CLINICAL IMPLICATIONS OF P53 GENE MUTATION IN THE PROGRESSION OF BARRETTS EPITHELIUM TO INVASIVE ESOPHAGEAL CANCER

The p53 tumor suppressor gene has been implicated in human esophageal tumorigenesis, and mutations are reported in primary esophageal adenoc arcinomas and associated Barrett's epithelium. To evaluate the potenti al clinical significance of this molecular genetic marker in the progr ession of Barrett's epithelium to invasive esophageal cancer, we studi ed 20 patients with Barrett's epithelium, 10 of whom had an associated adenocarcinoma. p53 gene mutations were screened using polymerase cha in reaction (PCR)/single-strand conformation polymorphism (SSCP) analy sis and p53 oncoprotein distribution by immunohistochemistry. Point mu tations were localized to exons 5 and 7 of the p53 gene, previously re cognized as ''hot spots.'' p53 gene mutations and immunoreactivity wer e detected in 7 of 10 patients with primary esophageal adenocarcinomas and in 6 patients with associated Barrett's epithelium, 3 of whom had high-grade dysplasia. Little correlation was observed between p53 pos itivity and clinicopathologic findings or outcome, although two patien ts with p53 mutations subsequently developed second primary cancers. O f 10 patients with Barrett's epithelium alone, 6 had p53 mutations, wi th mild or no dysplasia histologically, suggesting that p53 gene mutat ion may be an early event in progression to invasive cancer. No patien t has developed invasive cancer to date, with a median follow-up of 8 years. These studies further implicate the p53 gene in the Barrett's e pithelium-tocarcinoma sequence. Prospective surveillance studies incor porating molecular analysis of the p53 gene are warranted to further e valuate p53 as a predictor of patients at high risk for developing mal ignancy.