USP8 and TP53 Drivers are Associated with CNV in a Corticotroph Adenoma Cohort Enriched for Aggressive Tumors.

Pituitary corticotroph adenomas are rare tumors that can be associated with excess adrenocorticotropin (ACTH) and adrenal cortisol production, resulting in the clinically debilitating endocrine condition Cushing disease. A subset of corticotroph tumors behave aggressively, and genomic drivers behind the development of these tumors are largely unknown. To investigate genomic drivers of corticotroph tumors at risk for aggressive behavior. Whole-exome sequencing of patient-matched corticotroph tumor and normal deoxyribonucleic acid (DNA) from a patient cohort enriched for tumors at risk for aggressive behavior. Tertiary care center. Twenty-seven corticotroph tumors from 22 patients were analyzed. Twelve tumors were macroadenomas, of which 6 were silent ACTH tumors, 2 were Crooke's cell tumors, and 1 was a corticotroph carcinoma. Whole-exome sequencing. Somatic mutation genomic biomarkers. We found recurrent somatic mutations in USP8 and TP53 genes, both with higher allelic fractions than other somatic mutations. These mutations were mutually exclusive, with TP53 mutations occurring only in USP8 wildtype (WT) tumors, indicating they may be independent driver genes. USP8-WT tumors were characterized by extensive somatic copy number variation compared with USP8-mutated tumors. Independent of molecular driver status, we found an association between invasiveness, macroadenomas, and aneuploidy. Our data suggest that corticotroph tumors may be categorized into a USP8-mutated, genome-stable subtype versus a USP8-WT, genome-disrupted subtype, the latter of which has a TP53-mutated subtype with high level of chromosome instability. These findings could help identify high risk corticotroph tumors, namely those with widespread CNV, that may need closer monitoring and more aggressive treatment.

Uzilov AV ，Taik P ，Cheesman KC ，Javanmard P ，Ying K ，Roehnelt A ，Wang H ，Fink MY ，Lau CY ，Moe AS ，Villar J ，Bederson JB ，Stewart AF ，Donovan MJ ，Mahajan M ，Sebra R ，Post KD ，Chen R ，Geer EB ... -  《-》

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease.

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. Our objective was to determine the impact of USP8 mutations on the clinicopathological features of CD. 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. 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. 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.

Hayashi K ，Inoshita N ，Kawaguchi K ，Ibrahim Ardisasmita A ，Suzuki H ，Fukuhara N ，Okada M ，Nishioka H ，Takeuchi Y ，Komada M ，Takeshita A ，Yamada S ... -  《-》

The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing's Disease.

Perez-Rivas LG ，Theodoropoulou M ，Ferraù F ，Nusser C ，Kawaguchi K ，Stratakis CA ，Faucz FR ，Wildemberg LE ，Assié G ，Beschorner R ，Dimopoulou C ，Buchfelder M ，Popovic V ，Berr CM ，Tóth M ，Ardisasmita AI ，Honegger J ，Bertherat J ，Gadelha MR ，Beuschlein F ，Stalla G ，Komada M ，Korbonits M ，Reincke M ... -  《-》

Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease.

Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have been recently identified as the most common genetic alteration in patients with Cushing disease (CD). However, the frequency of these mutations in the pediatric population has not been extensively assessed. We investigated the status of the USP8 gene at the somatic level in a cohort of pediatric patients with corticotroph adenomas. The USP8 gene was fully sequenced in both germline and tumor DNA samples from 42 pediatric patients with CD. Clinical, biochemical, and imaging data were compared between patients with and without somatic USP8 mutations. Five different USP8 mutations (three missense, one frameshift, and one in-frame deletion) were identified in 13 patients (31%), all of them located in exon 14 at the previously described mutational hotspot, affecting the 14-3-3 binding motif of the protein. Patients with somatic mutations were older at disease presentation [mean 5.1 ± 2.1 standard deviation (SD) vs 13.1 ± 3.6 years, P = 0.03]. Levels of urinary free cortisol, midnight serum cortisol, and adrenocorticotropic hormone, as well as tumor size and frequency of invasion of the cavernous sinus, were not significantly different between the two groups. However, patients harboring somatic USP8 mutations had a higher likelihood of recurrence compared with patients without mutations (46.2% vs 10.3%, P = 0.009). Somatic USP8 gene mutations are a common cause of pediatric CD. Patients harboring a somatic mutation had a higher likelihood of tumor recurrence, highlighting the potential importance of this molecular defect for the disease prognosis and the development of targeted therapeutic options.

Faucz FR ，Tirosh A ，Tatsi C ，Berthon A ，Hernández-Ramírez LC ，Settas N ，Angelousi A ，Correa R ，Papadakis GZ ，Chittiboina P ，Quezado M ，Pankratz N ，Lane J ，Dimopoulos A ，Mills JL ，Lodish M ，Stratakis CA ... -  《-》

Identification of a novel RASD1 somatic mutation in a USP8-mutated corticotroph adenoma.

Uzilov AV ，Cheesman KC ，Fink MY ，Newman LC ，Pandya C ，Lalazar Y ，Hefti M ，Fowkes M ，Deikus G ，Lau CY ，Moe AS ，Kinoshita Y ，Kasai Y ，Zweig M ，Gupta A ，Starcevic D ，Mahajan M ，Schadt EE ，Post KD ，Donovan MJ ，Sebra R ，Chen R ，Geer EB ... -  《-》