Nature Communications (Aug 2018)

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

  • Jianhua Chen,
  • Xuemin Jian,
  • Siyu Deng,
  • Zengyi Ma,
  • Xuefei Shou,
  • Yue Shen,
  • Qilin Zhang,
  • Zhijian Song,
  • Zhiqiang Li,
  • Hong Peng,
  • Cheng Peng,
  • Min Chen,
  • Cheng Luo,
  • Dan Zhao,
  • Zhao Ye,
  • Ming Shen,
  • Yichao Zhang,
  • Juan Zhou,
  • Aamir Fahira,
  • Yongfei Wang,
  • Shiqi Li,
  • Zhaoyun Zhang,
  • Hongying Ye,
  • Yiming Li,
  • Jiawei Shen,
  • Hong Chen,
  • Feng Tang,
  • Zhenwei Yao,
  • Zhifeng Shi,
  • Chunjui Chen,
  • Lu Xie,
  • Ye Wang,
  • Chaowei Fu,
  • Ying Mao,
  • Liangfu Zhou,
  • Daming Gao,
  • Hai Yan,
  • Yao Zhao,
  • Chuanxin Huang,
  • Yongyong Shi

DOI
https://doi.org/10.1038/s41467-018-05275-5
Journal volume & issue
Vol. 9, no. 1
pp. 1 – 9

Abstract

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Abstract 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.