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 () and Yongyong Shi ()
Additional contact information
Jianhua Chen: Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University
Xuemin Jian: Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University
Siyu Deng: Shanghai Jiao Tong University School of Medicine
Zengyi Ma: Fudan University
Xuefei Shou: Fudan University
Yue Shen: Fudan University
Qilin Zhang: Fudan University
Zhijian Song: Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University
Zhiqiang Li: Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University
Hong Peng: Shanghai Jiao Tong University School of Medicine
Cheng Peng: Shanghai Jiao Tong University School of Medicine
Min Chen: Chinese Academy of Sciences
Cheng Luo: Chinese Academy of Sciences
Dan Zhao: University of Chinese Academy of Sciences
Zhao Ye: Fudan University
Ming Shen: Fudan University
Yichao Zhang: Fudan University
Juan Zhou: Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University
Aamir Fahira: Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University
Yongfei Wang: Fudan University
Shiqi Li: Fudan University
Zhaoyun Zhang: Shanghai Pituitary Tumor Center
Hongying Ye: Shanghai Pituitary Tumor Center
Yiming Li: Shanghai Pituitary Tumor Center
Jiawei Shen: Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University
Hong Chen: Shanghai Pituitary Tumor Center
Feng Tang: Shanghai Pituitary Tumor Center
Zhenwei Yao: Shanghai Pituitary Tumor Center
Zhifeng Shi: Fudan University
Chunjui Chen: Fudan University
Lu Xie: Shanghai Academy of Science and Technology
Ye Wang: Fudan University
Chaowei Fu: Fudan University
Ying Mao: Fudan University
Liangfu Zhou: Fudan University
Daming Gao: Chinese Academy of Sciences
Hai Yan: Duke University Medical Center
Yao Zhao: Fudan University
Chuanxin Huang: Shanghai Jiao Tong University School of Medicine
Yongyong Shi: Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05275-5

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