Case Report: Consecutive Adrenal Cushing's Syndrome and Cushing's Disease in a Patient With Somatic CTNNB1, USP8, and NR3C1 Mutations.
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ABSTRACT:
SUBMITTER: Detomas M
PROVIDER: S-EPMC8417750 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Medical treatment in Cushing's disease (CD) is limited due to poor understanding of its pathogenesis. Pathogenic variants of ubiquitin specific peptidase 8 (USP8) have been confirmed as causative in around half of corticotroph tumors. We aimed to further characterize the molecular landscape of those CD tumors lacking USP8 mutations in a large cohort of patients. METHODS:Exome sequencing was performed on 18 paired tumor-blood samples with wild-type USP8 status. Candidate gene variants were screened by Sanger sequencing in 175 additional samples. The most frequent variant was characterized by further functional in vitro assays. RESULTS:Recurrent somatic hotspot mutations in another deubiquitinase, USP48, were found in 10.3% of analyzed samples. Several possibly damaging variants were found in TP53 in 6 of 18 samples. USP48 variants were associated with smaller tumors and trended toward higher frequency in female patients. They also changed the structural conformation of USP48 and increased its catalytic activity toward its physiological substrates histone 2A and zinc finger protein Gli1, as well as enhanced the stimulatory effect of corticotropin releasing hormone (CRH) on pro-opiomelanocortin production and adrenocorticotropic hormone secretion. CONCLUSIONS:USP48 pathogenic variants are relatively frequent in USP8 wild-type tumors and enhance CRH-induced hormone production in a manner coherent with sonic hedgehog activation. In addition, TP53 pathogenic variants may be more frequent in larger CD tumors than previously reported.
| S-EPMC6784271 | biostudies-literature
Project description:Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.
| S-EPMC4349249 | biostudies-literature
Project description:Recent discoveries of somatic mutations permit the recognition of subtypes of aldosterone-producing adenomas with distinct clinical presentations and pathological features. Here we describe three women with hyperaldosteronism, two who presented in pregnancy and one who presented after menopause. Their aldosterone-producing adenomas harbored activating mutations of CTNNB1, encoding ?-catenin in the Wnt cell-differentiation pathway, and expressed LHCGR and GNRHR, encoding gonadal receptors, at levels that were more than 100 times as high as the levels in other aldosterone-producing adenomas. The mutations stimulate Wnt activation and cause adrenocortical cells to de-differentiate toward their common adrenal-gonadal precursor cell type. (Funded by grants from the National Institute for Health Research Cambridge Biomedical Research Centre and others.).
| S-EPMC4612399 | biostudies-literature
Project description:BackgroundCorticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing's syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition.MethodsWe genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo repeat containing 5 (ARMC5) inactivation and overexpression were tested in cell-culture models.ResultsThe most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival.ConclusionsSome cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management. (Funded by Agence Nationale de la Recherche and others.).
| S-EPMC4727443 | biostudies-literature
Project description: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.
| S-EPMC5546857 | biostudies-literature
Project description:Adrenal Cushing's syndrome is a rare cause of endogenous hypercortisolism in neonatal and early childhood stages. The most common causes of adrenal CS are hyperfunctioning adrenal tumours, adenoma or carcinoma. Rarer causes are primary bilateral macronodular adrenal hyperplasia (PBAMH), primary pigmented adrenocortical disease (PPNAD) and McCune Albright syndrome. The diagnosis represents a challenge for clinicians. In cases of clinical suspicion, confirmatory tests of hypercortisolism should be performed, similarly to those performed in adults. Radiological imaging should be always combined with biochemical confirmatory tests, for the differential diagnosis of adrenal CS causes. Treatment strategies for adrenal CS include surgery and in specific cases medical drugs. An adequate treatment is associated to an improvement of growth, bone health, reproduction and body composition from childhood into and during adult life. After cure, lifelong glucocorticoid replacement therapy and endocrine follow-up are required, notably in patients with Carney's complex disease.
| S-EPMC10773667 | biostudies-literature
Project description:Metastases are involved in most cancer deaths. Evidence has suggested that cancer cell detachment from primary tumors might occur largely via the mechanism of epithelial-mesenchymal transition (EMT) activated by epigenetic events, but data addressing other possible triggers of detachment, particularly genetic mutations, have been limited. Using the Profile study of cancer genomics at Dana-Farber Cancer Institute, we examined somatic mutations in the EMT genes CDH1 in 5,106 primary carcinomas and CTNNB1 in 7,578 primary carcinomas across 13 anatomic sites: urinary bladder, breast, colon/rectum, endometrium, esophagus, kidney, lung, ovary, pancreas, prostate, skin (non-melanoma), stomach, and thyroid. For each gene and anatomic site, we calculated the prevalence of primary carcinomas with at least one mutation. Across all anatomic sites, 4% of carcinomas had at least one CDH1 mutation and 4% of carcinomas had at least one CTNNB1 mutation. By anatomic site, the observed prevalence of carcinomas with at least one mutation was less than 5% at 10 sites for CDH1 and 12 sites for CTNNB1. Tumor stage data were available for a subset of breast, colorectal, lung, and prostate tumors. Among patients from this subset who were diagnosed with regional or distant disease, only 4% had a CDH1 mutation and 1% had a CTNNB1 mutation in the primary tumor. The low mutation prevalences, especially among those with diagnoses of regional or distant disease, suggest that somatic mutations in CDH1 and CTNNB1 are unlikely to explain a substantial proportion of cancer cell detachment from primary carcinomas originating at most anatomic sites.
| S-EPMC5689640 | biostudies-literature
Project description:BACKGROUND:In the spectrum of molecular alterations found in hepatocellular carcinoma (HCC), somatic mutations in the WNT/?-catenin pathway and the p53/cell cycle control pathway are among the most frequent ones. It has been suggested that both mutations occur in a mutually exclusive manner and they are used as molecular classifiers in HCC classification proposals. CASE PRESENTATION:Here, we report the case of a treatment-naïve mixed hepatocellular/cholangiocellular carcinoma (HCC/CCC) with morphological and genetic intratumor heterogeneity. Within the predominant part of the tumor with hepatocellular differentiation, a p.D32V mutation in exon 3 of the CTNNB1 gene occurred concomitantly with a TP53 intron 7/exon 8 splice site mutation. CONCLUSION:Intratumor heterogeneity challenges the concept of CTNNB1 and TP53 gene mutations being mutually exclusive molecular classifiers in HCC, which has implications for HCC classification approaches.
| S-EPMC4888639 | biostudies-literature
Project description:MiRNAs are important epigenetic players with tissue- and disease-specific effects. In this study, our aim was to investigate the putative differential expression of miRNAs in adrenal tissues from different forms of Cushing's syndrome (CS). For this, miRNA-based next-generation sequencing was performed in adrenal tissues taken from patients with ACTH-independent cortisol-producing adrenocortical adenomas (CPA), from patients with ACTH-dependent pituitary Cushing's disease (CD) after bilateral adrenalectomy, and from control subjects. A confirmatory QPCR was also performed in adrenals from patients with other CS subtypes, such as primary bilateral macronodular hyperplasia and ectopic CS. Sequencing revealed significant differences in the miRNA profiles of CD and CPA. QPCR revealed the upregulated expression of miR-1247-5p in CPA and PBMAH (log2 fold change > 2.5, p < 0.05). MiR-379-5p was found to be upregulated in PBMAH and CD (log2 fold change > 1.8, p < 0.05). Analyses of miR-1247-5p and miR-379-5p expression in the adrenals of mice which had been exposed to short-term ACTH stimulation showed no influence on the adrenal miRNA expression profiles. For miRNA-specific target prediction, RNA-seq data from the adrenals of CPA, PBMAH, and control samples were analyzed with different bioinformatic platforms. The analyses revealed that both miR-1247-5p and miR-379-5p target specific genes in the WNT signaling pathway. In conclusion, this study identified distinct adrenal miRNAs as being associated with CS subtypes.
| S-EPMC9320303 | biostudies-literature
Project description:Primary aldosteronism (PA) represents the most common cause of secondary hypertension, but little is known regarding its adrenal cellular origins. Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue. PA-causing aldosterone-producing adenomas (APAs) harbor mutations in genes encoding ion channels/pumps that alter intracellular calcium homeostasis and cause renin-independent aldosterone production through increased CYP11B2 expression. Herein, we hypothesized that APCCs have APA-related aldosterone-stimulating somatic gene mutations. APCCs were studied in 42 normal adrenals from kidney donors. To clarify APCC molecular characteristics, we used microarrays to compare the APCC transcriptome with conventional adrenocortical zones [zona glomerulosa (ZG), zona fasciculata, and zona reticularis]. The APCC transcriptome was most similar to ZG but with an enhanced capacity to produce aldosterone. To determine if APCCs harbored APA-related mutations, we performed targeted next generation sequencing of DNA from 23 APCCs and adjacent normal adrenal tissue isolated from both formalin-fixed, paraffin-embedded, and frozen tissues. Known aldosterone driver mutations were identified in 8 of 23 (35%) APCCs, including mutations in calcium channel, voltage-dependent, L-type, α1D-subunit (CACNA1D; 6 of 23 APCCs) and ATPase, Na(+)/(K+) transporting, α1-polypeptide (ATP1A1; 2 of 23 APCCs), which were not observed in the adjacent normal adrenal tissue. Overall, we show three major findings: (i) APCCs are common in normal adrenals, (ii) APCCs harbor somatic mutations known to cause excess aldosterone production, and (iii) the mutation spectrum of aldosterone-driving mutations is different in APCCs from that seen in APA. These results provide molecular support for APCC as a precursor of PA.
| S-EPMC4547250 | biostudies-other