J Cancer Res Clin Oncol (1992) 118:474-479 C~cer ~esearch Clinical 9 9 Springer-Verlag 1992 Expression of Her2/neu oncogene product p185 in correlation to clinicopathological and prognostic factors of gastric carcinoma *' * * J. Jaehne 1, C. Urmacher 2, H.T. Thaler 3, H. Friedlander-Klar 3, C. Cordon-Cardo 2, and H.J. Meyer 1 1 Clinic for Abdominal and Transplantation Surgery, Medical School Hannover, Konstanty-Gutschow-Str. 8, W-3000 Hannover 61, Federal Republic of Germany 2 Departments of Pathology and 3 Biostatistics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Received 18 December 1991/Accepted 27 February 1992 Summary. The expression of the Her2/neu gene product p185 was retrospectively analyzed in 58 patients with gas- tric carcinoma. The results were correlated to various clinicopathological and prognostic factors. Positive membrane staining for p185 could be detected in 38% of the patients (22/58). Membrane staining was significantly greater in well and moderately differentiated tumors of the intestinal type when compared with poorly differenti- ated lesions and carcinomas of the diffuse type (P < 0.01). Positive membrane staining did not correlate with site and tumor stage, but TI lesions had less membrane stain- ing than more advanced primary tumors. Overall sur- vival showed no difference between p185-positive and negative cases. Multivariate analysis defined a subgroup of curatively resected patients with stage III and IV dis- ease that had a statistically significant poorer survival when p185 was overexpressed (P=0.005). Overex- pression of the Her2/neu product p185 appears to be as- sociated with intestinal-type gastric carcinoma and may help in identifying a subset of patients at increased risk for shorter survival. Key words: Her2/neu oncogene product p185 - Gastric carcinoma - Clinicopathological variables - Prognosis Introduction Alterations of protooncogenes either in gene structure or gene copy presumably play an etiological role in carcino- genesis. One such gene with great potential for malignant * This work was supported by a research fellowship from the Deut- sche Forschungsgemeinschaft (Ja 509/2-1) and by a grant from the Wells foundation ** Dedicated to Professor Dr. R. Pichlmayr on the occasion of his 60th birthday Abbreviations: PBS, phosphate-buffered saline; BSA, bovine serum albumin Offprint requests to: J. Jaehne transformation is the Her2/neu gene located on chromo- some 17q21 (Fukushige et al. 1986; Di Fiore et al. 1987). This gene generates a messenger RNA of 4.8 • 103 bases (kb), which encodes a transmembrane glycoprotein (p185) with a molecular mass of 185 kDa (Schechter et al. 1984; Akiyama et al. 1986). p185 is similar, but distinct from epidermal growth factor receptor (Yamamoto et al. 1986), and its proposed ligand is a 30-kDa factor (Lupu et al. 1990). Amplification of the Her2/neu gene has been demon- strated in a variety of adenocarcinomas, such as those fn the breast and colon (Yokota et al. 1986; Tal et al. 1988; Gutman et al. 1989). It has been shown in breast carci- noma that amplification of this gene is strongly corre- lated with survival (Slamon et al. 1987; Slamon et al. 1989 a). In gastric carcinoma Her2/neu was found to be amplified in 10% of the tumors (Houldsworth et al. 1990). Since amplification of the Her2/neu gene results in elevated levels of Her2/neu mRNA and its protein prod- uct (Slamon et al. 1989 a), immunohistochemical studies using antibodies against the oncogene product sub- sequently showed overexpression in 19% of gastric adenocarcinoma (Falck and Gullick 1989). In contrast to breast carcinoma, however, there are only a few reports about the prognostic significance of the Her2/neu protein product, indicating that it may well be of prognostic rel- evance (Yonemura et al. 1991 a, b). In the present study we therefore analyzed alterations of the Her2/neu protein product in gastric carcinoma and correlated the results with different clinicopathological data and with the prognosis of the patients. Materials and methods Patients and tissue samples. A group of 58 patients with resectable primary adenocareinoma of the stomach was retrospectively ana- lyzed. The tumors to be studied by immunohistochemistry were ran- domly selected on the basis of tissue availability and excellent tissue preservation defined as non-necrotic cancerous lesion. The median age of the patients was 66.5 years (range: 25-83 years), 36 were male and 22 were female (male : female ratio = 1 : 0.6), All patients were