These results indicate that p53 gene alterations contribute to the development of esophageal adenocarcinoma and precede the development of invasive carcinoma in patients with Barrett's esophagus.
Our results indicate that wild-type p53 protein levels increase after treatment with each of these drugs via either post-translational and/or translational mechanisms and that this increase in wild-type p53 appears to be required for effective chemotherapeutic growth control of gastric/esophageal adenocarcinoma cells.
Esophageal adenocarcinoma is increasing in frequency in the western world at an alarming rate and is unique because there is a clear metaplasia (Barrett's mucosa)/ dysplasia/carcinoma sequence. p53 malfunction arises as an early event in this carcinogenic process and has been demonstrated in patients with nondysplastic Barrett's metaplasia.
The two types of tumor differed in the prevalence of TP53 mutations (31% in ADCC and 50% in ADCE) and of MDM2 gene amplification (19% in ADCC and 4% in ADCE), and in the pattern of expression of cytokeratin 7 (positive in 100% of ADCE and in 41% of ADCC) and cytokeratin 13 (positive in 81% of ADCE and in 36.5% of ADCC).
The incidence of oesophageal adenocarcinoma is rising; to date, no susceptibility genes have been identified. p73, a novel p53 homologue, maps to chromosome 1p36, a region commonly deleted in oesophageal cancers. p73 shares some p53-like activity, but in addition, may also play a role in gastrointestinal epithelial inflammatory responses.
The purpose of this study was to assess more accurately the incidence and types of p53 mutations in Barrett's esophagus (BE) with and without dysplasia and in esophageal adenocarcinoma, using pure preparations of epithelial cells obtained by laser capture microdissection (LCM).
The size of a clone with a p16 lesion is not a significant predictor of esophageal adenocarcinoma when we controlled for p53 loss of heterozygosity status.
Sequence analysis of the p53 coding sequence in three EA cell lines (Seg-1, Bic-1, and Flo-1) that retain Fas protein within the cytoplasm, demonstrated that Seg-1 contained wt-p53, but mutations were found in Flo-1 and Bic-1 cell lines.
This observation suggests that TP53 gene mutation may be a relatively late event in the progression from nondysplastic Barrett's esophagus to adenocarcinoma of esophagus.
In the present study, 132 samples of esophageal adenocarcinoma and 58 samples of normal esophageal tissue were investigated for MGMT hypermethylation status by methylation-specific real-time PCR and results were correlated to clinicopathological parameters, patient's survival, p53 mutation and expression of p53 protein and MGMT protein.
17p (TP53) loss of heterozygosity (LOH) has been reported to be predictive of progression from Barrett's esophagus to esophageal adenocarcinoma, but the mechanism by which TP53 LOH develops is unknown.
A combination of 17p LOH, 9p LOH, and DNA content abnormalities provided better EA risk prediction than any single TP53, CDKN2A, or DNA content lesion alone.
To investigate the role of NO in esophageal adenocarcinoma (EADC), we studied patterns of p53 mutations, expression of inducible nitric oxide synthase (iNOS) and the tissue accumulation of nitrotyrosine (NTS), a stable reaction product of NO and a marker for cellular protein damage, in human premalignant and malignant esophageal epithelia.
Mutations in p53 were identified in 75% (30/40) of the esophageal adenocarcinoma. p53 protein overexpression, detected by immunohistochemistry, was found in 58% (23/40) of the esophageal adenocarcinoma, 60% (6/10) of Barrett's esophagus with high-grade dysplasia, 12% (1/8) of Barrett's esophagus with low-grade dysplasia, and 0% of Barrett's esophagus without dysplasia.
No significant differences were found for patients with EADC who had p53 mutations (n = 21) compared with patients with wild-type p53 (n = 33) with respect to selected clinicopathologic variables (age, gender, tumor grade, stage, alcohol, or tobacco consumption) and dietary intake of folate or vitamin B(6).