Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity.

Abstract

Germ-line protein kinase A (PKA) regulatory-subunit type-Ialpha (RIalpha; PRKAR1A)-inactivating mutations and loss-of-heterozygosity (LOH) of its 17q22-24 locus have been found in Cushing syndrome (CS) caused by primary pigmented nodular adrenocortical disease (PPNAD). We examined whether somatic 17q22-24, PRKAR1A, or PKA changes are present in 44 sporadic adrenocortical tumors (29 adenomas and 15 cancers); 26 of these tumors were responsible for CS. A probe containing the PRKAR1A gene-mapped by fluorescent in situ hybridization to 17q22-24-and corresponding microsatellite markers were used to study allelic losses; PRKAR1A was sequenced in all samples. 17q22-24 losses were seen in 23 and 53% of adenomas and cancers, respectively. In three tumors, somatic, PRKAR1A-inactivating mutations were identified: (a) a nonsense mutation in exon 6 (A751G); (b) a splicing mutation (9IVS-1G/A); and (c) a transition (1050T>C) followed by a 22-bp deletion, also in exon 9; all predicted premature RIalpha protein terminations. Quantitative message and protein studies showed RIalpha down-regulation in tumors with genetic changes; their cortisol secretion pattern was similar to that of PPNAD, and they had higher PKA activity by enzymatic studies. We conclude that somatic allelic losses of the 17q22-24 region, PRKAR1A-inactivating mutations or down-regulation, and corresponding PKA activity changes are present in at least some sporadic adrenocortical tumors, especially those with a PPNAD-like clinical presentation of CS.

• Authors: Jerome Bertherat, Lionel Groussin, Fabiano Sandrini, Ludmila Matyakhina, Thalia Bei, Sotirios Stergiopoulos, Theocharis Papageorgiou, Isabelle Bourdeau, Lawrence S Kirschner, Caroline Vincent-Dejean, Karine Perlemoine, Christine Gicquel, Xavier Bertagna, Constantine A Stratakis
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 17 Pg. 5308-19 (Sep 01 2003) ISSN: 0008-5472 [Print] United States
• PMID: 14500362 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
• PRKAR1A protein, human
• RNA, Messenger
• Cyclic AMP-Dependent Protein Kinases

Topics

• Adrenal Cortex Neoplasms (enzymology, genetics)
• Adrenocortical Adenoma (enzymology, genetics)
• Adult
• Aged
• Alleles
• Blotting, Western
• Chromosome Mapping
• Chromosomes, Human, Pair 17 (genetics)
• Cushing Syndrome (complications, enzymology, genetics)
• Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
• Cyclic AMP-Dependent Protein Kinases (biosynthesis, genetics, metabolism)
• Female
• Humans
• Immunohistochemistry
• Loss of Heterozygosity
• Male
• Middle Aged
• Mutation
• RNA, Messenger (biosynthesis, genetics)