The detection of early p53 mutations in non-dysplastic Barrett's tissues.

GJS Jenkinsa, SH Doakb, AP Griffithsc, JM Parryb and JN Baxtera

aMolecular Pathology Group, Swansea Clinical School, University of Wales Swansea, SA28PP U.K. bSchool of Biological Sciences, University of Wales Swansea, SA28PP U.K. cDepartment of Pathology, Morriston Hospital, Swansea SA6 6NL U.K.

Aim: Barrett's oesophagus is a pre-malignant condition affecting up to 1% of Western populations. Due to the large numbers of people presenting with this condition and the relatively small number of these people developing cancer (<10%) it is essential to discriminate early between low risk and high risk cancer patients. This would allow the more effective targeting of cancer patients and lead to a reduction in the health costs associated with the regular screening of low risk patients. Methods: In an effort to develop diagnostic markers to stratify patients with respect to cancer risk, we have been analysing biopsies from Barrett's patients with a range of pre-malignant conditions, for early p53 mutations. We have employed a molecular technique, the Restriction Site Mutation (RSM) assay to detect the presence of these early p53 mutations. The RSM assay selects mutated sequences at the molecular level, hence microdissection or flow cytometry of the tissue is not required to enrich the mutant cell population. P53 mutations are detectable, even if the cells carrying such mutations are present within an excess of normal cells (sensitivity 1 mutant sequence amongst 10,000-100,000 normal sequences). Results: Our results have shown that approximately 20-30% of metaplastic and dysplastic Barrett's biopsies carry p53 mutations. These p53 mutations were mainly located in exon 7 of the p53 gene (specifically at codon 248) and resemble the type of mutation induced by oxidative DNA damage (GC to AT transitions). Conclusion: Our study has identified a subset of Barrett's patients carrying rare p53 mutations, 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 diagnostic marker in Barrett's oesophagus.

KEY WORDS: Barrett's esophagus, screening, cancer.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Predictive Markers.