title: Mutational analysis of PRKAR1A and Gs(alpha) in sporadic adrenocortical tumors.
abstract: Little is known about the pathogenesis of adrenocortical tumors. The cAMP-dependent pathway is physiologically activated by ACTH in adrenocortical cells and different components of this cascade may be altered in some functioning adrenocortical tumors. Recently, mutations of the gene encoding the PKA type 1 A regulatory subunit (R1 A), PRKAR1A, associated with loss of heterozygosity (LOH) at PRKAR1A locus, have been demonstrated in primary pigmented nodular adrenocortical disease (PPNAD), either isolated or associated with Carney complex. Moreover, activating mutations of the Gs(alpha) gene (the gsp oncogene) have also been found in a small number of adrenocortical cortisol-secreting adenomas. Aim of this study was to investigate the presence of such genetic alterations on a series of 10 ACTH-independent Cushing syndrome due to non-PPNAD adrenocortical adenomas. The coding sequence of PRKAR1A, evaluated by PCR and direct sequencing analysis, revealed the absence of mutations while heterozygosity for at least 1 polymorphism excluded LOH in most tumors. In one single adenoma gsp mutation was detected. In conclusion, we provide additional evidence that the only mutational changes able to activate the cAMP pathway so far identified, i.e. PRKAR1A mutations and gsp oncogene, are a rare event in adrenocortical tumors.
authors.affiliation: Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore IRCCS, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Libé
authors.forename: G
authors.initials: G
authors.lastname: Mantovani
authors.forename: S
authors.initials: S
authors.lastname: Bondioni
authors.forename: A G
authors.initials: AG
authors.lastname: Lania
authors.forename: C
authors.initials: C
authors.lastname: Pedroni
authors.forename: P
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: A
authors.initials: A
authors.lastname: Spada
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000201:enzymology / Q000235:genetics*; D000328:Adult; D000368:Aged; D000242:Cyclic AMP / Q000502:physiology; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases; D004252:DNA Mutational Analysis; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D011506:Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs