Kyohei Hayashi1, Naoko Inoshita2, Kohei Kawaguchi2, Arif Ibrahim Ardisasmita2, Hisanori Suzuki2, Noriaki Fukuhara2, Mitsuo Okada2, Hiroshi Nishioka1, Yasuhiro Takeuchi1, Masayuki Komada2, Akira Takeshita1, Shozo Yamada3. 1. 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. 2. 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. 3. 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.
Abstract
CONTEXT: 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. SUBJECTS AND 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.
CONTEXT: 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. SUBJECTS AND 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: Antonella Sesta; Maria Francesca Cassarino; Mariarosa Terreni; Alberto G Ambrogio; Laura Libera; Donatella Bardelli; Giovanni Lasio; Marco Losa; Francesca Pecori Giraldi Journal: Neuroendocrinology Date: 2019-10-16 Impact factor: 4.914
Authors: Ashley B Grossman; Shereen Ezzat; Sylvia L Asa; Ozgur Mete; Michael D Cusimano; Ian E McCutcheon; Arie Perry; Shozo Yamada; Hiroshi Nishioka; Olivera Casar-Borota; Silvia Uccella; Stefano La Rosa Journal: Mod Pathol Date: 2021-05-21 Impact factor: 7.842
Authors: Andrew L Lin; Mark T A Donoghue; Sharon L Wardlaw; T Jonathan Yang; Lisa Bodei; Viviane Tabar; Eliza B Geer Journal: J Clin Endocrinol Metab Date: 2020-12-01 Impact factor: 5.958