Microsatellite Instability and Overexpression of p53 Protein in Human Gastric Carcinomas: Clinicopathologic Implications and Prognosis

ABSTRACT

PURPOSE: Striking advances in molecular analysis of human gastrointestinal cancer indicate that malignant transformation of normal epithelial cells is necessary for a multiple process associated with an accumulation of multiple gene abnormalities affecting DNA repair genes, oncogenes, and tumor suppressor genes. Microsatellites are short repeated DNA sequences scattered throughtout the human genome. Microsatellite instability (MSI) may underlie the etiology of mutistep gastric carcinogenesis. The altered microsatellites observed in tumors with DNA replication error (RER) phenotypes may represent the expression of such an instability. METHODS: Fourty-four gastrectomy specimens from patients with gastric carcinomas were examined in an attempt to study the molecular mechanisms of gastric carcinogenesis, to assess the prognostic value of genetic instability and mutant p53 protein expressions, and to evaluate a possible interaction between genetic instability and mutation of the p53 protein. Pairs of tumor and adjacent normal tissue were amplified at six microsatellite loci, and their sizes were compared. Tumors with microsatellite sizes different from their normal tissue sizes for at least two of the tested loci were designated as MSI. Mutations of the p53 protein were investigated with immunohistochemical staining. RESULTS: MSI was detected in 33.3% of the early gastric carcinomas and in 41.4% of the advanced gastric carcinomas with an overall frequency of 38.6%. The frequency of MSI tended to occur more frequently in poorly differentiated adenocarcinomas. The frequency of MSI was not significanctly different with repect to age, sex, size of tumor, location of tumor, depth of invasion,lymph-node metastasis, and Helicobacter pylori infection. Mutation of the p53 protein was detected in 40.0% of the early gastric carcinomas and in 48.3% of the advanced gastric carcinomas with an overall frequency of 45.5%. Mutation of the p53 protein occurred more frequently in positive lymph-node metastasis and advanced stage. There were no correlations between microsatellite instability and p53 expression.The overall 5-year surval rate was 56.6%. The 5-year survival rate of patients with MSI was 58.5%, and that for patient with mutant p53 protein was 42.8%. Gastric cancers with MSI showed a relatively good prognosis, but the result was not statistically significant (p=0.976), and patients with mutant p53 protein had a statistically significant poorer prognosis (p=0.049). CONCLUSION: These findings suggest that both MSI and mutation of the p53 protein are present in early and later stages of malignant transformation. Based on this study, investigations with a larger number of patients are needed to establish their roles as prognostic indicators in gastric cancer.