1. ¹Department of Pathology, Otto-von-Guericke University, Magdeburg, Germany
2. ²Department of General Surgery, Otto-von-Guericke University, Magdeburg, Germany
3. ³Department of Gastroenterology and Hepatology, Otto-von-Guericke University, Magdeburg, Germany

Correspondence: Thomas Günther, M.D., Department of Pathology, Otto-von-Guericke University, Leipziger Strasse 44, 39120 Magdeburg, Germany. e-mail: Thomas.Guenther@Medizin.Uni-Magdeburg.de; fax: 0049-391-67-15818

Accepted 6 December 1999.

Abstract

Mdm2, localized on chromosome 12, is considered a negative regulator of p53 function and seems to play a role in the pathogenesis of a variety of tumors. The mdm2 amplification in advanced-stage gastric carcinoma has not yet been investigated.

Mdm2 amplification was determined in 43 gastric carcinomas, and the genetic results were correlated with mdm2 protein expression, p53 alterations, and clinicopathologic data. The tumors were classified according to Lauren: 20 intestinal-type tumors, 19 tumors of diffuse growth inclusive of a primary small cell carcinoma, and 4 carcinomas with mixed differentiation. Staging was based on the pTNM classification system. Mdm2 and p53 were demonstrated by immunohistology on formalin-fixed and paraffin-embedded tumor tissue. The mdm2 oncogene was amplified by nonradioactive hybridization of tumor DNA with an mdm2 cDNA probe. The Southern blots were evaluated densitometrically. For p53 mutation screening, we analyzed the highly conservative regions of the p53 gene (exons 4 to 8) with the use of the polymerase chain reaction–single-strand conformation polymorphism technique. Polymerase chain reaction products with band shifting were directly sequenced.

Mdm2 amplification was demonstrated in 18 tumors (41.8%). The mdm2 gene was amplified more frequently in carcinomas with a diffuse growth pattern. Gastric carcinomas of the intestinal type, however, showed a higher frequency of p53 alterations. There was no statistical significance of the molecular genetic and immunohistologic results of the mdm2/p53 status to staging as well as to age and sex of the patients.

The mdm2/p53 pathway is a part of the carcinogenesis of gastric carcinoma. Only approximately 20% of gastric carcinomas failed to show mdm2 and/or p53 alterations. The upregulation of the mdm2 oncogene and the accompanying inactivation of the tumor suppressor gene 53 seem to play a role above all in carcinomas of the diffuse type.