| 3. |
- Ramel, Stig
(författare)
-
p53 and neoplastic progression in Barrett's esophagus
- 1995
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Barrett's esophagus is a condition in which the normal squamous epithelium is replaced by columnar epithelium as a response to acid reflux. It develops as a complication in 10-20% of patients with gastroesophageal reflux disease. The presence of specialized columnar epithelium is necessary for the development of adenocarcinoma of the esophagus and gastric cardia, the most rapidly increasing malignancies in many western countries. A DNA content/p53 protein multiparameter flow cytometry technique was developed for the analysis of p53 abnormalities in endoscopic biopsies from patients in surveillance for the detection of neoplastic progression in Barrett's esophagus. p53 abnormalities as assessed by p53 protein overexpression and p53 allele deletion (17 pallelic loss) were evaluated in patients with esophageal adenocarcinomas. 92% of patients had17p allelic loss and 67% had p53 protein overexpression indicating a high frequency of p53abnormalities in Barrett's adenocarcinomas. During neoplastic progression in premalignant Barrett's epithelium p53 protein overexpression was detected both in diploid and aneuploid premalignant tissue at increasing frequency in advancing stages of histologic progression to malignancy. Proliferative abnormalities with increased S phase fractions and DNA content abnormalities with the development of aneuploidy are frequently detected in Barrett's esophagus during neoplastic progression. The relationship with p53 inactivation was studied in SV 40 transgenic mice and in p53 deficient mice in vitro and in vivo. Aneuploid and tetraploid cell populations occur after the development of p53 inactivation, indicating a function of p53 in maintaining the diploid state. In mouse embryo fibroblasts in vitro a p53 dependent checkpoint function in mitosis is present, preventing new cell cycle rounds without completion of chromosome segregation in previous mitosis. The relationship between p53 inactivation, aneuploidy, and increased S phase fractions was studied in premalignant Barrett's epithelium in wvo; the results indicating that p53 inactivation may be sufficient for the frequently detected development of aneuploid cell populations, but that p53 inactivation alone is not sufficient to cause the increased S phase fractions, also frequently detected during neoplastic progression in Barrett's esophagus. p53 overexpression, 17p allelic loss, and mutations of the remaining p53 allele were investigated in 12 esophagectomy specimens, all of which were found to have 17p allelic loss and mutations of the remaining 17p allele. p53 overexpression was detected in all but 4 patients. In all cases without p53 overexpression the mutations caused stop codons, presumably with truncated proteins, not detectable by flow cytometry. p53 protein overexpression can be detected in endoscopic biopsies from patients with Barrett's esophagus by multiparameter flow cytometry. The assay may prove useful in detecting patients at high risk of neoplastic progression, but has to be interpreted with caution because some p53 mutations do not cause protein overexpression.
|
|
