Transcriptome sequencing reveals two subtypes of cortisol-secreting adrenocortical tumors in dogs and identifies CYP26B1 as a potential new therapeutic target

Cushing’s syndrome (CS) is a serious endocrine disorder that is rare in humans, but relatively common in dogs. In ~15-20% of cases, CS is caused by a cortisol-secreting adrenocortical tumor (csACT). To identify differentially expressed genes that can improve prognostic predictions after surgery and represent novel treatment targets, we performed RNA sequencing on csACTs (n=48) and normal adrenal cortices (NACs; n=10) of dogs. A gene was declared differentially expressed when the adjusted P-value was <0.05 and the log2 fold change was >2 or <-2. Between NACs and csACTs, 98 genes were differentially expressed. Based on the principal component analysis (PCA) the csACTs were separated in two groups, of which group 1 had significantly better survival after adrenalectomy (P=0.002) than group 2. Between csACT group 1 and group 2, 77 genes were differentially expressed. One of these, cytochrome P450 26B1 (CYP26B1), was significantly associated with survival in both our canine csACTs and in a publicly available dataset of 33 human cortisol-secreting adrenocortical carcinomas. In the validation cohort, CYP26B1 was also expressed significantly higher (P=0.012) in canine csACTs compared to NACs. In future studies it would be interesting to determine whether CYP26B1 inhibitors could inhibit csACT growth in both dogs and humans. whole transcriptome sequencing of canine cortisol-secreting adrenocortical tumor and normal adrenal cortices