P53 Mutations in Barrett's adenocarcinoma and high-grade dysplasia

Abstract

Background/Aims: Allelic losses of chromosome 17p and overexpression of p53 protein have been reported in Barrett's adenocarcinomas. This study aimed to determine the stage in which p53 mutations arise in neoplastic progression in Barrett's esophagus and their relationship to the clonal evolution of cancer. Methods: Fourteen patients with high-grade dysplasia, adenocarcinoma, or both arising in Barrett's esophagus were evaluated. Flow cytometric cell sorting was used to obtain purified populations of neoplastic cells for analysis of p53 mutations. DNA was extracted, and exons 5 through 9 of thep53 gene were amplified by polymerase chain reaction. Amplified DNA was sequenced and analyzed by automated sequencing. Results: Nine of the 14 patients had p53 mutations. Six of the 9 patients had regions of high-grade dysplasia that could be evaluated; all 6 had p53 mutations in high-grade dysplasia. In 3 patients, the same p53 mutations were found in both high-grade dysplasia and adenocarcinoma. All 14 patients had aneuploidy. In 4 patients, diploid cell populations could also be evaluated for p53 mutations; 3 of the 4 patients had p53 mutations in diploid cell populations. In 2 patients, the same p53 mutation was found in multiple aneuploid cell populations within a cancer. Conclusions: p53 mutations occur frequently in Barrett's adenocarcinomas. They develop in diploid cell populations. The same p53 mutations are then found in aneuploid cell populations in high-grade dysplasia, in cancer, and in multiple aneuploid cell populations in cancer.