Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Mucosa
 The
 Esophagogastric  Junction
 Barrett's
 Esophagus

  Browse by Author
  Browse by Movies
OESO©2015
 
Volume: The Esophagogastric Junction
Chapter: Esophageal columnar metaplasia (Barrett s esophagus)
 

What is the relationship between p53 gene aberrations and other genetic events in the progression from benign Barrett's mucosa to carcinoma?

J.F. Fléjou (Paris)

Barrett's mucosa is a privileged model for the study of the sequence of events that lead to the onset of cancer. In contrast to the colon, where the pre-neoplastic lesion usually presents itself in the form of an adenomatous polyp which is resected as soon as it is discovered, radical treatment is only given for Barrett's esophagus once cancer has developed or possibly at the onset of high grade dysplasia, since surgical excision is the only treatment available and in view of the morbidity and mortality associated with this operation. It is thus possible, by monitoring the patients through repeated endoscopy and biopsy, to establish the sequence of morphological and genetic events that lead to the development of cancer. What is more, in addition to the cancer, the esophagectomy specimens carry a whole spectrum of pre-neoplastic lesions in the neighboring Barrett's mucosa making it possible to study the various stages of the neoplastic process in a single specimen.

From the morphological point of view, the neoplastic process evolves through various stages of dysplasia of increasing grade which are often difficult to diagnose. Studies of cell proliferation and DNA ploidy have demonstrated the frequency and early nature of certain anomalies, especially the increase in the number of cells engaged in the cell cycle (in phase G1, and then phases S and G2) and the high frequency of development of cell clones with an abnormal DNA content (DNA aneuploids) thereby confirming the hypothesis formulated by Nowell in 1976 that cancer develops because of an acquired genetic instability which predisposes to the development of abnormal cell clones that accumulate genetic aberrations.

In common with other authors, we have shown that there is extremely frequent involvement of abnormalities in the tumor suppressor gene p53 [1] situated on the short arm of chromosome 17, which is involved at an early stage of this process before onset of the other most frequent genetic aberration in cancer associated with Barrett's esophagus, the loss of alleles on the long arm of chromosome 5 [2]. The tumor suppresser gene or genes that are inactivated at this level in Barrett's carcinoma remain to be identified with certainty. Other genetic alterations, that are frequent in colonic cancer, appear to be much rarer or even absent in cancer associated with Barrett's esophagus, such as changes in the K-ras oncogene [3], and the onset of effects of acquired genetic instability related to the non-repair of DNA replication errors [4]. These data can be used to construct a model of the neoplastic progression of Barrett's mucosa as proposed by Neschat et al. [5]. According to this model, the earliest markers of cancer risk are changes in the cell cycle and in the DNA content of tumor cells, and aberrations in the p53 gene. Most of these latter aberrations have the advantage of being detectable by simple immunohistochemical investigation of the expression of p53 protein [6] which may become a useful technique for the monitoring of patients with Barrett's esophagus.

References

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

2. Blount PL, Meltzer SJ, Yin J, Huang Y, Krasna MJ, Reid BJ. Clonal ordering of 17p and 5q allelic losses in Barrett's dysplasia and adenocarcinoma. Proc Natl Acad Sci USA 1993;90:3221-3225.

3. Lagorce C, Fléjou JF, Muzeau F, Hénin D, Potet F. Absence of c-Ki-ras gene mutation in malignant and premalignant Barrett's esophagus. J Clin Pathol, Clin Molecular Pathol 1995;48:M198-M199.

4. Gleeson CM, Sloan JM, McGuigan JA, Ritchie AJ, Weber JL, Russell SEH. Ubiquitous somatic alterations at microsatellite alleles occur infrequently in Barrett's-associated esophageal adenocarcinoma. Cancer Res 1996;56:259-263.

5. Neshat K, Sanchez CA, Galipeau PC, Cowan DS, Ramel S, Levine DS, Reid BJ. Barrett's esophagus: a model of human neoplastic progression. Cold Spring Harbor Symposia on Quantitative Biology 1994;59:577-583.

6. Fléjou JF, Volant A, Diebold MD, Sagan C, Vissuzaine C, Croué A, Robaszkiewicz M, Potet F, et le Groupe d'étude de l'œsophage de Barrett. Surexpression de la protéine p53 et endobrachyœsophage : un événement fréquent et précoce au cours de la carcinogenèse. Gastroenterol Clin Biol 1995;19:475-481.


Publication date: May 1998 OESO©2015