title: Multiple genetic alterations in malignant metastatic insulinomas.
abstract: Proto-oncogenes, growth factors/receptors, and tumour suppressor genes were analysed in malignant metastatic insulinomas. Normal pancreas showed only a moderate immunoreaction for c-myc proto-oncogene and a strong reaction for insulin. Benign insulinomas were slightly or moderately positive for transforming growth factor alpha (TGF alpha), weakly positive for epidermal growth factor receptor (EGF-R), and strongly positive for c-myc and insulin. In malignant insulinomas, besides a strong immunoreaction for c-myc and TGF alpha, activation of c-K-ras and overexpression of p53 protein were found. Insulin reaction was moderate or strong. Three out of six malignant insulinomas displayed a c-K-ras point mutation at codon 12. All mutations were guanine to cytosine transversion, resulting in amino acid substitution, glycine to arginine. Mutations were present in metastatic insulinomas only. Patients with mutated c-K-ras oncogene had overexpression of p53 protein as well as c-myc and TGF alpha overexpression. Our results support the view that malignant progression is a consequence of more than one genetic lesion and suggest that activation of myc, TGF alpha an ras genes plays a role in a multistep process of tumour progression, perhaps serving as an initiating event.
authors.affiliation: Department of Molecular Medicine, Ruder Bosković Institute, Zagreb, Croatia.
authors.forename: K
authors.initials: K
authors.lastname: Pavelić
authors.forename: R
authors.initials: R
authors.lastname: Hrasćan
authors.forename: S
authors.initials: S
authors.lastname: Kapitanović
authors.forename: N
authors.initials: N
authors.lastname: Karapandza
authors.forename: Z
authors.initials: Z
authors.lastname: Vranes
authors.forename: M
authors.initials: M
authors.lastname: Belicza
authors.forename: B
authors.initials: B
authors.lastname: Kruslin
authors.forename: T
authors.initials: T
authors.lastname: Cabrijan
mesh_terms: D000368:Aged; D001483:Base Sequence; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D011905:Genes, ras; D006801:Humans; D007124:Immunoenzyme Techniques; D007340:Insulinoma / Q000235:genetics* / Q000378:metabolism / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D012150:Polymorphism, Restriction Fragment Length; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D016211:Transforming Growth Factor alpha; D016159:Tumor Suppressor Protein p53; D066246:ErbB Receptors