近期论文

Identification of recurrent USP48 and BRAF mutations in Cushing's disease.(IF=12.353)

 2018 Aug 9;9(1):3171. doi: 10.1038/s41467-018-05275-5.

Author information

1.Shanghai Key Laboratory of Psychotic Disorders, 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, Shanghai, 200030, China.
2.Department of Otolaryngology Head and Neck Surgery & Center of Sleep Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
3.Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
4.Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China.
5.Shanghai Pituitary Tumor Center, Shanghai, 200040, China.
6.Institute of Neurosurgery, Fudan University, Shanghai, 200040, China.
7.CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China.
8.University of Chinese Academy of Sciences, Beijing, 100049, China.
9.Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
10.Department of Endocrinology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China.
11.Department of Pathology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China.
12.Department of Radiology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China.
13.Shanghai Center for Bioinformation Technology (SCBIT), Shanghai Academy of Science and Technology, Shanghai, 201203, China.
14.Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China.
15.State Key Laboratory of Medical Neurobiology, Institute of Neurosurgery, Shanghai Medical College, Fudan University, 200040, Shanghai, China.
16.Department of Pathology, Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, 27710, USA.
17.Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China. zhaoyaohs@vip.sina.com.
18.Shanghai Pituitary Tumor Center, Shanghai, 200040, China. zhaoyaohs@vip.sina.com.
19.Institute of Neurosurgery, Fudan University, Shanghai, 200040, China. zhaoyaohs@vip.sina.com.
20.State Key Laboratory of Medical Neurobiology, Institute of Neurosurgery, Shanghai Medical College, Fudan University, 200040, Shanghai, China. zhaoyaohs@vip.sina.com.
21.Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. huangcx@shsmu.edu.cn.
22.Shanghai Key Laboratory of Psychotic Disorders, 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, Shanghai, 200030, China. shiyongyong@gmail.com.
23.Department of Otolaryngology Head and Neck Surgery & Center of Sleep Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. shiyongyong@gmail.com.
24.Institute of Neuropsychiatric Science and Systems Biological Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China. shiyongyong@gmail.com.
25.Department of Psychiatry, First Teaching Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, China. shiyongyong@gmail.com.
26.The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, Shandong, 266003, China. shiyongyong@gmail.com.

 

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.

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