E pluribus unum? The main protein kinase A catalytic subunit (PRKACA), a likely oncogene, and cortisol-producing tumors.

Abstract

Evidence has been accumulating for years that increased cAMP signaling (Figure 1) is the culprit behind the development of most benign cortisol-producing tumors of the adrenal gland (1, 2). First, GNAS1 mutations in McCune-Albright syndrome (MAS) were responsible for cortisol-producing tumors in the context of an otherwise normal adrenal gland in toddlers with MAS and Cushing syndrome (CS) (3). Then, a rare disease, massive macronodular adrenocortical disease (MMAD) or ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), now aptly renamed as primary macronodular hyperplasia (PMAH) (4), was found to be linked to the ectopic expression of G protein-coupled receptors (GPCRs) (5, 6). And we found mutations of the main cAMP receptor in all cells, PRKAR1A, the gene that codes for the regulatory subunit type 1α (R1α) of the cAMP-dependent protein kinase or protein kinase A (PKA) to cause another rare form of cortisol-producing hyperplasia: primary pigmented nodular adrenocortical disease (PPNAD) is caused in both its isolated form and the type associated with Carney complex, a multiple endocrine neoplasia syndrome, by PRKAR1A-inactivating mutations (7, 8). However, proof that increased cAMP signaling was involved in almost all benign cortisol-producing lesions, and especially the “garden variety” cortisol-producing adenoma (CPA), was lacking. Yes, we showed that MMAD/AIMAH/PMAH tissues showed allelic losses of the PRKAR1A gene and/or its 17q locus (9), and that up to one out of five CPAs (especially those with dexamethasone-responsive increase in their cortisol production) could harbor somatic mutations of PRKAR1A (10) and that CPAs with no GNAS1 or PRKAR1A mutations (or mutations in any other genes) had increased cAMP levels and/or PKA activation (11), but this was all circumstantial evidence. The circumstantial evidence was somewhat strengthened by our discovery of the involvement of cAMP-binding phosphodiesterases (PDEs) PDE11A (12, 13) and PDE8B (14,–16) in predisposition to a variety of cortisol-producing adrenal tumors, from cancer (17) to MMAD/AIMAH/PMAH (18, 19), and even in conjunction with PRKAR1A mutations (20). The latter was in fact the first evidence of any digenic involvement in predisposition to a cortisol-producing lesion, and both genes (PRKAR1A and PDE11A) were regulating cAMP signaling. Nevertheless, it was all circumstantial evidence, especially because a number of the identified molecules have a multitude of functions and are expressed in almost every tissue; why would the adrenal cortex be specifically targeted by an increase in cAMP signaling mediated by the ubiquitous PKA? Surely other tissues, the bone, the pituitary, and thyroid glands would be affected.