Endocrine Abstracts

Recently, mutations in the PRKACA (catalytic subunit α of the PKA) gene have been identified as causative in 35% of adrenocortical adenomas (ACA) with overt Cushing’s syndrome (Beuschlein et al. 2014). These mutations lead to constitutive activation of PKA signaling and subsequently to an excessive production of cortisol. Protein kinase A is a heterotetramer consisting of two catalytic and two regulatory subunits with several isoforms (Cα, β, γ, RIα, IIα, Iβ, and IIβ). The stable tetramer is inactive, only upon cAMP induced dissociation of the regulatory subunits the active catalytic subunits are released. Here, we investigated the expression of the different PKA subunits in a large set of adrenal tumors. We performed immunohistochemistry staining of all PKA regulatory subunits and Cα on FFPE tissue from normal adrenal glands (n=8), ACA (n=65, 30 cortisol-producing/CPA, 17 aldosterone-producing, and 18 inactive) and adrenocortical carcinomas (ACC: n=29, seven cortisol-, three androgen-, 12 mixed hormone-producing, and seven inactive). Our results indicate a significantly decreased expression of RIIβ in CPAs, but only in the PRKACA mutated samples. A tendency for reduced expression under PRKACA mutation was also observed for RIα. No change in expression was found for the other two regulatory subunits or Cα. While reduced RIIβ expression in CPAs had previously been described (Mantovani et al. 2008), until now, this phenomena could not be linked to PRKACA mutational status. The former hypothesis that the decreased level of RIIβ leads by itself to the cortisol excess seems to be wrong, because RIIβ was not significantly changed in both ACA and ACC from patients with overt Cushing’s syndrome but without PRKACA mutation. We therefore postulate that the reduced protein expression of RIIβ in CPA described earlier is a direct or indirect consequence of the newly identified mutation and not a general feature in CPAs. If this decrease arises post-transcriptionally or at transcriptional levels still needs to be elucidated.

Disclosure: This work was supported by the Deutsche Forschungsgemeinschaft (grant number: FA466/4-1 to M Fassnacht), IZKF Würzburg (grant number: B-281 to M Fassnacht), and the ERA NET ‘E-rare’ (grant number: 01GM1407B to M Fassnacht).