Identification of recurrent USP48 and BRAF mutations in Cushing’s disease

<jats:title>Abstract</jats:title><jats:p>Cushing’s disease results from corticotroph adenomas of the pituitary that hypersecrete adrenocorticotropin (ACTH), leading to excess glucocorticoid and hypercortisolism. Mutations of the deubiquitinase gene <jats:italic>USP8</jats:italic> occur in 35–62% of corticotroph adenomas. However, the major driver mutations in <jats:italic>USP8</jats:italic> wild-type tumors remain elusive. Here, we report recurrent mutations in the deubiquitinase gene <jats:italic>USP48</jats:italic> (predominantly encoding p.M415I or p.M415V; 21/91 subjects) and <jats:italic>BRAF</jats:italic> (encoding p.V600E; 15/91 subjects) in corticotroph adenomas with wild-type <jats:italic>USP8</jats:italic>. Similar to <jats:italic>USP8</jats:italic> mutants, both <jats:italic>USP48</jats:italic> and <jats:italic>BRAF</jats:italic> mutants enhance the promoter activity and transcription of the gene encoding proopiomelanocortin (POMC), which is the precursor of ACTH, providing a potential mechanism for ACTH overproduction in corticotroph adenomas. Moreover, primary corticotroph tumor cells harboring <jats:italic>BRAF</jats:italic> V600E are sensitive to the BRAF inhibitor vemurafenib. Our study thus contributes to the understanding of the molecular mechanism of the pathogenesis of corticotroph adenoma and informs therapeutic targets for this disease.</jats:p>