Somatic mutations in adrenocortical carcinoma with primary aldosteronism or hyperreninemic hyperaldosteronism

Several somatic mutations specific to aldosterone-producing adenomas (APAs) have been described. A small proportion of adrenocortical carcinomas (ACCs) are associated with hyperaldosteronism, either primary aldosteronism or hyperreninemic hyperaldosteronism. However, it is unknown whether they harbor mutations of the same spectrum as APAs. The objective of this study is to describe the clinical phenotype and molecular genotype of ACCs with hyperaldosteronism, particularly the analysis for common APA-associated genetic changes. Patients were identified by retrospective chart review at a specialized referral center and by positive staining for CYP11B2 of tissue microarrays. Twenty-five patients with ACC and hyperaldosteronism were initially identified by retrospective chart review, and tissue for further analysis was available on 13 tumors. Seven patients were identified by positive staining for CYP11B2 in a tissue microarray, of which two were already identified in the initial chart review. Therefore, a total number of 18 patients with a diagnosis of ACC and features of either primary aldosteronism or hyperreninemic hyperaldosteronism were therefore included in the final study. Mutational status for a select list of oncogenes, tumor suppressor genes and genes known to carry mutations in APAs were analyzed by next-generation sequencing. Review of clinical data suggested autonomous aldosterone production in the majority of cases, while for some cases, hyperreninemic hyperaldosteronism was the more likely mechanism. The mutational landscape of ACCs associated with hyperaldosteronism was not different from ACCs with a different hormonal phenotype. None of the ACCs harbored mutations of known APA-associated genes, suggesting an alternative mechanism conferring aldosterone production.

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Molecular mechanisms in primary aldosteronism

Journal of Endocrinology ◽

10.1530/joe-19-0193 ◽

2019 ◽

Vol 242 (3) ◽

pp. R67-R79 ◽

Cited By ~ 1

Author(s):

Kelly De Sousa ◽

Alaa B Abdellatif ◽

Rami M El Zein ◽

Maria-Christina Zennaro

Keyword(s):

Arterial Hypertension ◽

Adrenal Cortex ◽

Primary Aldosteronism ◽

Molecular Mechanisms ◽

Somatic Mutations ◽

Type I ◽

Adrenal Hyperplasia ◽

New Genes ◽

Aldosterone Production ◽

Bilateral Adrenal Hyperplasia

Primary aldosteronism (PA) is the most common form and an under-diagnosed cause of secondary arterial hypertension, accounting for up to 10% of hypertensive cases and associated to increased cardiovascular risk. PA is caused by autonomous overproduction of aldosterone by the adrenal cortex. It is mainly caused by a unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. Excess aldosterone leads to arterial hypertension with suppressed renin, frequently associated to hypokalemia. Mutations in genes coding for ion channels and ATPases have been identified in APA, explaining the pathophysiology of increased aldosterone production. Different inherited genetic abnormalities led to the distinction of four forms of familial hyperaldosteronism (type I to IV) and other genetic defects very likely remain to be identified. Somatic mutations are identified in APA, but also in aldosterone-producing cell clusters (APCCs) in normal adrenals, in image-negative unilateral hyperplasia, in transitional lesions and in APCC from adrenals with bilateral adrenal hyperplasia (BAH). Whether these structures are precursors of APA or whether somatic mutations occur in a proliferative adrenal cortex, is still a matter of debate. This review will summarize our knowledge on the molecular mechanisms responsible for PA and the recent discovery of new genes related to early-onset and familial forms of the disease. We will also address new issues concerning genomic and proteomic changes in adrenals with APA and discuss adrenal pathophysiology in relation to aldosterone-producing structures in the adrenal cortex.

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Transcriptomics, Epigenetics, and Metabolomics of Primary Aldosteronism

Cancers ◽

10.3390/cancers13215582 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5582

Author(s):

Ariadni Spyroglou ◽

George P. Piaditis ◽

Gregory Kaltsas ◽

Krystallenia I. Alexandraki

Keyword(s):

Primary Aldosteronism ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Treatment Strategies ◽

Micro Rna ◽

The Past ◽

Mutational Status ◽

Endocrine Hypertension ◽

Protein Receptors ◽

Aldosterone Production

Introduction: Primary aldosteronism (PA) is the most common cause of endocrine hypertension, mainly caused by aldosterone-producing adenomas or hyperplasia; understanding its pathophysiological background is important in order to provide ameliorative treatment strategies. Over the past several years, significant progress has been documented in this field, in particular in the clarification of the genetic and molecular mechanisms responsible for the pathogenesis of aldosterone-producing adenomas (APAs). Methods: Systematic searches of the PubMed and Cochrane databases were performed for all human studies applying transcriptomic, epigenetic or metabolomic analyses to PA subjects. Studies involving serial analysis of gene expression and microarray, epigenetic studies with methylome analyses and micro-RNA expression profiles, and metabolomic studies focused on improving understanding of the regulation of autonomous aldosterone production in PA were all included. Results: In this review we summarize the main findings in this area and analyze the interplay between primary aldosteronism and several signaling pathways with differential regulation of the RNA and protein expression of several factors involved in, among others, steroidogenesis, calcium signaling, and nuclear, membrane and G-coupled protein receptors. Distinct transcriptomic and metabolomic patterns are also presented herein, depending on the mutational status of APAs. In particular, two partially opposite transcriptional and steroidogenic profiles appear to distinguish APAs carrying a KCNJ5 mutation from all other APAs, which carry different mutations. Conclusions: These findings can substantially contribute to the development of personalized treatment in patients with PA.

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Somatic mutations in adrenals from patients with primary aldosteronism not cured after adrenalectomy suggest common pathogenic mechanisms between unilateral and bilateral disease

Acta Endocrinologica ◽

10.1530/eje-21-0338 ◽

2021 ◽

Author(s):

Inès Hacini ◽

Kelly De Sousa ◽

Sheerazed Boulkroun ◽

Tchao Meatchi ◽

Laurence Amar ◽

...

Keyword(s):

Clinical Data ◽

Primary Aldosteronism ◽

Somatic Mutations ◽

Adrenal Glands ◽

Morphological Characteristics ◽

Driver Genes ◽

Genetic Characteristics ◽

Aldosterone Production ◽

Biochemical Cure ◽

Lateralization Index

Objective: Primary aldosteronism (PA) is the most common form of secondary and curable hypertension. Different germline and somatic mutations are found in aldosterone producing adenoma (APA) and familial forms of the disease, while the causes of bilateral adrenal hyperplasia (BAH) remain largely unknown. Adrenalectomy is the recommended treatment for patients with APA; however, 6% of patients are not cured and show persistent PA after surgery suggesting BAH. The objective of this study was to analyze clinical data of patients with APA without biochemical success after adrenalectomy as well as the histological and genetic characteristics of their adrenal glands. Design and Methods: Clinical data of 12 patients without biochemical cure were compared to those from 39 PA patients with hormonal cure after surgery. Histological, morphological and genetic characterization of the adrenals was carried out by CYP11B2 and CYP11B1 immunostaining and by CYP11B2-guided NGS. Results: Patients with absent hormonal cure displayed longer duration of arterial hypertension and lower lateralization index of aldosterone production. In 10 patients, APA expressing CYP11B2 were identified. No difference in histological and morphological characteristics was observed between patients with our without hormonal cure. Somatic mutations in APA driver genes were identified in all CYP11B2 positive APA; CACNA1D mutations were the most frequent genetic abnormality. Conclusions: Patients with absent biochemical cure were diagnosed later and exhibited lower lateralization index of aldosterone production, suggesting asymmetric aldosterone production in the context of BAH. Somatic mutations in adrenal glands from those patients indicate common mechanisms underlying BAH and APA.

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Bupropion treatment of youths with depressive episode: a retrospective chart review

10.26226/morressier.5785edd1d462b80296c9a2c1 ◽

2016 ◽

Author(s):

Kukju Kweon

Keyword(s):

Depressive Episode ◽

Chart Review ◽

Retrospective Chart Review

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Cancer of the vulva: genetic aspects of pathogenesis

GYNECOLOGY ◽

10.26442/2079-5696_2018.4.9-11 ◽

2018 ◽

Vol 20 (4) ◽

pp. 9-11 ◽

Cited By ~ 1

Author(s):

V V Sobolev ◽

Z A Nevozinskaya ◽

A G Soboleva ◽

I M Korsunskaya

Keyword(s):

Squamous Cell Carcinoma ◽

Nucleotide Sequence ◽

Cell Carcinoma ◽

Squamous Cell ◽

Somatic Mutations ◽

Genetic Research ◽

Tp53 Gene ◽

Gene Activity ◽

Genetic Changes ◽

Methylation Of Dna

The review is devoted to genetic research in cancer of the vulva. In genetic changes, the mutation irreversibly changes the nucleotide sequence of DNA, or the number of copies of chromosomes changes per cell. In epigenetics, the nucleotide sequence remains unchanged, but gene activity is regulated by methylation of DNA or modification of histones. Most of the studies analyzed are devoted to the study of mutations in the TP53 gene. Many studies indicate that somatic mutations are more common in HPV-negative than in HPV-positive patients. Epigenetic studies in the main devoted to hypermethylation. The gene CDKN2A is most often studied in epigenetic terms. For most of the studied genes, hypermethylation occurs more often in squamous cell carcinoma of the vulva than in the precursors.

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