Genetics of pituitary tumors: Focus on G-protein mutations.
In recent years the demonstration that human pituitary adenomas are monoclonal in origin has provided further evidence that pituitary neoplasia arise from the replication of a single mutated cell in which growth advantage results from either activation of proto-oncogenes or inactivation of tumor suppressor genes. While common oncogenes, such as Ras, are only exceptionally involved, the only mutations identified in a significant proportion of pituitary tumors, and particular in GH-secreting adenomas, occur in the Gsalpha gene (GNAS1) and cause constitutive activation of the cAMP pathway (gsp oncogene). Moreover, pituitary tumors overexpress hypothalamic releasing hormones, growth factors, and their receptors as well as cyclins involved in cell cycle progression. As far as the role of tumor suppressor genes in pituitary tumorigenesis is concerned, reduced expression of these genes seems to frequently occur in pituitary tumors as a consequence of abnormal methylation processes. Although the only mutational change so far identified in pituitary tumors is the gsp oncogene, this oncogene is not associated with a clear phenotype in patients bearing positive tumors. Mechanisms able to counteract the cAMP pathway, such as high sensitivity to somatostatin, and induction of genes with opposite actions, such as phosphodiesterases, CREB end ICER, or instability of mutant Gsalpha, have been proposed to account for the lack of genotype/phenotype relationships.
Lania
Andrea
A
Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore IRCCS, 20122, Milano, Italy.
Mantovani
Giovanna
G
Spada
Anna
A
D000818:Animals; D002453:Cell Cycle; D000242:Cyclic AMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D010911:Pituitary Neoplasms / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015398:Signal Transduction
D011518:Proto-Oncogene Proteins; D000242:Cyclic AMP; D019204:GTP-Binding Proteins