Endocrine Abstracts

Background: Molecular mechanisms underlying the pathogenesis of adrenocortical adenomas (ACAs) and autonomous cortisol secretion remains frequently unexplained despite previous comprehensive genomics studies.Aim: To gain novel insights into molecular pathogenesis of adrenocortical tumours by investigating transcriptome profiles of ACAs at single-nuclei resolution (snRNA-Seq), using adult human normal adrenal glands (NAGs) as reference.<p class="abste...

Introduction: Transcriptional regulation of gene expression by miRNAs is critical for the fine-tuning of stress response. However, its role in hypercortisolism has not been explored well. After exploring circulating miRNAs in Cushing’ Syndrome (CS) as biomarkers our aim was to investigate their origin and their role in adrenal tissue.Methods: Next generation sequencing (NGS) based miRNA profiling was performed in adrenal samples from patients of Ger...

Background: Adrenocortical carcinoma (ACC) is a very rare and aggressive, endocrine malignancy with still limited treatment options. Approximately 60% of patients with ACC show endogenous glucocorticoid excess which could be one potential cause, why first clinical trials with immunotherapies, like immune checkpoint inhibitors, showed only modest results. Due to the lack of an ACC-specific antigen structure, other immunotherapeutic approaches, like specialized cancer treatments...

Adrenocortical carcinomas (ACC) are associated with heterogeneous prognosis and limited treatment options for advanced stages. Until now no efficient targeted therapies have been identified. This study aims to identify possible new molecular drug targets for a future personalized therapeutic approach. RNA was isolated from 40 formalin-fixed paraffin-embedded tumor samples from ACC patients (26F&14M, median age 46 yrs) with known genetic background (Lippert et al. JCEM ...

Adrenocortical carcinoma (ACC) is an orphan tumor entity the pathogenesis of which is poorly understood. In advanced tumour stages, prognosis is unfavorable, but biomarkers for early diagnosis are lacking. MALDI-Mass Spectrometry Imaging (MALDI-MSI) enables semi-quantitative detection of a broad spectrum of analytes including endogenous cell metabolites in tissue sections. MALDI-MSI was used as a discovery approach to analyse tissue specimens of 72 ACC patients in FFPE tissue ...

Previously, we identified seven mutations in the main catalytic subunit of protein kinase A (PKA Cα) to be responsible for cortisol-secreting adrenocortical adenomas (CPAs): L206R, L199_C200_insW, S213R_L212_K214insIILR, C200_GlyinsV, W197R, del244-248+E249Q, E32V. Here we performed a functional characterization of these mutants. Specifically, we evaluated the association between PKA regulatory and catalytic subunits using co-immunoprecipitation and PKA activity using a k...

Adrenocortical carcinoma (ACC) is a rare tumor with heterogeneous outcome and no available targeted therapy. The aim of the study is to identify prognostic molecular markers and novel potential drug targets.A total of 43 FFPE tumor samples were retrospectively investigated for somatic mutations and copy number variations (CNV) by next-generation sequencing (160 cancer-related genes, Qiagen). Gene expression was evaluated by quantitative RT-PCR in a subgr...

Mitotane is the only approved drug for the treatment of advanced adrenocortical carcinoma (ACC) and we recently demonstrated that a high expression of cytochrome P450 2W1 (CYP2W1) correlated with response to mitotane. The association between CYP2W1 alleles and a generally increased cancer risk is under debate. Aim of the study was to evaluate the frequency of CYP2W1 polymorphisms and its correlation with the response to mitotane treatment in ACC patients.<p class="abstext"...

Recently, somatic, heterozygous mutations in the gene encoding the deubiquitinase USP8 have been identified in 30–60% of corticotroph tumors. These mutations were found to hinder binding of 14-3-3 proteins, increasing its deubiquitinating activity. One substrate is Epidermal Growth Factor Receptor (EGFR), USP8 triggering EGFR recycling and increased EGFR signaling. However, tumors harboring mutations in USP8 are smaller than WT tumors, raising the debate if EGFR, as a pot...

Background: Heterozygous activating somatic mutations in the catalytic subunit α (Cα) of Protein Kinase A (PKA) underlie 30–40% of cortisol producing adrenocortical adenomas (CPA). The activity of the catalytic subunits α,β,γ is controlled by the regulatory subunits (Iα,Iβ, IIα, IIβ). Previous reports found uncommonly reduced levels of RIIβ in CPA compared to other adrenocortical tumors.Aim: Investig...