Gene expression analysis of bone biospies from nine patients with endogenous Cushings syndrome before and after treatment
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE30159 | GEO | 2012/04/08
SECONDARY ACCESSION(S): PRJNA143923
REPOSITORIES: GEO
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Project description:Mutations in the catalytic subunit of protein kinase A (PKAc) drive the stress hormone disorder adrenal Cushing’s syndrome. We define mechanisms of action for the PKAcL205R and W196R variants. Proximity proteomic techniques demonstrate that both Cushing’s mutants are excluded from A kinase anchoring protein (AKAP) signaling islands, whereas live-cell photoactivation microscopy reveals that these kinase mutants indiscriminately diffuse throughout the cell. Only cAMP analog drugs that displace native PKAc from AKAPs enhance cortisol release. Rescue experiments that incorporate PKAc mutants into AKAP complexes abolish cortisol overproduction, indicating that kinase anchoring restores normal endocrine function. Analyses of adrenal-specific PKAc-W196R knock-in mice and Cushing’s syndrome patient tissue reveal defective signaling mechanisms of the disease. Surprisingly each Cushing’s mutant engages a different mitogenic signaling pathway, with upregulation of YAP/TAZ by PKAc-L205R and ERK kinase activation by PKAc-W196R. Thus, aberrant spatiotemporal regulation of each Cushing’s variant promotes the transmission of distinct downstream pathogenic signals.
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Project description:Cushing’s syndrome (CS) is a rare disease with high morbidity and mortality. Diagnosis and subtyping are complex and challenging. Circulating microRNAs were described to be useful as minimally invasive diagnostic markers. Our aim was to determine and compare the circulating microRNA expression profiles of patients with CS and controls. We included three groups of patients of the German Cushing’s registry: A.) patients with florid adrenal dependent CS scheduled for adrenalectomy (CPA); B.) patients with florid pituitary dependent CS scheduled for surgery (CD); and C.) patients in whom CS had been ruled out (controls). Next-generation sequencing was performed in the 30 CS serum samples before and after curative surgery, respectively, and in 10 baseline samples of controls. No significant differential expression was observed between all the CS samples and controls by NGS as well as by QPCR. The sequencing of the preoperative samples revealed a significant differential expression of miR-182-5p (p=0.02) between CD and controls. The differential expression was validated by QPCR in the discovery cohort and in an independent validation cohort. MiR-96-5p, miR-146b-5p, miR-183-5p, miR-185-5p, miR-616-5p and miR-629-5p were found to be significantly upregulated in CPA samples in comparison to CD group of the preoperative group in NGS. However, similar upregulation pattern could not be observed by QPCR in the discovery and validation cohorts. Additionally, miR-96-5p and miR-185-5p were found to be modulated by dexamethasone in controls. Thus, our study reports miR-182-5p as a possible biomarker for CD, which has to be validated in a prospective cohort.
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Project description:Cushing’s syndrome (CS) is a serious endocrine disorder that is rare in humans, but relatively common in dogs. In ~15-20% of cases, CS is caused by a cortisol-secreting adrenocortical tumor (csACT). To identify differentially expressed genes that can improve prognostic predictions after surgery and represent novel treatment targets, we performed RNA sequencing on csACTs (n=48) and normal adrenal cortices (NACs; n=10) of dogs. A gene was declared differentially expressed when the adjusted P-value was <0.05 and the log2 fold change was >2 or <-2. Between NACs and csACTs, 98 genes were differentially expressed. Based on the principal component analysis (PCA) the csACTs were separated in two groups, of which group 1 had significantly better survival after adrenalectomy (P=0.002) than group 2. Between csACT group 1 and group 2, 77 genes were differentially expressed. One of these, cytochrome P450 26B1 (CYP26B1), was significantly associated with survival in both our canine csACTs and in a publicly available dataset of 33 human cortisol-secreting adrenocortical carcinomas. In the validation cohort, CYP26B1 was also expressed significantly higher (P=0.012) in canine csACTs compared to NACs. In future studies it would be interesting to determine whether CYP26B1 inhibitors could inhibit csACT growth in both dogs and humans.
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Project description:Adrenal Cushing’s syndrome is a disease of cortisol hypersecretion often caused by mutations in protein kinase A catalytic subunit (PKAc). Using a personalized medicine screening platform, we discovered a new Cushing’s driver mutation, PKAc-W196G, in ~20% of patient samples analyzed. Proximity proteomics and photokinetic imaging reveal that PKAcW196G is distinct from other Cushing’s variants. This mutant surprisingly retains association with type I regulatory subunits (RI) and their corresponding A kinase anchoring proteins (AKAPs). Molecular dynamics simulations predict that substitution of glycine for tryptophan 196 creates a 653 Å3 cleft between the catalytic core of PKAcW196G and type II regulatory subunits (RII), but only a 395 Å3 cleft with RI. Endocrine measurements show that overexpression of RIα or redistribution of PKAcW196G via AKAP recruitment counteracts stress hormone overproduction. We conclude that a W196G mutation in the kinase catalytic core skews R subunit selectivity and biases AKAP association to drive Cushing’s syndrome.
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Project description:ACTH-dependent hypercortisolism caused by a pituitary adenoma [Cushing’s disease (CD)] is the most common cause of endogenous Cushing’s syndrome. CD is often associated with several morbidities, including hypertension, diabetes, osteoporosis/bone fractures, secondary infections, and increased cardiovascular mortality. While the majority (≈80%) of the corticotrophinomas visible on pituitary magnetic resonance imaging are microadenomas (MICs, <10 mm of diameter), some tumors are macroadenomas (MACs, ≥10 mm) with increased growth potential and invasiveness, exceptionally exhibiting malignant demeanor. In addition, larger and invasive MACs are associated with a significant increased risk of local complications, such as hypopituitarism and visual defects. Given the clinical and molecular heterogeneity of corticotrophinomas, the aim of this study was to investigate the pattern of genetic differential expression between MIC and MAC, including the invasiveness grade as a criterion for categorizing these tumors. In this study, were included tumor samples from patients with clinical, laboratorial, radiological, and histopathological diagnosis of hypercortisolism due to an ACTH-producing pituitary adenoma. Differential gene expression was studied using an Affymetrix microarray platform in 12 corticotrophinomas, classified as non-invasive MIC (n = 4) and MAC (n = 5), and invasive MAC (n = 3), according to modified Hardy criteria. Somatic mutations in USP8 were also investigated, but none of the patients exhibited USP8 variants. Differential expression analysis demonstrated that non-invasive MIC and MAC have a similar genetic signature, while invasive MACs exhibited a differential expression profile. Among the genes differentially expressed, we highlighted CCND2, ZNF676, DAPK1, and TIMP2, and their differential expression was validated through quantitative real-time PCR in another cohort of 15 non-invasive and 3 invasive cortocotrophinomas. We also identified potential biological pathways associated with growth and invasiveness, TGF-β and G protein signaling pathways, DNA damage response pathway, and pathways associated with focal adhesion. Our study revealed a differential pattern of genetic signature in a subgroup of MAC, supporting a genetic influence on corticotrophinomas in patients with CD.
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Project description:Chronic glucocorticoids (GCs) exposure, resulting from endogenous Cushing Syndrome (CS) or prescribed GCs therapy, is associated with a high cardiometabolic burden. Moreover, previous studies have reported persistence of metabolic syndrome features after remission of hypercortisolism and in particular in visceral adipose tissue (VAT). Thus, in this study we want to analyze the transcriptomic alterations in VAT during active and cured CS and correlate these persistent gene expression changes with changes in histone modifications induced by GCs.
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Project description:We have previously shown in sheep that 10 days of modest chronic increase in maternal cortisol result in fetal heart enlargement and Purkinje cell apoptosis. In subsequent studies in which we extended the duration of cortisol infusion (1mg/kg/d) to term, we found a dramatic incidence of stillbirth in the pregnancies with chronically increased cortisol and associated maternal hyperglycemia. To investigate the effects on the heart, transcriptomic analyses were performed on the septa using ovine microarrays and Webgestalt and Cytoscape programs for pathway inference. Analyses of the effects of 10 days of maternal cortisol infusion (130d-cortisol vs 130d control), ~25 days (term at ~140d-cortisol vs 140d control), normal maturation (140d-control vs 130d control) were performed. In all analyses gene ontology (GO) terms related to immune function and cytokine actions were significantly over-represented. After 10 days of cortisol, growth factor and muscle cell apoptosis pathways were significantly over-represented, consistent with our previous findings. We found significantly differentially regulated genes in the term fetuses (ie after ~25 days of cortisol) in pathways consistent with altered metabolism in the heart, particularly in mitochondria, associated with responses to hypoxia and to nutrient. Analysis of mitochondrial number by quantitative real-time PCR confirmed a significant decrease. These pathways were different from those modeled following the normal increase in cortisol in late gestation which contributes to normal maturation of the heart, and thus may be indicative of the fetal heart pathophysiologies seen in pregnancies complicated by diabetes, Cushing’s disease and chronic stress.
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