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.
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.
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.
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.
Diagnosis of Primary Hypophysitis in Germany Honegger, Jürgen; Schlaffer, Sven; Menzel, Christa ...
The journal of clinical endocrinology and metabolism,
10/2015, Letnik:
100, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Context:
Representative data on diagnostic findings in primary hypophysitis (PrHy) are scarce.
Objective:
The objective of the study was to collate consistent data on clinical features in a large ...series of patients with PrHy. Another objective was to gain information on current practice in a diagnostic work-up.
Design:
The Pituitary Working Group of the German Society of Endocrinology conducted a nationwide retrospective cross-sectional cohort study in Germany.
Patients:
Seventy-six patients with PrHy were identified.
Main Outcome Measures:
Clinical and endocrinological features were assessed.
Results:
Headache (50%) and increase in body mass (18%) were the most frequent nonendocrine symptoms. Hypophysitis was associated with pregnancy in only 11% of the female patients. Diabetes insipidus was found in 54% of the patients at presentation. Hypogonadotropic hypogonadism was the most frequent endocrine failure (62%), whereas GH deficiency was the least frequent (37%). With 86%, thickening of the pituitary stalk was the prevailing neuroradiological sign. Compared with surgical cases, the cases without histological confirmation presented more often with suprasellar lesions and had less severe nonendocrine symptoms. Granulomatous hypophysitis was associated with more severe clinical symptoms than lymphocytic hypophysitis. Examination of cerebrospinal fluid was predominantly performed in participating neurosurgical centers, whereas thyroid antibodies were almost exclusively assessed in endocrinological centers.
Conclusion:
In contrast to the literature, hypogonadism was found to be the most frequent endocrine failure in PrHy. Weight gain was identified as a clinical sign of PrHy. In the majority of patients, PrHy can be reliably identified by characteristic clinical signs and symptoms, obviating histological confirmation. The diagnostic approach should be standardized in PrHy.
Cushing's disease (CD) is a rare condition caused by adrenocorticotropic hormone (ACTH)-producing adenomas of the pituitary, which lead to hypercortisolism that is associated with high morbidity and ...mortality. Treatment options in case of persistent or recurrent disease are limited, but new insights into the pathogenesis of CD are raising hope for new therapeutic avenues. Here, we have performed a meta-analysis of the available sequencing data in CD to create a comprehensive picture of CD's genetics. Our analyses clearly indicate that somatic mutations in the deubiquitinases are the key drivers in CD, namely USP8 (36.5%) and USP48 (13.3%). While in USP48 only Met415 is affected by mutations, in USP8 there are 26 different mutations described. However, these different mutations are clustering in the same hotspot region (affecting in 94.5% of cases Ser718 and Pro720). In contrast, pathogenic variants classically associated with tumorigenesis in genes like TP53 and BRAF are also present in CD but with low incidence (12.5% and 7%). Importantly, several of these mutations might have therapeutic potential as there are drugs already investigated in preclinical and clinical setting for other diseases. Furthermore, network and pathway analyses of all somatic mutations in CD suggest a rather unified picture hinting towards converging oncogenic pathways.
Purpose
Patients with acromegaly oftentimes exhibit a reduced physical and psychological health-related quality of life (HRQoL). Maladaptive coping styles are associated with poor HRQoL in a number ...of diseases and patients with pituitary adenomas in general exhibit less effective coping styles than healthy controls. This study aimed to assess coping strategies in acromegaly patients in order to explore leverage points for the improvement of HRQoL.
Methods
In this cross-sectional study, we administered self-report surveys for coping strategies and HRQoL (Short Form SF-36, Freiburg questionnaire on coping with illness, FKV-LIS) in patients with acromegaly. These were set into relation with a variety of health variables.
Results
About half of the 106 patients (44.3% female) with a mean age of 56.4 ± 1.3 years showed impaired physical and psychological HRQoL on average 11.2 years after the initial diagnosis. Body mass index, age at survey date and concomitant radiotherapy explained 27.8% of the variance of physical HRQoL, while depressive coping added an additional 9.2%. Depressive coping style and trivialization and wishful thinking were pivotal predictors of an impaired psychological HRQoL with a total explained variance of 51.6%, whereas patient health variables did not affect psychological HRQoL.
Conclusion
Our results show that maladaptive coping styles have a substantial negative impact on psychological HRQoL in patients with acromegaly, whereas physical HRQoL is influenced to a lesser extent. Specialized training programs aimed at improving coping strategies could reduce long-term disease burden and increase HRQoL in the affected patients.
Objective
Immune checkpoint inhibitors can cause various immune-related adverse events including secondary hypophysitis. We compared clinical characteristics of immunotherapy-induced hypophysitis ...(IIH) and primary hypophysitis (PH)
Design
Retrospective multicenter cohort study including 56 patients with IIH and 60 patients with PH.
Methods
All patients underwent extensive endocrine testing. Data on age, gender, symptoms, endocrine dysfunction, MRI, immunotherapeutic agents and autoimmune diseases were collected.
Results
Median time of follow-up was 18 months in IIH and 69 months in PH. The median time from initiation of immunotherapy to IIH diagnosis was 3 months. IIH affected males more frequently than PH (p < 0.001) and led to more impaired pituitary axes in males (p < 0.001). The distribution of deficient adenohypophysial axes was comparable between both entities, however, central hypocortisolism was more frequent (p < 0.001) and diabetes insipidus considerably less frequent in IIH (p < 0.001). Symptoms were similar except that visual impairment occurred more rarely in IIH (p < 0.001). 20 % of IIH patients reported no symptoms at all. Regarding MRI, pituitary stalk thickening was less frequent in IIH (p = 0.009). Concomitant autoimmune diseases were more prevalent in PH patients before the diagnosis of hypophysitis (p = 0.003) and more frequent in IIH during follow-up (p = 0.002).
Conclusions
Clinically, IIH and PH present with similar symptoms. Diabetes insipidus very rarely occurs in IIH. Central hypocortisolism, in contrast, is a typical feature of IIH. Preexisting autoimmunity seems not to be indicative of developing IIH.
Abstract
Context
Cushing disease (CD) is a rare disorder with severe sequels and incompletely understood pathogenesis. The underlying corticotroph adenomas harbor frequently somatic mutations in the ...ubiquitin-specific peptidase 8 (USP8) gene. These mutations render USP8 hyperactive and prevent client proteins from degradation.
Objective
To investigate the impact of USP8 mutations on proteins deregulated in CD.
Design
One hundred eight pituitary adenomas (75 corticotroph 58 USP8 wild type (WT) and 17 USP8 mutated, 14 somatotroph, and 19 nonfunctioning) were investigated by immunohistochemistry. All evaluated proteins USP8, arginine vasopressin receptor 1b and 2, corticotropin-releasing hormone receptor, cAMP response element-binding protein (CREB), p27/kip1, cyclin E, heat shock protein 90 (HSP90), orphan nuclear receptor 4, epidermal growth factor receptor, histone deacetylase 2, glucocorticoid receptor, cyclin-dependent kinase 5 and Abelson murine leukemia viral oncogene homolog 1 enzyme substrate 1 were known to be deregulated in CD. Furthermore, AtT20 cells were transfected with USP8 to investigate the expression of possible downstream proteins by immunoblot.
Results
Whereas most of the investigated proteins were not differentially expressed, the cell-cycle inhibitor p27 was significantly reduced in USP8 mutated corticotroph adenoma (H-score 2.0 ± 1.0 vs 1.1 ± 1.1 in WT adenomas; P = 0.004). In contrast, the chaperone HSP90 was expressed higher (0.5 ± 0.4 vs 0.2 ± 0.4; P = 0.29), and the phosphorylation of the transcription factor CREB was increased in USP8 mutated adenomas (1.30.5 ± 0.40.9 vs 0.70.5 ± 0.40.7; P = 0.014). Accordingly, AtT20 cells transfected with the USP8 P720R mutant had higher phosphorylated CREB (pCREB) levels than WT transfected cells (1.3 ± 0.14 vs 1 ± 0.23; P = 0.13).
Conclusions
We could demonstrate that USP8 mutations are associated with deregulation of p27/kip1, HSP90, and pCREB. These findings suggest that these proteins are direct or indirect clients of USP8 and could therefore be potential targets for therapeutic approaches in patients with CD.
We provide a correlation between ubiquitin-specific peptidase 8 (USP8) mutations and the expression of key proteins in corticotroph tumors, suggesting these proteins to be USP8 substrates and potential treatment targets against Cushing disease.
Context:
Surgery is the standard of care for localized adrenocortical carcinomas, but its role for recurrent disease is not well defined.
Objective:
Our objective was to evaluate clinical outcome ...after surgery for recurrence.
Design:
We conducted a retrospective analysis in 154 patients with first recurrence after initial radical resection from the German Adrenocortical Carcinoma Registry.
Main Outcome Measures:
We evaluated progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier method and identified prognostic factors by Cox regression analysis.
Result:
A total of 101 patients underwent repeated surgery (radical resection, n = 78), and 99 received (additional) nonsurgical therapy. After a median of 6 (1–221) months, 144 patients (94%) experienced progression. Multivariate analysis adjusted for age, sex, tumor burden, time to first recurrence (TTFR), surgery for recurrence (including resection status), and additional therapy indicated that only two factors were significantly associated with shorter PFS hazard ratio for progression: for TTFR ≤ 12 months, 1.8 (95% confidence interval = 1.3–2.6) vs. TTFR > 12 months; for macroscopically incomplete resection, 3.4 (1.5–7.9), and for no surgery, 3.4 (1.6–7.0) vs. microscopically complete (R0)-resection and OS hazard ratio for death: for TTFR > 12 months, 3.1 (2.0–4.7) vs. TTFR ≤ 12 months; for macroscopically incomplete resection, 2.7 (1.1–6.9), and no surgery, 4.2 (1.8–9.6) vs. R0-resection. Patients who had both TTFR over 12 months and R0-resection of recurrent tumors (n = 22) had the best prognosis (median PFS, 24 months; median OS, >60 months).
Conclusions:
The best predictors of prolonged survival after first recurrence are TTFR over 12 months and R0-resection. Our data suggest that patients with longer TTFR and tumors amenable to radical resection should be operated, whereas individualized treatment decisions are needed for patients with short TTFR or with not completely resectable tumors.
Adrenal incidentalomas with cortisol autonomy are associated with increased cardiovascular morbidity and mortality. Specific data on the clinical and biochemical course of affected patients are ...lacking.
Retrospective study from a tertiary referral centre in Germany. After exclusion of overt hormone excess, malignancy and glucocorticoid medication, patients with adrenal incidentalomas were stratified according to serum cortisol after 1 mg dexamethasone: autonomous cortisol secretion (ACS), >5.0; possible ACS (PACS), 1.9-5.0; non-functioning adenomas (NFA), ≤1.8 µg/dl.
A total of 260 patients were enrolled (147 women (56.5%), median follow-up 8.8 (2.0-20.8) years). At initial diagnosis, median age was 59.5 (20-82) years, and median tumour size was 27 (10-116) mm. Bilateral tumours were more prevalent in ACS (30.0%) and PACS (21.9%) than in NFA (8.1%). Over time, 40/124 (32.3%) patients had a shift of their hormonal secretion pattern (NFA to PACS/ACS, n=15/53; PACS to ACS, n=6/47; ACS to PACS, n=11/24; PACS to NFA, n=8/47). However, none of the patients developed overt Cushing's syndrome. Sixty-one patients underwent adrenalectomy (NFA, 17.9%; PACS, 24.0%; ACS, 39.0%). When non-operated patients with NFA were compared to PACS and ACS at last follow-up, arterial hypertension (65.3% vs. 81.9% and 92.0%; p<0.05), diabetes (23.8% vs. 35.6% and 40.0%; p<0.01), and thromboembolic events (PACS: HR 3.43, 95%-CI 0.89-13.29; ACS: HR 5.96, 95%-CI 1.33-26.63; p<0.05) were significantly less frequent, along with a trend towards a higher rate of cardiovascular events in case of cortisol autonomy (PACS: HR 2.23, 95%-CI 0.94-5.32; ACS: HR 2.60, 95%-CI 0.87-7.79; p=0.1). Twenty-five (12.6%) of the non-operated patients died, with higher overall mortality in PACS (HR 2.6, 95%-CI 1.0-4.7; p=0.083) and ACS (HR 4.7, 95%-CI 1.6-13.3; p<0.005) compared to NFA. In operated patients, prevalence of arterial hypertension decreased significantly (77.0% at diagnosis to 61.7% at last follow-up; p<0.05). The prevalence of cardiovascular events and mortality did not differ significantly between operated and non-operated patients, whereas thromboembolic events were significantly less frequent in the surgical treatment group.
Our study confirms relevant cardiovascular morbidity in patients with adrenal incidentalomas (especially those with cortisol autonomy). These patients should therefore be monitored carefully, including adequate treatment of typical cardiovascular risk factors. Adrenalectomy was associated with a significantly decreased prevalence of hypertension. However, more than 30% of patients required reclassification according to repeated dexamethasone suppression tests. Thus, cortisol autonomy should ideally be confirmed before making any relevant treatment decision (e.g. adrenalectomy).
Abstract
Context
Pheochromocytomas and paragangliomas (PPGLs) are characterized by distinct genotype-phenotype relationships according to studies largely restricted to Caucasian populations.
...Objective
To assess for possible differences in genetic landscapes and genotype-phenotype relationships of PPGLs in Chinese versus European populations.
Design
Cross-sectional study.
Setting
2 tertiary-care centers in China and 9 in Europe.
Participants
Patients with pathologically confirmed diagnosis of PPGL, including 719 Chinese and 919 Europeans.
Main Outcome Measures
Next-generation sequencing performed in tumor specimens with mutations confirmed by Sanger sequencing and tested in peripheral blood if available. Frequencies of mutations were examined according to tumor location and catecholamine biochemical phenotypes.
Results
Among all patients, higher frequencies of HRAS, FGFR1, and EPAS1 mutations were observed in Chinese than Europeans, whereas the reverse was observed for NF1, VHL, RET, and SDHx. Among patients with apparently sporadic PPGLs, the most frequently mutated genes in Chinese were HRAS (16.5% 13.6-19.3 vs 9.8% 7.6-12.1) and FGFR1 (9.8% 7.6-12.1 vs 2.2% 1.1-3.3), whereas among Europeans the most frequently mutated genes were NF1 (15.9% 13.2-18.6 vs 6.6% 4.7-8.5) and SDHx (10.7% 8.4–13.0 vs 4.2% 2.6–5.7). Among Europeans, almost all paragangliomas lacked appreciable production of epinephrine and identified gene mutations were largely restricted to those leading to stabilization of hypoxia inducible factors. In contrast, among Chinese there was a larger proportion of epinephrine-producing paragangliomas, mostly due to HRAS and FGFR1 mutations.
Conclusions
This study establishes Sino-European differences in the genetic landscape and presentation of PPGLs, including ethnic differences in genotype-phenotype relationships indicating a paradigm shift in our understanding of the biology of these tumors.
The New Molecular Landscape of Cushing's Disease Sbiera, Silviu; Deutschbein, Timo; Weigand, Isabel ...
Trends in endocrinology and metabolism,
10/2015, Letnik:
26, Številka:
10
Journal Article
Recenzirano
Cushing's disease (CD) is caused by corticotropin-secreting pituitary adenomas and results in substantial morbidity and mortality. Its molecular basis has remained poorly understood until the past ...few years, when several proteins and genes such as testicular orphan nuclear receptor 4 (TR4) and heat shock protein 90 (HSP90) were found to play key roles in the disease. Most recently, mutations in the gene of ubiquitin-specific peptidase 8 (USP8) increasing its deubiquination activity were discovered in a high percentage of corticotroph adenomas. Here, we will discuss emerging insights in the molecular alterations that finally result in CD. The therapeutic potential of these findings needs to be carefully evaluated in the near future, hopefully resulting in new treatment options for this devastating disorder.
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