Background - Given the current lack of effective medical treatment for pheochromocytomas and paragangliomas (PPGLs), there is a need for novel therapeutic strategies. Hypothesis/Objectives – To identify druggable pathways driving PPGL development, RNA sequencing was performed on PPGLs and normal adrenal medullas (NAMs) of dogs. Animals – 10 healthy dogs, 19 PPGL dogs. Methods - Tissue was snap-frozen in liquid nitrogen or fixed in RNAlater stabilization solution and stored at -70°C until RNA extraction. RNA sequencing was performed. The Mann–Whitney U-test was used to calculate P-values, which were corrected for multiple comparisons using the false discovery rate method. Genes were considered differentially expressed when the corrected P-value was < 0.05 and the log2 fold change was >3 or <-3. Results - Principal component analysis revealed that PPGLs clearly clustered apart from NAMs. Between PPGLs and NAMS, 232 genes were differentially expressed. Compared with NAMs, PPGLs had increased expression of genes related to the cell cycle (e.g., PCLAF, CCNB2, CDC6, TOP2A), tumor development, progression and metastasis (e.g., POSTN, FOXI3, MYBL2), hypoxia and angiogenesis (e.g., CDCP1, EDN2, ESM1), and the Wnt signaling pathway (e.g., WNT3, SFRP2), and decreased expression of genes related to adrenal steroidogenesis (e.g., SF-1, SOAT1, CYP11A1). Our data revealed several overexpressed genes that could provide targets for novel therapeutics, such as RET, DRD2, and SFRP2. Conclusions and clinical importance - This study has shed light on the transcriptomic profile of canine PPGL, which will be instrumental in understanding the pathogenesis of PPGL in dogs, and revealed novel targets for therapy.
