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. 1994 Jun;35(6):764–768. doi: 10.1136/gut.35.6.764

Adenocarcinoma arising in Barrett's oesophagus: evidence for the participation of p53 dysfunction in the dysplasia/carcinoma sequence.

R H Hardwick 1, N A Shepherd 1, M Moorghen 1, P V Newcomb 1, D Alderson 1
PMCID: PMC1374874  PMID: 8020801

Abstract

Adenocarcinoma arising in Barrett's oesophagus is often preceded by mucosal dysplasia, but little is currently known about the aetiology or natural history of this dysplasia/carcinoma sequence. To investigate the participation of the tumour suppressor gene p53 in this sequence, an immunohistochemical analysis of p53 protein overexpression, which is known to closely correlate with point mutation of the p53 gene, was conducted in 30 patients with Barrett's adenocarcinoma. Adjacent Barrett's mucosa was dysplastic in 21 (70%) patients. Sixteen (53%) tumours overexpressed p53, 10 of which had adjacent dysplastic Barrett's mucosa. In all 10 patients, this dysplastic mucosa also overexpressed p53, predominantly in areas of high grade compared with low grade dysplasia. In contrast, none of the dysplastic mucosa adjacent to 11 tumours lacking p53 overexpression showed detectable values of p53. These results suggest that p53 dysfunction may participate in the progression from dysplasia to carcinoma in some patients with Barrett's oesophagus.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Altorki N. K., Sunagawa M., Little A. G., Skinner D. B. High-grade dysplasia in the columnar-lined esophagus. Am J Surg. 1991 Jan;161(1):97–100. doi: 10.1016/0002-9610(91)90367-m. [DOI] [PubMed] [Google Scholar]
  2. BARRETT N. R. Chronic peptic ulcer of the oesophagus and 'oesophagitis'. Br J Surg. 1950 Oct;38(150):175–182. doi: 10.1002/bjs.18003815005. [DOI] [PubMed] [Google Scholar]
  3. BARRETT N. R. The lower esophagus lined by columnar epithelium. Surgery. 1957 Jun;41(6):881–894. [PubMed] [Google Scholar]
  4. Baker S. J., Fearon E. R., Nigro J. M., Hamilton S. R., Preisinger A. C., Jessup J. M., vanTuinen P., Ledbetter D. H., Barker D. F., Nakamura Y. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989 Apr 14;244(4901):217–221. doi: 10.1126/science.2649981. [DOI] [PubMed] [Google Scholar]
  5. Baker S. J., Preisinger A. C., Jessup J. M., Paraskeva C., Markowitz S., Willson J. K., Hamilton S., Vogelstein B. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res. 1990 Dec 1;50(23):7717–7722. [PubMed] [Google Scholar]
  6. Bartek J., Iggo R., Gannon J., Lane D. P. Genetic and immunochemical analysis of mutant p53 in human breast cancer cell lines. Oncogene. 1990 Jun;5(6):893–899. [PubMed] [Google Scholar]
  7. Bartek J., Iggo R., Gannon J., Lane D. P. Genetic and immunochemical analysis of mutant p53 in human breast cancer cell lines. Oncogene. 1990 Jun;5(6):893–899. [PubMed] [Google Scholar]
  8. Bennett W. P., Hollstein M. C., He A., Zhu S. M., Resau J. H., Trump B. F., Metcalf R. A., Welsh J. A., Midgley C., Lane D. P. Archival analysis of p53 genetic and protein alterations in Chinese esophageal cancer. Oncogene. 1991 Oct;6(10):1779–1784. [PubMed] [Google Scholar]
  9. Blount P. L., Meltzer S. J., Yin J., Huang Y., Krasna M. J., Reid B. J. Clonal ordering of 17p and 5q allelic losses in Barrett dysplasia and adenocarcinoma. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3221–3225. doi: 10.1073/pnas.90.8.3221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Blount P. L., Ramel S., Raskind W. H., Haggitt R. C., Sanchez C. A., Dean P. J., Rabinovitch P. S., Reid B. J. 17p allelic deletions and p53 protein overexpression in Barrett's adenocarcinoma. Cancer Res. 1991 Oct 15;51(20):5482–5486. [PubMed] [Google Scholar]
  11. Bremner C. G., Lynch V. P., Ellis F. H., Jr Barrett's esophagus: congenital or acquired? An experimental study of esophageal mucosal regeneration in the dog. Surgery. 1970 Jul;68(1):209–216. [PubMed] [Google Scholar]
  12. Cameron A. J., Lomboy C. T. Barrett's esophagus: age, prevalence, and extent of columnar epithelium. Gastroenterology. 1992 Oct;103(4):1241–1245. doi: 10.1016/0016-5085(92)91510-b. [DOI] [PubMed] [Google Scholar]
  13. Casson A. G., Mukhopadhyay T., Cleary K. R., Ro J. Y., Levin B., Roth J. A. p53 gene mutations in Barrett's epithelium and esophageal cancer. Cancer Res. 1991 Aug 15;51(16):4495–4499. [PubMed] [Google Scholar]
  14. Feurle G. E., Helmstaedter V., Buehring A., Bettendorf U., Eckardt V. F. Distinct immunohistochemical findings in columnar epithelium of esophageal inlet patch and of Barrett's esophagus. Dig Dis Sci. 1990 Jan;35(1):86–92. doi: 10.1007/BF01537228. [DOI] [PubMed] [Google Scholar]
  15. Finlay C. A., Hinds P. W., Tan T. H., Eliyahu D., Oren M., Levine A. J. Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life. Mol Cell Biol. 1988 Feb;8(2):531–539. doi: 10.1128/mcb.8.2.531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fléjou J. F., Potet F., Muzeau F., Le Pelletier F., Fékété F., Hénin D. Overexpression of p53 protein in Barrett's syndrome with malignant transformation. J Clin Pathol. 1993 Apr;46(4):330–333. doi: 10.1136/jcp.46.4.330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gannon J. V., Greaves R., Iggo R., Lane D. P. Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific for the mutant form. EMBO J. 1990 May;9(5):1595–1602. doi: 10.1002/j.1460-2075.1990.tb08279.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gannon J. V., Greaves R., Iggo R., Lane D. P. Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific for the mutant form. EMBO J. 1990 May;9(5):1595–1602. doi: 10.1002/j.1460-2075.1990.tb08279.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gillen P., Keeling P., Byrne P. J., West A. B., Hennessy T. P. Experimental columnar metaplasia in the canine oesophagus. Br J Surg. 1988 Feb;75(2):113–115. doi: 10.1002/bjs.1800750208. [DOI] [PubMed] [Google Scholar]
  20. Gusterson B. A., Anbazhagan R., Warren W., Midgely C., Lane D. P., O'Hare M., Stamps A., Carter R., Jayatilake H. Expression of p53 in premalignant and malignant squamous epithelium. Oncogene. 1991 Oct;6(10):1785–1789. [PubMed] [Google Scholar]
  21. Hall P. A., McKee P. H., Menage H. D., Dover R., Lane D. P. High levels of p53 protein in UV-irradiated normal human skin. Oncogene. 1993 Jan;8(1):203–207. [PubMed] [Google Scholar]
  22. Hameeteman W., Tytgat G. N., Houthoff H. J., van den Tweel J. G. Barrett's esophagus: development of dysplasia and adenocarcinoma. Gastroenterology. 1989 May;96(5 Pt 1):1249–1256. doi: 10.1016/s0016-5085(89)80011-3. [DOI] [PubMed] [Google Scholar]
  23. Hamilton S. R., Smith R. R. The relationship between columnar epithelial dysplasia and invasive adenocarcinoma arising in Barrett's esophagus. Am J Clin Pathol. 1987 Mar;87(3):301–312. doi: 10.1093/ajcp/87.3.301. [DOI] [PubMed] [Google Scholar]
  24. Hollstein M. C., Smits A. M., Galiana C., Yamasaki H., Bos J. L., Mandard A., Partensky C., Montesano R. Amplification of epidermal growth factor receptor gene but no evidence of ras mutations in primary human esophageal cancers. Cancer Res. 1988 Sep 15;48(18):5119–5123. [PubMed] [Google Scholar]
  25. Iggo R., Gatter K., Bartek J., Lane D., Harris A. L. Increased expression of mutant forms of p53 oncogene in primary lung cancer. Lancet. 1990 Mar 24;335(8691):675–679. doi: 10.1016/0140-6736(90)90801-b. [DOI] [PubMed] [Google Scholar]
  26. Kaklamanis L., Gatter K. C., Mortensen N., Baigrie R. J., Heryet A., Lane D. P., Harris A. L. p53 expression in colorectal adenomas. Am J Pathol. 1993 Jan;142(1):87–93. [PMC free article] [PubMed] [Google Scholar]
  27. Kastan M. B., Onyekwere O., Sidransky D., Vogelstein B., Craig R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 1991 Dec 1;51(23 Pt 1):6304–6311. [PubMed] [Google Scholar]
  28. Kuerbitz S. J., Plunkett B. S., Walsh W. V., Kastan M. B. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7491–7495. doi: 10.1073/pnas.89.16.7491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Maestro R., Dolcetti R., Gasparotto D., Doglioni C., Pelucchi S., Barzan L., Grandi E., Boiocchi M. High frequency of p53 gene alterations associated with protein overexpression in human squamous cell carcinoma of the larynx. Oncogene. 1992 Jun;7(6):1159–1166. [PubMed] [Google Scholar]
  30. Maltzman W., Czyzyk L. UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol Cell Biol. 1984 Sep;4(9):1689–1694. doi: 10.1128/mcb.4.9.1689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Midgley C. A., Fisher C. J., Bártek J., Vojtesek B., Lane D., Barnes D. M. Analysis of p53 expression in human tumours: an antibody raised against human p53 expressed in Escherichia coli. J Cell Sci. 1992 Jan;101(Pt 1):183–189. doi: 10.1242/jcs.101.1.183. [DOI] [PubMed] [Google Scholar]
  32. Miros M., Kerlin P., Walker N. Only patients with dysplasia progress to adenocarcinoma in Barrett's oesophagus. Gut. 1991 Dec;32(12):1441–1446. doi: 10.1136/gut.32.12.1441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Naef A. P., Savary M., Ozzello L. Columnar-lined lower esophagus: an acquired lesion with malignant predisposition. Report on 140 cases of Barrett's esophagus with 12 adenocarcinomas. J Thorac Cardiovasc Surg. 1975 Nov;70(5):826–835. [PubMed] [Google Scholar]
  34. Nigro J. M., Baker S. J., Preisinger A. C., Jessup J. M., Hostetter R., Cleary K., Bigner S. H., Davidson N., Baylin S., Devilee P. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989 Dec 7;342(6250):705–708. doi: 10.1038/342705a0. [DOI] [PubMed] [Google Scholar]
  35. Pignatelli M., Stamp G. W., Kafiri G., Lane D., Bodmer W. F. Over-expression of p53 nuclear oncoprotein in colorectal adenomas. Int J Cancer. 1992 Mar 12;50(5):683–688. doi: 10.1002/ijc.2910500503. [DOI] [PubMed] [Google Scholar]
  36. Purdie C. A., O'Grady J., Piris J., Wyllie A. H., Bird C. C. p53 expression in colorectal tumors. Am J Pathol. 1991 Apr;138(4):807–813. [PMC free article] [PubMed] [Google Scholar]
  37. Ramel S., Reid B. J., Sanchez C. A., Blount P. L., Levine D. S., Neshat K., Haggitt R. C., Dean P. J., Thor K., Rabinovitch P. S. Evaluation of p53 protein expression in Barrett's esophagus by two-parameter flow cytometry. Gastroenterology. 1992 Apr;102(4 Pt 1):1220–1228. [PubMed] [Google Scholar]
  38. Reid B. J., Blount P. L., Rubin C. E., Levine D. S., Haggitt R. C., Rabinovitch P. S. Flow-cytometric and histological progression to malignancy in Barrett's esophagus: prospective endoscopic surveillance of a cohort. Gastroenterology. 1992 Apr;102(4 Pt 1):1212–1219. [PubMed] [Google Scholar]
  39. Reid B. J., Haggitt R. C., Rubin C. E., Roth G., Surawicz C. M., Van Belle G., Lewin K., Weinstein W. M., Antonioli D. A., Goldman H. Observer variation in the diagnosis of dysplasia in Barrett's esophagus. Hum Pathol. 1988 Feb;19(2):166–178. doi: 10.1016/s0046-8177(88)80344-7. [DOI] [PubMed] [Google Scholar]
  40. Reid B. J., Weinstein W. M., Lewin K. J., Haggitt R. C., VanDeventer G., DenBesten L., Rubin C. E. Endoscopic biopsy can detect high-grade dysplasia or early adenocarcinoma in Barrett's esophagus without grossly recognizable neoplastic lesions. Gastroenterology. 1988 Jan;94(1):81–90. doi: 10.1016/0016-5085(88)90613-0. [DOI] [PubMed] [Google Scholar]
  41. Riddell R. H., Goldman H., Ransohoff D. F., Appelman H. D., Fenoglio C. M., Haggitt R. C., Ahren C., Correa P., Hamilton S. R., Morson B. C. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol. 1983 Nov;14(11):931–968. doi: 10.1016/s0046-8177(83)80175-0. [DOI] [PubMed] [Google Scholar]
  42. Robertson C. S., Mayberry J. F., Nicholson D. A., James P. D., Atkinson M. Value of endoscopic surveillance in the detection of neoplastic change in Barrett's oesophagus. Br J Surg. 1988 Aug;75(8):760–763. doi: 10.1002/bjs.1800750813. [DOI] [PubMed] [Google Scholar]
  43. Rodrigues N. R., Rowan A., Smith M. E., Kerr I. B., Bodmer W. F., Gannon J. V., Lane D. P. p53 mutations in colorectal cancer. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7555–7559. doi: 10.1073/pnas.87.19.7555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Saubier E. C., Gouillat C., Samaniego C., Guillaud M., Moulinier B. Adenocarcinoma in columnar-lined Barrett's esophagus. Analysis of 13 esophagectomies. Am J Surg. 1985 Sep;150(3):365–369. doi: 10.1016/0002-9610(85)90080-7. [DOI] [PubMed] [Google Scholar]
  45. Shivji K. K., Kenny M. K., Wood R. D. Proliferating cell nuclear antigen is required for DNA excision repair. Cell. 1992 Apr 17;69(2):367–374. doi: 10.1016/0092-8674(92)90416-a. [DOI] [PubMed] [Google Scholar]
  46. Skinner D. B., Walther B. C., Riddell R. H., Schmidt H., Iascone C., DeMeester T. R. Barrett's esophagus. Comparison of benign and malignant cases. Ann Surg. 1983 Oct;198(4):554–565. doi: 10.1097/00000658-198310000-00016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Spechler S. J., Goyal R. K. Barrett's esophagus. N Engl J Med. 1986 Aug 7;315(6):362–371. doi: 10.1056/NEJM198608073150605. [DOI] [PubMed] [Google Scholar]
  48. Spechler S. J., Robbins A. H., Rubins H. B., Vincent M. E., Heeren T., Doos W. G., Colton T., Schimmel E. M. Adenocarcinoma and Barrett's esophagus. An overrated risk? Gastroenterology. 1984 Oct;87(4):927–933. [PubMed] [Google Scholar]
  49. Tytgat G. N., Hameeteman W. The neoplastic potential of columnar-lined (Barrett's) esophagus. World J Surg. 1992 Mar-Apr;16(2):308–312. doi: 10.1007/BF02071538. [DOI] [PubMed] [Google Scholar]
  50. Vogelstein B., Fearon E. R., Hamilton S. R., Kern S. E., Preisinger A. C., Leppert M., Nakamura Y., White R., Smits A. M., Bos J. L. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525–532. doi: 10.1056/NEJM198809013190901. [DOI] [PubMed] [Google Scholar]
  51. Vogelstein B., Kinzler K. W. p53 function and dysfunction. Cell. 1992 Aug 21;70(4):523–526. doi: 10.1016/0092-8674(92)90421-8. [DOI] [PubMed] [Google Scholar]
  52. Winters C., Jr, Spurling T. J., Chobanian S. J., Curtis D. J., Esposito R. L., Hacker J. F., 3rd, Johnson D. A., Cruess D. F., Cotelingam J. D., Gurney M. S. Barrett's esophagus. A prevalent, occult complication of gastroesophageal reflux disease. Gastroenterology. 1987 Jan;92(1):118–124. [PubMed] [Google Scholar]
  53. Wynford-Thomas D. P53 in tumour pathology: can we trust immunocytochemistry? J Pathol. 1992 Apr;166(4):329–330. doi: 10.1002/path.1711660402. [DOI] [PubMed] [Google Scholar]
  54. Zwas F., Shields H. M., Doos W. G., Antonioli D. A., Goldman H., Ransil B. J., Spechler S. J. Scanning electron microscopy of Barrett's epithelium and its correlation with light microscopy and mucin stains. Gastroenterology. 1986 Jun;90(6):1932–1941. doi: 10.1016/0016-5085(86)90264-7. [DOI] [PubMed] [Google Scholar]

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