Molecular Genetics of Cushing's Disease

Cushing's disease is a rare severe condition caused by pituitary tumors that chronically hypersecrete ACTH leading to excessive endogenous glucocorticoid production. Cushing's disease tumors or corticotropinomas are typically monoclonal neoplasms that mainly occur sporadically. Cushing's disease is very rarely encountered in genetic familial syndromes, such as MEN, FIPA, McCune–Albright and DICER syndrome, tuberosis sclerosis, and Carney complex. Oncogenes and tumor suppressor genes commonly associated with other tumor types are 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.