Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas

Losa, Marco; Mortini, Pietro; Pagnano, Angela; Detomas, Mario; Cassarino, Maria Francesca; Giraldi, Francesca Pecori

doi:10.1007/s12020-018-1776-0

Cited by 41 publications

(51 citation statements)

References 29 publications

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“…In our cohort of 62 patients, more than one-third of corticotroph pituitary tumors were silent tumors, clinically classified as nonfunctioning pituitary tumors but reclassified after pathology analysis as corticotroph tumors. Overall, USP8 mutations were found in 13/50 tumors and SST5 was expressed in 26/62 tumors, results which are in accordance with previous findings (20,21,22,23,24,25,26,27,28). Compared to silent tumors, functioning tumors more frequently showed USP8 mutations and positive SST5 expression, with about one-third expressing SST5 receptor with an IRS either moderate or strong.…”

Section: Discussionsupporting

confidence: 90%

“…However, using immunohistochemistry (IHC), SST5 expression was only found in 20 to 55% of corticotroph tumors (20,21,22). Somatic driver mutations in the ubiquitin-specific protease 8 (USP8) gene, identified in 35% to 60% of corticotroph tumors (21,23,24,25,26,27,28), lead to an increase in the deubiquitinase activity of USP8 and to an increase of ACTH secretion by the tumor (28). SST5 expression has been found to be higher in USP8mut corticotroph tumors (21).…”

Section: Introductionmentioning

confidence: 99%

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SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors

Castellnou

Vasiljevic

Lapras

et al. 2020

Endocrine Connections

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Objective Somatostatin receptor type 5 (SST5) is inconsistently expressed by corticotroph tumors, with higher expression found in corticotropinomas having ubiquitin-specific protease 8 (USP8) mutations. Aims were to study the correlation between characteristics of corticotropinomas and SST5 expression/USP8 mutation status and to describe the response to pasireotide in five patients. Design Retrospective cohort study. Methods Clinico-biochemical, radiological and pathological data of 62 patients, operated for a functioning or silent corticotropinoma between 2013 and 2017, were collected. SST5 expression was measured by immunohistochemistry (clone UMB-4, Abcam, IRS > 1 being considered positive), and Sanger sequencing was performed on 50 tumors to screen for USP8 mutations. Results SST5 expression was positive in 26/62 pituitary tumors. A moderate or strong IRS was found in 15/58 corticotropinomas and in 13/35 functioning corticotropinomas. Among functioning tumors, those expressing SST5 were more frequent in women (22/24 vs 9/15, P = 0.04) and had a lower grade (P = 0.04) compared to others. USP8 mutations were identified in 13/50 pituitary tumors and were more frequent in functioning compared to silent tumors (11/30 vs 2/20, P = 0.05). SST5 expression was more frequent in USP8mut vs USP8wt tumors (10/11 vs 7/19, P = 0.007). Among treated patients, normal urinary free cortisol levels were obtained in three patients (IRS 0, 2 and 6), while a four-fold decrease was observed in one patient (IRS 4). Conclusion SST5 expression appears to be associated with functioning, USP8mut and lower grade corticotropinomas. A correlation between SST5 expression or USP8mut and response to pasireotide remains to be confirmed.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors

Castellnou

Vasiljevic

Lapras

et al. 2020

Endocrine Connections

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“…RNA was obtained from formalin-fixed or fresh specimens and carried out as previously described [12,103].…”

Section: Usp8 Sequencingmentioning

confidence: 99%

Sexual Dimorphism in Cellular and Molecular Features in Human ACTH-Secreting Pituitary Adenomas

Giraldi

Cassarino

Sesta

et al. 2020

Cancers

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(1) Background. Cushing’s disease presents gender disparities in prevalence and clinical course. Little is known, however, about sexual dimorphism at the level of the corticotrope adenoma itself. The aim of the present study was to evaluate molecular features of ACTH-secreting pituitary adenomas collected from female and male patients with Cushing’s disease. (2) Methods. We analyzed 153 ACTH-secreting adenomas collected from 31 men and 122 women. Adenomas were established in culture and ACTH synthesis and secretion assessed in basal conditions as well as during incubation with CRH or dexamethasone. Concurrently, microarray analysis was performed on formalin-fixed specimens and differences in the expression profiles between specimens from male and female patients identified. (3) Results. ACTH medium concentrations in adenomas obtained from male patients were significantly lower than those observed in adenomas from female patients. This could be observed for baseline as well as modulated secretion. Analysis of corticotrope transcriptomes revealed considerable similarities with few, selected differences in functional annotations. Differentially expressed genes comprised genes with known sexual dimorphism, genes involved in tumour development and genes relevant to pituitary pathophysiology. (4) Conclusions. Our study shows for the first time that human corticotrope adenomas present sexual dimorphism and underlines the need for a gender-dependent analysis of these tumours. Differentially expressed genes may represent the basis for gender-tailored target therapy.

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“…The prognosis of patients with somatic USP8 mutations differs in various studies. Some reports of increased risk for recurrence of patients with somatic USP8 mutations have not been replicated by others [104,106,107]. However, the potentially aggressive behavior of this genetic defect is evident in the patient with germline USP8 defect, described recently by Cohen et al [108].…”

Section: Ubiquitin Specific Peptidase 8 (Usp8)mentioning

confidence: 99%

“…In corticotroph cells, this defect results in high POMC expression and ACTH secretion [101,102]. Somatic defects of USP8 represent the most frequent genetic defect in CD, present in approximately 20-60% of all ACTH-secreting adenomas [101][102][103][104][105][106]. However, they are uncommon in other PAs.…”

Section: Ubiquitin Specific Peptidase 8 (Usp8)mentioning

confidence: 99%

The Genetics of Pituitary Adenomas

Tatsi

Stratakis

2019

JCM

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The genetic landscape of pituitary adenomas (PAs) is diverse and many of the identified cases remain of unclear pathogenetic mechanism. Germline genetic defects account for a small percentage of all patients and may present in the context of relevant family history. Defects in AIP (mutated in Familial Isolated Pituitary Adenoma syndrome or FIPA), MEN1 (coding for menin, mutated in Multiple Endocrine Neoplasia type 1 or MEN 1), PRKAR1A (mutated in Carney complex), GPR101 (involved in X-Linked Acrogigantism or X-LAG), and SDHx (mutated in the so called "3 P association" of PAs with pheochromocytomas and paragangliomas or 3PAs) account for the most common familial syndromes associated with PAs. Tumor genetic defects in USP8, GNAS, USP48 and BRAF are some of the commonly encountered tissue-specific changes and may explain a larger percentage of the developed tumors. Somatic (at the tumor level) genomic changes, copy number variations (CNVs), epigenetic modifications, and differential expression of miRNAs, add to the variable genetic background of PAs.

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Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas

Cited by 41 publications

References 29 publications

SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors

SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors

Sexual Dimorphism in Cellular and Molecular Features in Human ACTH-Secreting Pituitary Adenomas

The Genetics of Pituitary Adenomas

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