GNAS mutations in adrenal aldosterone-producing adenomas.

Mutations in GNAS, which encodes Gsα, have been documented in detail, particularly in human pituitary GH-secreting adenomas. Mutations have also recently been reported in adrenal cortisol-producing adenomas (CPAs), in addition to those in the PRKACA gene. However, mutations have not yet been examined in aldosterone-producing adenomas (APAs). Therefore, we herein investigated mutations in the GNAS gene in APAs. Two of the 15 (13%) CPAs with overt Cushing's syndrome and one of the 9 (11%) CPAs with subclinical Cushing's syndrome examined had the somatic mutations, p.R201S and p.R201C in the GNAS gene. We identified mutations in the GNAS gene (p.R201C) in 2 out of the 33 (6%) APAs tested, both of which showed autonomous cortisol secretion, while 24 APAs had mutations in the KCNJ5 gene (18 with p.G151R and 6 with p.L168R). These GNAS and KCNJ5 mutations were mutually exclusive in these adenomas. We herein demonstrated for the first time the presence of GNAS mutations in APAs, as well as in some cortisol-secreting adenomas. Our results suggest that these mutations, in addition to mutations in the KCNJ5 gene and other genes such as ATP1A1, ATP2B3 and CACNA1D, may be responsible for the tumorigenesis of APAs and CPAs with subclinical Cushing's syndrome.

Somatic mutations of the catalytic subunit of cyclic AMP-dependent protein kinase (PRKACA) gene in Japanese patients with several adrenal adenomas secreting cortisol [Rapid Communication].

Somatic mutations of the catalytic subunit of the cyclic AMP-dependent protein kinase (PRKACA) gene have recently been identified in about 35% of cortisol-producing adenomas (CPAs), with the affected patients showing overt Cushing's syndrome. Since we recently reported higher prevalence of mutations of the KCNJ5 gene and associations with autonomous cortisol secretion in Japanese aldosterone-producing adenomas than in Western countries, there might be different features of CPAs between Japan and the West. We therefore investigated mutations of the PRKACA gene in Japanese patients with several adrenal tumors secreting cortisol, including overt Cushing's syndrome, subclinical Cushing's syndrome, and aldosterone-producing adenomas (APAs) co-secreting cortisol operated on at Gunma University Hospital. Of the 13 patients with CPA who showed overt Cushing's syndrome, 3 (23%) had recurrent somatic mutations of the PRKACA gene, p.L206R (c.617 T>G), and there were no mutations in subclinical Cushing's syndrome. Among 33 APAs, 24 had somatic mutations of the KCNJ5 gene, either G151R or L168R, 11 (33%) had autonomous cortisol secretion, but there were no mutations of the PRKACA gene. We established a PCR-restriction fragment length polymorphism assay and revealed that the mutated allele was expressed at a similar level to the wild-type allele. These findings demonstrated that 1) the prevalence of Japanese patients with CPA who showed overt Cushing's syndrome and whose somatic mutations in the PRKACA gene was similar to that in Western countries, 2) the mutation might be specific for CPAs causing overt Cushing's syndrome, and 3) the mutant PRKACA allele was expressed appropriately in CPAs.