Identification of recurrent USP48 and BRAF mutations in Cushing's disease.

Journal Article (Journal Article)

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 USP8 occur in 35-62% of corticotroph adenomas. However, the major driver mutations in USP8 wild-type tumors remain elusive. Here, we report recurrent mutations in the deubiquitinase gene USP48 (predominantly encoding p.M415I or p.M415V; 21/91 subjects) and BRAF (encoding p.V600E; 15/91 subjects) in corticotroph adenomas with wild-type USP8. Similar to USP8 mutants, both USP48 and BRAF 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 BRAF 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.

Full Text

Duke Authors

Cited Authors

  • Chen, J; Jian, X; Deng, S; Ma, Z; Shou, X; Shen, Y; Zhang, Q; Song, Z; Li, Z; Peng, H; Peng, C; Chen, M; Luo, C; Zhao, D; Ye, Z; Shen, M; Zhang, Y; Zhou, J; Fahira, A; Wang, Y; Li, S; Zhang, Z; Ye, H; Li, Y; Shen, J; Chen, H; Tang, F; Yao, Z; Shi, Z; Chen, C; Xie, L; Wang, Y; Fu, C; Mao, Y; Zhou, L; Gao, D; Yan, H; Zhao, Y; Huang, C; Shi, Y

Published Date

  • August 9, 2018

Published In

Volume / Issue

  • 9 / 1

Start / End Page

  • 3171 -

PubMed ID

  • 30093687

Pubmed Central ID

  • PMC6085354

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-018-05275-5


  • eng

Conference Location

  • England