Comment on "A unified cause for adrenal Cushing`s syndrome": Mutations in a signaling protein underlie a class of functional adrenal tumors

Recently, attention has been given to the whole exome sequencing of cortisol-producing adrenocortical adenomas (23 May, p. 804) and four papers demonstrated mutations in the protein kinase A (PKA) signaling pathway (1-4). Interestingly, in 2013 we have already reported activation of the PKA pathway, due to activating mutations in the stimulatory G protein alpha subunit (GNAS) gene, in dogs with cortisol-producing adrenocortical tumors (5). This may now prove to be an important observation, because a pet dog is an excellent animal model to study adrenal tumorigenesis in men. Compared to mouse or ferret models, in pet dogs adrenocortical tumors occur spontaneously and more accurately reflect the tumor heterogeneity seen in the population of human patients. In addition, the incidence of cortisol-secreting adrenocortical tumors is ~1000-fold higher than in men, providing a solid base for effective research. Furthermore, the necessary tools and infrastructure have been developed to utilize this powerful model of human disease, including a publically available genome assembly and various high-throughput techniques (6,7). Given the activation of the PKA signaling cascade in both human and canine cortisol-producing adrenocortical tumors, a pet dog is the ideal candidate to serve as animal model in clinical trials investigating the pharmacological modulation of the PKA signaling pathway.