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

Castellnou, Solène; Vasiljevic, Alexandre; Lapras, V.; Raverot, Véronique; Alix, Eudéline; Borson‐Chazot, Françoise; Jouanneau, Emmanuel; Raverot, Gérald; Lasolle, Hélène

doi:10.1530/ec-20-0035

Cited by 32 publications

(36 citation statements)

References 56 publications

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“…These results raise the question of whether this may also be the case for other SSTs and whether the histological subtype may be a predictor of response to SSTs ligands. Moreover, from a biological point of view, it suggests that different tumorigenesis mechanisms may be responsible for SST2+ versus SST2− gonadotroph tumors, as recently proposed for SST5+ versus SST5− corticotroph PitNETs [20,21].…”

Section: Discussionmentioning

confidence: 59%

Gonadotroph Tumors Show Subtype Differences that Might Have Implications for Therapy

Ilie

Vasiljevic

Louvet

et al. 2020

Cancers

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Gonadotroph tumors, although frequent, are poorly studied and understood, being usually included in the larger nonfunctioning pituitary neuroendocrine tumors (PitNETs) group. Moreover, in comparison to the other types of PitNETs, no established medical treatment is currently available for gonadotroph tumors. Here, we performed a retrospective study and analyzed the clinicopathological characteristics of 98 gonadotroph tumors operated in a single large pituitary center. Although being larger in men (p = 0.01), the aggressiveness of gonadotroph tumors did not appear to be sex-related. LH tumors were rare (4/98) and exclusively encountered in men. Somatostatin receptor type 5 (SST5) was absent in all analyzed tumors. The immunoreactive score (IRS) of somatostatin receptor type 2 (SST2) and of estrogen receptor alpha (ERα) was associated with the histological subtype (p = 0.01 and p = 0.02). IRS ERα correlated moderately with IRS SST2 in all (rho = 0.44, adjusted p-value = 0.0001) and in male (rho = 0.51, adjusted p-value = 0.0002) patients, and with follicle-stimulating hormone (FSH) percentage in all (rho = 0.40, adjusted p-value = 0.0005) and in female (rho = 0.58, adjusted p-value = 0.004) patients. In conclusion, gonadotroph tumors exhibit histological characteristics pinpointing the existence of several subtypes. Their heterogeneity warrants further investigations and may have to be taken into account when studying these tumors and investigating treatment options.

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Section: Discussionmentioning

confidence: 59%

Gonadotroph Tumors Show Subtype Differences that Might Have Implications for Therapy

Ilie

Vasiljevic

Louvet

et al. 2020

Cancers

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“…The mutations are less frequent in this group of patients than in the case of Cushing's disease. We identified the mutations in 20% of patients, while the mutation rate was 10% in the other study by Castellnoum, which included 20 SCAs [9]. No SCA with mutation was found in a study that included 11 such patients [6].…”

Section: Discussionmentioning

confidence: 66%

“…Recently, notable progress in the understanding of pathogenesis of CD has been made [3], including the discovery of recurrent USP8 mutations [4][5][6]. These mutations are observed in approximately 30-40% of patients suffering from Cushing's disease as well as in silent tumors [4,[6][7][8][9]. Patients with Cushing's disease with and without USP8 mutations have a slightly different clinical profile according to previously published data [4,6,8,[10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 84%

Differential microRNA Expression in USP8-Mutated and Wild-Type Corticotroph Pituitary Tumors Reflect the Difference in Protein Ubiquitination Processes

Bujko

Kober

Boresowicz

et al. 2021

JCM

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Background: USP8 mutations are the most common driver changes in corticotroph pituitary tumors. They have direct effect on cells’ proteome through disturbance of ubiquitination process and also influence gene expression. The aim of this study was to compare microRNA profiles in USP8-mutated and wild-type tumors and determine the probable role of differential microRNA expression by integrative microRNA and mRNA analysis. Methods: Patients with Cushing’s disease (n = 28) and silent corticotroph tumors (n = 20) were included. USP8 mutations were identified with Sanger sequencing. MicroRNA and gene expression was determined with next-generation sequencing. Results: USP8-mutated patients with Cushing’s disease showed higher rate of clinical remission and trend towards lower tumor volume than wild-type patients. Comparison of microRNA profiles of USP8-mutated and wild-type tumors revealed 68 differentially expressed microRNAs. Their target genes were determined by in silico prediction and microRNA/mRNA correlation analysis. GeneSet Enrichment analysis of putative targets showed that the most significantly overrepresented genes are involved in protein ubiquitination-related processes. Only few microRNAs influence the expression of genes differentially expressed between USP8-mutated and wild-type tumors. Conclusions: Differences in microRNA expression in corticotropinomas stratified according to USP8 status reflect disturbed ubiquitination processes, but do not correspond to differences in gene expression between these tumors.

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“…The frequency of USP8 mutations observed in our cohort is lower than in most cohorts described so far. Indeed, according to a recent published meta-analysis, USP8 somatic mutations have been reported in about 35% (20-60%) of cases [10], with the lowest and highest prevalence registered in European studies [16,22,34] and a large Chinese cohort [3], respectively, probably suggesting a role of genetic background and ethnicity differences. Mutations in USP48 and BRAF have also been recently detected in corticotroph tumors, mostly wild type for USP8 itself [9,24,35].…”

Section: Discussionmentioning

confidence: 99%

“…It has been observed that V600E variant has an increased kinase activity, resulting in activation of MAPK pathway and elevation of POMC transcription and ACTH synthesis [9]. Following the identification of driver mutations in ACTH-secreting tumors, in the past few years many groups reported the results of genetic analysis of CD patients, mainly performed for USP8 by exome sequencing or targeted sequencing [11][12][13][14][15][16][17][18][19][20][21][22][23][24]. The aim of the present study was to characterize the genetic profile of a cohort of 60 patients subjected to surgery excision of ACTH-secreting tumors, searching for somatic mutations in USP8, USP48, and BRAF hotspot regions.…”

Section: Introductionmentioning

confidence: 99%

Genetic Profiling of a Cohort of Italian Patients with ACTH-Secreting Pituitary Tumors and Characterization of a Novel USP8 Gene Variant

Treppiedi

Barbieri

Muro

et al. 2021

Cancers

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Cushing’s Disease (CD) is a rare condition characterized by an overproduction of ACTH by an ACTH-secreting pituitary tumor, resulting in an excess of cortisol release by the adrenal glands. Somatic mutations in the deubiquitinases USP8 and USP48, and in BRAF genes, have been reported in a subset of patients affected by CD. The aim of this study was to characterize the genetic profile of a cohort of 60 patients with ACTH-secreting tumors, searching for somatic mutations in USP8, USP48, and BRAF hotspot regions. Seven patients were found to carry USP8 somatic mutations in the well-characterized 14-3-3 protein binding motif (n = 5 P720R, n = 1 P720Q, n = 1 S718del); 2 patients were mutated in USP48 (M415I); no mutation was identified in BRAF. In addition, a novel USP8 variant, G664R, located in exon 14, upstream of the 14-3-3 protein binding motif, was identified in 1 patient. Functional characterization of USP8 G664R variant was performed in murine corticotroph tumor AtT-20 cells. Transient transfection with the USP8 G664R variant resulted in a significant increase of ACTH release and cell proliferation (+114.5 ± 53.6% and +28.3 ± 2.6% vs. empty vector transfected cells, p < 0.05, respectively). Notably, USP8 proteolytic cleavage was enhanced in AtT-20 cells transfected with G664R USP8 (1.86 ± 0.58–fold increase of N-terminal USP8 fragment, vs. WT USP8, p < 0.05). Surprisingly, in situ Proximity Ligation Assay (PLA) experiments showed a significant reduction of PLA positive spots, indicating USP8/14-3-3 proteins colocalization, in G664R USP8 transfected cells with respect to WT USP8 transfected cells (−47.9 ± 6.6%, vs. WT USP8, p < 0.001). No significant difference in terms of ACTH secretion, cell proliferation and USP8 proteolytic cleavage, and 14-3-3 proteins interaction was observed between G664R USP8 and S718del USP8 transfected cells. Immunofluorescence experiments showed that, contrary to S718del USP8 but similarly to WT USP8 and other USP8 mutants, G664R USP8 displays an exclusive cytoplasmic localization. In conclusion, somatic mutations were found in USP8 (13.3% vs. 36.5% incidence of all published mutations) and USP48 (3.3% vs. 13.3% incidence) hotspot regions. A novel USP8 variant was identified in a CD patient, and in vitro functional studies in AtT-20 cells suggested that this somatic variant might be clinically relevant in ACTH-secreting tumor pathogenesis, expanding the characterization of USP8 functional domains.

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

Cited by 32 publications

References 56 publications

Gonadotroph Tumors Show Subtype Differences that Might Have Implications for Therapy

Gonadotroph Tumors Show Subtype Differences that Might Have Implications for Therapy

Differential microRNA Expression in USP8-Mutated and Wild-Type Corticotroph Pituitary Tumors Reflect the Difference in Protein Ubiquitination Processes

Genetic Profiling of a Cohort of Italian Patients with ACTH-Secreting Pituitary Tumors and Characterization of a Novel USP8 Gene Variant

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