Jenkins, G.J.S.; Doak, S.H.; Griffiths, A.P.; Parry, J.M.; Baxter, J.N.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA57
Academic Journal
We have analysed multiple biopsies from over 40 Barrett's patients with a range of pre-malignant conditions, for the presence of p53 mutations. We have employed a molecular technique, the Restriction Site Mutation (RSM) assay to detect the presence of Iow-frequency p53 mutations. The advantage of employing the RSM methodology in this study is that microdissection or flow cytometry of the tissue is not required to enrich the mutant cell population. Instead, the RSM methodology selects mutated sequences at the DNA level. Hence p53 mutations are detectable, even if the cells carrying such mutations are present within an excess of normal cells (sensitivity 1 mutant sequence amongst 10 000 normal sequences). Our results have shown that approximately 30% of our metaplastic and Low Grade Dysplastic Barrett's patients carry p53 mutations. This figure increases to 40% with High Grade Dysplastic patients. These p53 mutations were mainly located in exon 7 of the p53 gene (specifically at codon 248) and resemble the type of mutation (GC to AT) previously shown by ourselves to be induced by oxidative DNA damage. This strengthens the argument that inflammatory mediated release of Reactive Oxygen Species (ROS) may play a role in tumour development in Barrett's oesophagus. Interestingly, our study has identified a subset of Barrett's patients carrying early p53 mutations, before clonal expansion has occurred. The key question we would like answered is—do these patients exhibit an increased rate of adenocarcinoma development compared to the patients without p53 mutations? If so, then the early detection of p53 mutations may represent a useful prognostic marker in Barrett's oesophagus. Only long term follow up of this cohort of patients will answer this question. Through concurrently studying the chromosomal instability of these same Barrett's patients, we have shown a lack of correlation between p53 mutation and chromosomal instability. This contradicts suggestions that...


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