Abstract
Canine Cushing's syndrome (hypercortisolism) can be caused by a pituitary tumor (pituitary-dependent hypercortisolism; PDH) or a cortisol-secreting adrenocortical tumor (csACT). For both cases, non-invasive biomarkers that could pre-operatively predict the risk of recurrence after surgery would greatly impact clinical decision making. The aim of this study was to determine whether circulating microRNAs (miRNAs) can be used as diagnostic (presence of PDH or csACT) and/or prognostic (disease recurrence, histological grade) non-invasive biomarkers for canine Cushing's syndrome. After a pilot study with 40 miRNAs in blood samples of healthy dogs (n = 3), dogs with PDH (n = 3) and dogs with a csACT (n = 4), we selected a total of 20 miRNAs for the definitive study. In the definitive study, these 20 miRNAs were analyzed in blood samples of healthy dogs (n = 6), dogs with PDH (n = 19, pre- and post-operative samples) and dogs with a csACT (n = 26, pre-operative samples). In dogs with PDH, six miRNAs (miR-122-5p, miR-126-5p, miR-141-3p, miR-222-3p, miR-375-3p and miR-483-3p) were differentially expressed compared to healthy dogs. Of one miRNA, miR-122-5p, the expression levels did not overlap between healthy dogs and dogs with PDH (p = 2.9x10−4), significantly decreased after hypophysectomy (p = 0.013), and were significantly higher (p = 0.017) in dogs with recurrence (n = 3) than in dogs without recurrence for at least one year after hypophysectomy (n = 7). In dogs with csACTs, two miRNAs (miR-483-3p and miR-223-3p) were differentially expressed compared to healthy dogs. Additionally, miR-141-3p was expressed significantly lower (p = 0.009) in dogs with csACTs that had a histopathological Utrecht score of ≥ 11 compared to those with a score of <11. These results indicate that circulating miRNAs have the potential to be non-invasive biomarkers in dogs with Cushing's syndrome that may contribute to clinical decision making.
Highlights
Spontaneous Cushing’s syndrome, or hypercortisolism, is one of the most commonly diagnosed endocrinopathies in dogs [1]
The most clearly altered miRNA was miR-122-5p, which was significantly overexpressed in dogs with PDH and did not overlap with expression in healthy dogs
MiR122-5p expression was higher in dogs with recurrence after hypophysectomy than in dogs without reported recurrence
Summary
Spontaneous Cushing’s syndrome, or hypercortisolism, is one of the most commonly diagnosed endocrinopathies in dogs [1]. It is caused by an ACTH-secreting pituitary tumor (pituitarydependent hypercortisolism; PDH) in ∼80–85% of cases, and by a cortisol-secreting adrenocortical tumor (csACT) in ∼15–20% of cases [1]. Both PDH and csACT can be treated by surgically removing the causative tumor. Because surgery is not without risks and not suitable for every patient, dogs with Cushing’s syndrome are often treated with the steroidogenesis inhibitor trilostane [2]. The mRNA expression of pituitary tumor transforming gene 1 (PTTG1) was previously reported to be associated with disease-free interval after surgery, but can only be assessed post-operatively [7]
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