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 relatively common in dogs, but rare in humans. 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 log 2 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.