MUTATIONS OF P53 IN BARRETTS-ESOPHAGUS AND BARRETTS-CANCER - A PROSPECTIVE-STUDY OF 98 CASES

We had previously identified p53 mutations in Barrett's esophagus and therefore began a multiinstitutional study to determine their signific ance as a marker for malignancy, Ninety-eight patients from four insti tutions were studied, Forty-eight patients (37 men and 11 women, mean age 56.2 years) had Barrett's esophagus with metaplasia or dysplasia b ut no evidence of malignancy at a mean follow-up of 2.2 years, Barrett 's esophagus was classified as metaplasia with no evidence of dysplasi a in 32 patients, as low-grade dysplasia in 13, and as high-grade dysp lasia in three, The other 50 patients (46 men and four women, mean age 60.2 years) had adenocarcinoma arising in Barrett's esophagus, Tissue s from normal stomach or esophagus, humor, and Barrett's esophagus wer e obtained for deoxyribonucleic acid analysis by endoscopic biopsy fro m patients with Barrett's esophagus or cancer or during operations on some patients with Barrett's cancer, Exons 5 through 9 of the p53 gene were studied for mutations by single-strand conformational polymorphi sm analysis after polymerase chain reaction amplification, Mutations d etected by single-strand conformational polymorphism analysis were con firmed by deoxyribonucleic acid sequencing, None of the tissue samples from patients with Barrett's esophagus alone and no dysplasia or low- grade dysplasia had any p53 mutations, but one of the three patients w ith high-grade dysplasia and no evidence of invasive malignancy did ha ve a p53 mutation, Of the 50 patients with Barrett's cancer, however, 23 (46%) had p53 mutations in Barrett's epithelium, tumors, or both, T wenty of these patients had p53 mutations in the tumor only (n = 16) o r in both tumor and Barrett's epithelium (n = 4), suggesting that the mutation plays a direct role in carcinogenesis, Mutations in Barrett's epithelium were found in one patient in the group without malignancy and in seven patients with cancer (one with no dysplasia, two with low -grade dysplasia, and five with high-grade dysplasia), In three patien ts with cancer, mutations occurred only in Barrett's epithelium, sugge sting that such mutations may also be a marker for genomic instability , Mutations were predominantly found in exons 5, 7, and 8, and transit ions from guanine to adenine were the most frequent changes, Mutations of p53 are clearly involved in the pathogenesis of Barrett's cancer f or a subset of patients (46%), and the fact that we could detect mutat ions in premalignant Barrett's epithelium supports the hypothesis that p53 mutations may be a useful marker for patients at increased risk f or development of invasive cancer.