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[Cancer Research 63, 5308-5319, September 1, 2003]
© 2003 American Association for Cancer Research

Regular Articles

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 Activity1

Jerome Bertherat, Lionel Groussin2, Fabiano Sandrini2, Ludmila Matyakhina, Thalia Bei, Sotirios Stergiopoulos, Theocharis Papageorgiou, Isabelle Bourdeau, Lawrence S. Kirschner, Caroline Vincent-Dejean, Karine Perlemoine, Christine Gicquel, Xavier Bertagna and Constantine A. Stratakis3

Department of Endocrinology, Institut Cochin, Institut National de la Santé et de la Recherche Médicale U567, CNRS UMR8104, Université Paris V, Hôpital Cochin, Paris 75014, France [J. B., L. G., C. V-D., K. P., X. B.]; Section on Endocrinology and Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland 20892 [F. S., L. M., T. B., I. B., C. A. S.]; and COMETE Network [J. B., L. G., C. G., X. B.] and Laboratoire d’Explorations Fonctionnelles Endocriniennes [C. G.], Hôpital Trousseau, Paris 75012, France

Germ-line protein kinase A (PKA) regulatory-subunit type-I{alpha} (RI{alpha}; 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 RI{alpha} protein terminations. Quantitative message and protein studies showed RI{alpha} 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.




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