Abstract
PurposeCushing’s disease (CD), also known as pituitary-dependent hyperadrenocorticism, is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. Affected humans and dogs have similar clinical manifestations, however, the incidence of the canine disease is thousand-fold higher. This makes the dog an obvious model for studying the pathogenesis of pituitary-dependent hyperadrenocorticism. Despite certain similarities identified at the molecular level, the question still remains whether the two species have a shared oncogenetic background. Recently, hotspot recurrent mutations in the gene encoding for ubiquitin specific protease 8 (USP8) have been identified as the main driver behind the formation of ACTH-secreting pituitary adenomas in humans. In this study, we aimed to verify whether USP8 mutations also play a role in the development of such tumours in dogs.MethodsPresence of USP8 mutations was analysed by Sanger and PCR-cloning sequencing in 38 canine ACTH-secreting adenomas. Furthermore, the role of USP8 and EGFR protein expression was assessed by immunohistochemistry in a subset of 25 adenomas.ResultsNone of the analysed canine ACTH-secreting adenomas presented mutations in the USP8 gene. In a subset of these adenomas, however, we observed an increased nuclear expression of USP8, a phenotype characteristic for the USP8 mutated human tumours, that correlated with smaller tumour size but elevated ACTH production in those tumours.ConclusionsCanine ACTH-secreting pituitary adenomas lack mutations in the USP8 gene suggesting a different genetic background of pituitary tumourigenesis in dogs. However, elevated nuclear USP8 protein expression in a subset of tumours was associated with a similar phenotype as in their human counterparts, indicating a possible end-point convergence of the different genetic backgrounds in the two species. In order to establish the dog as a useful animal model for the study of CD, further comprehensive studies are needed.
Highlights
Cushing’s disease (CD) in humans is a rare disease, with an annual incidence of 2–4 cases/million [1, 2]
In a subset of these adenomas, we observed an increased nuclear expression of ubiquitin specific protease 8 (USP8), a phenotype characteristic for the USP8 mutated human tumours, that correlated with smaller tumour size but elevated adrenocorticotropic hormone (ACTH) production in those tumours
Elevated nuclear USP8 protein expression in a subset of tumours was associated with a similar phenotype as in their human counterparts, indicating a possible end-point convergence of the different genetic backgrounds in the two species
Summary
Cushing’s disease (CD) in humans is a rare disease, with an annual incidence of 2–4 cases/million [1, 2]. While the clinical and histological phenotype is similar, canine CD ( frequently called in veterinary medicine pituitary-dependent hyperadrenocorticism) has an estimated incidence of 1000–2000 cases/million is a much more common disorder [3] In both species, overproduction of ACTH and cortisol leads to similar clinical manifestations including abdominal obesity, hypertension, muscle atrophy, and an increase in patient overall mortality [3]. Patients with inoperable tumours or recurrent disease are candidates for focused radiotherapy and/or medical therapy The latter may ameliorate the clinical symptoms through inhibition of pituitary ACTH release (i.e., dopamine agonists, somatostatin analogues), glucocorticoid receptor (GR) action (i.e., mifepristone), or adrenal cortisol synthesis (i.e., metyrapone, etomidate, mitotane) [5, 6]. The main treatment usually consists of medical therapy with drugs such as mitotane or trilostane [7] while to date hypophysectomy or radiotherapy are performed in a few specialized centres only [8, 9]
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