title: The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease.
abstract: BACKGROUND
  Somatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one- to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion.
  
  
  OBJECTIVE
  Our objective was to determine the impact of USP8 mutations on the clinicopathological features of CD.
  
  
  METHODS
  USP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry.
  
  
  RESULTS
  USP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT.
  
  
  CONCLUSIONS
  Microadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT.
authors.affiliation: Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Inoshita
authors.affiliation: Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kawaguchi
authors.affiliation: Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan.
authors.forename: Arif
authors.initials: A
authors.lastname: Ibrahim Ardisasmita
authors.affiliation: Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Fukuhara
authors.affiliation: Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Okada
authors.affiliation: Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishioka
authors.affiliation: Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takeuchi
authors.affiliation: Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komada
authors.affiliation: Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Takeshita
authors.affiliation: Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan Departments of Endocrinology and MetabolismPathologyToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, JapanDepartment of Hypothalamic and Pituitary SurgeryToranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo 105-8470, JapanOkinaka Memorial Institute for Medical Research2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan coactivator@mac.com.
authors.forename: Shozo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D049913:ACTH-Secreting Pituitary Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000097:blood / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D010450:Endopeptidases / Q000235:genetics*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics*; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047748:Pituitary ACTH Hypersecretion / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011333:Pro-Opiomelanocortin; D017481:Receptors, Somatostatin; D012737:Sex Factors; D013004:Somatostatin / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D056827:Endosomal Sorting Complexes Required for Transport; D017481:Receptors, Somatostatin; D025521:Tumor Suppressor Proteins; D013004:Somatostatin; D011333:Pro-Opiomelanocortin; C094573:somatostatin receptor 5; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase; D045643:DNA Repair Enzymes