovasc Surg 1996;111:323-333.

25. Moskaluk C, Heitmiller R, Zahurak M, Schwab D, Sidransky D, Hamilton S. p53 and p21 (waf1/cip1/sdi1) gene products in Barrett's esophagus and adenocarcinoma of the esophagus and esophagogastric junction. Hum Pathol 1996;27:1211-1220.

26. Coggi G, Bosari S, Roncalli M, Graziana D, Bossi P, Viale G, Buffa R, Ferraro S, Piazza M, Blandamura S, Bonavina L, Peracchia A. p53 protein accumulation and p53 gene mutation in esophageal carcinoma. Cancer 1997;79:425-432.

27. Casson A, Tammermagi M, Eskandarian S, Redston M, McLaughlin J, Ozcelik H. p53 alterations in oesophageal cancer: association with clinicopathological features, risk factors, and survival. Mol Pathol 1998;51:71-79.

28. Wu T, Watanabe T, Heitmiller R, Zahurak M, Forastiere A, Hamilton S. Genetic alterations in Barrett's esophagus and adenocarcinomas of the esophagus and esophagogastric junction region. Am J Pathol 1998;153:287-294.

29. Gleeson C, Sloan J, McManus D, Maxwell P, Arthur K, Ritchie A, Russell S. Comparison of p53 and DNA content abnormalities in adenocarcinomas of the oesophagus and gastric cardia. Br J Cancer 1998;77(2):277-286.

30. Schneider P, Stoeltzing O, Roth J, Hoelscher A, Wergerer S, Mizumoto S, Becker K, Dittler H, Fink U, Siewert J. p53 mutational status improves estimation of prognosis in patients with curatively resected adenocarcinomas in Barrett's esophagus. Clin Cancer Res 2000;.6:3153-158.

31. Werner M, Flejou J, Hainaut P, Hofler H, Lambert R, Keller G, Stein H. Adenocarcinoma of the oesophagus. In: Hamilton S, Aaltonen L, eds. Pathology & genetics of tumours of the digestive system. Lyon: IARC Press, 2000:20-26.

32. Hainaut P, Vanakangas K. p53 as a sensor of carcinogenic exposures: mechanisms of p53 protein induction and lessons from p53 gene mutations. Pathol Biol 1997;45:833-844.

33. Prives C, Hall P. The p53 pathway. J Pathol 1999;187:112-126.


Publication date: August 2003 OESO©2015