Cushing’s disease is a rare severe condition caused by pituitary tumors that secrete ACTH leading to excessive endogenous glucocorticoid production. Tumors causing Cushing’s disease, also called corticotropinomas, are typically monoclonal neoplasms that mainly occur sporadically. Cushing’s disease is very rarely encountered in genetic familial syndromes. Oncogenes and tumor suppressor genes commonly associated with other tumor types are only rarely muted in this tumor type. The advent of next generation sequencing led to the identification of a single mutational hotspot in the ubiquitin specific protease 8 (USP8) gene in almost half of Cushing’s disease tumors. This new discovery showcases a novel mechanism responsible for corticotroph tumorigenesis and ACTH hypersecretion and highlights USP8 and its downstream signaling pathways as potential promising pharmacological targets for the management of Cushing’s disease.
Corticotroph tumors are characterized by aberrant expression of proteins involved in the regulation of cell cycle, proliferation, growth and differentiation. Epidermal growth factor (EGF) is a major mitogenic and differentiation factor of particular importance in corticotroph pathophysiology.Cytokines such as interleukin 2 (IL2) and 6 (IL6) have been implicated in corticotroph tumorigenesis via their autocrine-paracrine loops.

References

1.Albani A,et al. Endocr Pract. 2018;24(10):907–914.