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 suppressor gene are present in 40 to 70% of EAs, so it is possible that p53 expression might occur as a result of mechanisms other than gene mutation. The human homologue of the murine double minute-2 gene (mdm-2) is a known regulator of p53 activity, and its expression results in stabilization of the wild-type p53 protein and loss of its tumor suppressor function. In this study, we evaluated the frequency of mdm-2 amplification and expression in EA and investigated the relationship between mdm-2 expression and p53 mutation. Thirty-three resection specimens of EAs and associated Barrett's esophagus were evaluated by immunohistochemical methods for p53 and mdm-2 expression. Sixteen of these cases were also evaluated for p53 mutations with use of 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 present 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 immunohistochemical 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 expression in cases with p53 overexpression but without p53 mutation exceeded mdm-2 expression in cases with p53 overexpression and p53 gene mutation. In cases without p53 mutation, overexpression of mdm-2 occurred in 50% of cases and might be responsible for stabilization of p53 protein and possible loss of tumor suppressor function.
Soslow
R A
RA
Department of Pathology, New York Presbyterian Hospital-Weill Medical College, Cornell University, New York City 10021, USA. rasoslow@mail.med.cornell.edu
Altorki
N K
NK
Yang
G
G
Xie
D
D
Yang
C S
CS
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001471:Barrett Esophagus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000032:analysis; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D007124:Immunoenzyme Techniques; D008679:Metaplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D017931:DNA Primers; D004273:DNA, Neoplasm; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2