POINT MUTATION OF TUMOR-SUPPRESSOR GENE P53 IN 2 HIGHLY MALIGNANT METASTATIC INSULINOMAS

Background: The objective of the study was to define the molecular alt erations of the tumor suppressor p53 gene that are associated with tum ors of the endocrine pancreas: benign and malignant pancreatic insulin omas. Materials and Methods: The expression of the mutant p53 protein was evaluated immunohistochemically on formalin-fixed paraffin-embedde d tumor sections (29 benign insulinoma tissues, 9 malignant insulinoma s, 2 B-cell hyperplasia specimens, 3 normal pancreatic tissue samples) using monoclonal (Ab-6) antibodies for p53 proteins. Point mutations of the p53 gene were defined by direct sequencing of amplified DNA (as ymmetric PCR, exons 4-9) obtained from one B-cell hyperplasia tissue, 5 benign insulinomas and 5 malignant insulinomas. Results: All of the normal pancreatic and B-cell hyperplasia samples as well as most of th e benign insulinoma tissues (24 out of 29 samples) were negative for t he mutated p53 protein. In malignant insulinomas an overexpression of the p53 protein was found (in 6 out of 9 samples). Point mutation (sin gle base substitution) was detected in two out of five malignant insul inomas. The first tumor harbored a point mutation at codon 151 (CCC->T CC), while the second tumor harbored a mutation at codon 248 (CGG->GGG ). Both patients survived 6 and 8 months respectively, after surgery a nd chemotherapy. No p53 mutations were identified in 5 benign insulino mas and one hyperplasia of the endocrine pancreas. Conclusions: Our re sults suggest a link between p53 gene alterations and the malignant st age of pancreatic insulinomas. Based upon these results, we have concl uded that, in some rare cases, point mutation of the p53 tumor-suppres sor gene may play a role in the development of malignant metastatic in sulinomas.