mdm-2 expression correlates with wild-type p53 status in esophageal adenocarcinoma

Several immunohistochemical studies showed that p53 protein is expressed in 50 to 80% of esophageal adenocarcinomas (EAs). Mutations of this tumor sup pressor gene are present in 40 to 70% of EAs, so it is possible that p53 ex pression might occur as a result of mechanisms other than gene mutation. Th e human homologue of the murine double minute-2 gene (mdm-2) is a known reg ulator of p53 activity, and its expression results in stabilization of the wild-type p53 protein and loss of its tumor suppressor function. In this st udy, we evaluated the frequency of mdm-2 amplification and expression in EA and investigated the relationship between mdm-2 expression and p53 mutatio n. Thirty-three resection specimens of EAs and associated Barrett's esophag us were evaluated by immunohistochemical methods for p53 and mdm-2 expressi on. Sixteen of these cases were also evaluated for p53 mutations with use o f polymerase chain reaction, single-strand conformational polymorphism, and DNA sequencing and for mdm-2 amplification with a differential polymerase chain reaction-based amplification analysis. Overexpression of p53 was pres ent in 23 EAs (70%), and 18 EAs (55%) overexpressed mdm-2, p53 mutation was observed in 7 (43%) of 16 cases, whereas mdm-2 gene amplification was not detected in any. To summarize, we found substantial discordance of p53 immu nohistochemical features and mutation in EA. Significant expression of mdm- 2 occurred only in cases with wild-type p53, whereas all of the cases with p53 mutation showed little if any expression of mdm-2, Also, mdm-2 expressi on in cases with p53 overexpression but with-out p53 mutation exceeded mdm- 2 expression in cases with p53 overexpression and p53 gene mutation. In cas es without p53 mutation, overexpression of mdm-2 occurred in 50% of cases a nd might be responsible for stabilization of p53 protein and possible loss of tumor suppressor function.