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Biomedicines
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Pathogenesis and Treatment of Adrenal Tumors
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Pathogenesis and Treatment of Adrenal Tumors

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular Genetics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 May 2022) | Viewed by 17728

Special Issue Editors

Dr. Anna Angelousi

E-Mail Website
Guest Editor
Department of Endocrinology, First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
Interests: adrenals; pituitary; thyroid; tumorigenesis; diabetes
Special Issues, Collections and Topics in MDPI journals
Dr. Danae Delivanis

E-Mail Website
Guest Editor
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN 55905, USA
Interests: adrenals; pituitary; thyroid; diabetes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Advances in genomics have enormously improved our understanding of adrenal tumorigenesis and led to the development of prognostic markers and therapeutic targets. Bilateral nodular hyperplasias causing Cushing’s syndrome are frequently caused by germline alterations leading to cAMP/PKA pathway activation (micronodular) and ARMC5 inactivation (macronodular). Somatic mutations of β-catenin and PRKACA are observed in non-secreting or cortisol producing adenomas, respectively. Alterations of the β-catenin (CTNN1B, ZNFR3) or TP53 pathways are found in carcinomas. Mutations in cancers are more common in aggressive tumors and correlate with transcriptome or methylation profiles. Identification of these alterations helps to refine the molecular classification of these tumors and to develop molecular targeted treatment.

Dr. Anna Angelousi
Dr. Danae Delivanis
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • adrenal
  • genes
  • adenoma
  • pheochromocytoma
  • adrenocortical carcinoma
  • adrenal hyperplasia
  • PKA
  • ARMC5
  • b-catenin

Published Papers (6 papers)

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Research

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10 pages, 1529 KiB  
Article
Diagnostic Accuracy of Dehydroepiandrosterone Sulfate and Corticotropin in Autonomous Cortisol Secretion
by Lindsay E. Carafone, Catherine D. Zhang, Dingfeng Li, Natalia Lazik, Oksana Hamidi, Maria Daniela Hurtado, William F. Young, Jr., Melinda A. Thomas, Benzon M. Dy, Melanie L. Lyden, Trenton R. Foster, Travis J. McKenzie and Irina Bancos
Biomedicines 2021, 9(7), 741; https://doi.org/10.3390/biomedicines9070741 - 28 Jun 2021
Cited by 9 | Viewed by 3074
Abstract
Autonomous cortisol secretion (ACS) affects up to 50% of patients with adrenal adenomas. Despite the limited evidence, clinical guidelines recommend measurement of serum concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and corticotropin (ACTH) to aid in the diagnosis of ACS. Our objective was to determine the [...] Read more.
Autonomous cortisol secretion (ACS) affects up to 50% of patients with adrenal adenomas. Despite the limited evidence, clinical guidelines recommend measurement of serum concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and corticotropin (ACTH) to aid in the diagnosis of ACS. Our objective was to determine the accuracy of serum concentrations of DHEA-S and ACTH in diagnosing ACS. We conducted a retrospective single center study of adults with adrenal adenoma evaluated between 2000−2020. Main outcome measure was diagnostic accuracy of DHEA-S and ACTH. ACS was defined as post-dexamethasone cortisol >1.8 mcg/dL. Of 468 patients, ACS was diagnosed in 256 (55%) patients with a median post-DST cortisol of 3.45 mcg/dL (range, 1.9–32.7). Patients with ACS demonstrated lower serum concentrations of DHEA-S (35 vs. 87.3 mcg/dL, p < 0.0001) and ACTH (8.3 vs. 16 pg/mL, p < 0.0001) compared to patients with non-functioning adrenal tumors (NFAT). Serum DHEA-S concentration <40 mcg/dL diagnosed ACS with 84% specificity and 81% PPV, while serum ACTH concentration <10 pg/mL diagnosed ACS with 75% specificity and 78% PPV. The combination of serum concentrations of DHEA-S <40 mcg/dL and ACTH <10 pg/mL diagnosed ACS with the highest accuracy with 92% specificity and 87% PPV. Serum concentrations of DHEA-S and ACTH provide additional value in diagnosing ACS. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Adrenal Tumors)
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13 pages, 2083 KiB  
Article
Estrogen-Like Effect of Mitotane Explained by Its Agonist Activity on Estrogen Receptor-α
by Elisa Rossini, Edoardo Giacopuzzi, Fabrizio Gangemi, Mariangela Tamburello, Deborah Cosentini, Andrea Abate, Marta Laganà, Alfredo Berruti, Salvatore Grisanti and Sandra Sigala
Biomedicines 2021, 9(6), 681; https://doi.org/10.3390/biomedicines9060681 - 16 Jun 2021
Cited by 7 | Viewed by 2087
Abstract
Mitotane is the cornerstone of medical treatment of adrenocortical carcinoma. Estrogenic-like side effects frequently occur in patients, and previous studies explored the chemical nature of the interaction between estrogen receptor-α (ER-α) and toxic compounds, including the DDD derivatives. We used molecular docking and [...] Read more.
Mitotane is the cornerstone of medical treatment of adrenocortical carcinoma. Estrogenic-like side effects frequently occur in patients, and previous studies explored the chemical nature of the interaction between estrogen receptor-α (ER-α) and toxic compounds, including the DDD derivatives. We used molecular docking and molecular dynamics (MD) simulations to explore the possible interaction between mitotane and the ER-α receptor and the induced conformational changes. The ER-α expressing MCF-7 cells were exposed to mitotane with/without tamoxifen, and the cell viability/proliferation was evaluated by MTT assay and direct count. The transient ER-α silencing was performed using two ER-α siRNA (50 nM) and verified by Western blot. MDA-MB-231 cells were used as a negative control. Mitotane showed a similar docking configuration to 17β-estradiol and bisphenol A (BPA) and a significant binding affinity to ER-α. MD simulations showed that mitotane preserves the active conformation of ER-α more than both BPA and Bisphenol C, classifying it as an agonist. Exposure of MCF-7 cells to mitotane led to the concentration-dependent increase of cell viability and proliferation, which was reduced in the presence of tamoxifen and nullified by the transient ER-α knock-down. Integrating bioinformatics approaches with cell biology and pharmacological methods, we demonstrated that mitotane directly binds and activates ER-α. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Adrenal Tumors)
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Review

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18 pages, 1760 KiB  
Review
Genetic Alterations in Benign Adrenal Tumors
by Georgia Pitsava and Constantine A. Stratakis
Biomedicines 2022, 10(5), 1041; https://doi.org/10.3390/biomedicines10051041 - 30 Apr 2022
Cited by 8 | Viewed by 3035
Abstract
The genetic basis of most types of adrenal adenomas has been elucidated over the past decade, leading to the association of adrenal gland pathologies with specific molecular defects. Various genetic studies have established links between variants affecting the protein kinase A (PKA) signaling [...] Read more.
The genetic basis of most types of adrenal adenomas has been elucidated over the past decade, leading to the association of adrenal gland pathologies with specific molecular defects. Various genetic studies have established links between variants affecting the protein kinase A (PKA) signaling pathway and benign cortisol-producing adrenal lesions. Specifically, genetic alterations in GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B have been identified. The PKA signaling pathway was initially implicated in the pathogenesis of Cushing syndrome in studies aiming to understand the underlying genetic defects of the rare tumor predisposition syndromes, Carney complex, and McCune-Albright syndrome, both affected by the same pathway. In addition, germline variants in ARMC5 have been identified as a cause of primary bilateral macronodular adrenal hyperplasia. On the other hand, primary aldosteronism can be subclassified into aldosterone-producing adenomas and bilateral idiopathic hyperaldosteronism. Various genes have been reported as causative for benign aldosterone-producing adrenal lesions, including KCNJ5, CACNA1D, CACNA1H, CLCN2, ATP1A1, and ATP2B3. The majority of them encode ion channels or pumps, and genetic alterations lead to ion transport impairment and cell membrane depolarization which further increase aldosterone synthase transcription and aldosterone overproduction though activation of voltage-gated calcium channels and intracellular calcium signaling. In this work, we provide an overview of the genetic causes of benign adrenal tumors. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Adrenal Tumors)
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17 pages, 308 KiB  
Review
Progress on Genetic Basis of Primary Aldosteronism
by Izabela Karwacka, Łukasz Obołończyk, Sonia Kaniuka-Jakubowska, Michał Bohdan and Krzysztof Sworczak
Biomedicines 2021, 9(11), 1708; https://doi.org/10.3390/biomedicines9111708 - 17 Nov 2021
Cited by 6 | Viewed by 2047
Abstract
Primary aldosteronism (PA) is a heterogeneous group of disorders caused by the autonomous overproduction of aldosterone with simultaneous suppression of plasma renin activity (PRA). It is considered to be the most common endocrine cause of secondary arterial hypertension (HT) and is associated with [...] Read more.
Primary aldosteronism (PA) is a heterogeneous group of disorders caused by the autonomous overproduction of aldosterone with simultaneous suppression of plasma renin activity (PRA). It is considered to be the most common endocrine cause of secondary arterial hypertension (HT) and is associated with a high rate of cardiovascular complications. PA is most often caused by a bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA); rarer causes of PA include genetic disorders of steroidogenesis (familial hyperaldosteronism (FA) type I, II, III and IV), aldosterone-producing adrenocortical carcinoma, and ectopic aldosterone-producing tumors. Over the last few years, significant progress has been made towards understanding the genetic basis of PA, classifying it as a channelopathy. Recently, a growing body of clinical evidence suggests that mutations in ion channels appear to be the major cause of aldosterone-producing adenomas, and several mutations within the ion channel encoding genes have been identified. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D) have been identified in nearly 60% of the sporadic APAs, while germline mutations in KCNJ5 and CACNA1H have been reported in different subtypes of familial hyperaldosteronism. These new insights into the molecular mechanisms underlying PA may be associated with potential implications for diagnosis and therapy. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Adrenal Tumors)
21 pages, 1064 KiB  
Review
Bilateral Adrenal Hyperplasia: Pathogenesis and Treatment
by Benjamin Chevalier, Marie-Christine Vantyghem and Stéphanie Espiard
Biomedicines 2021, 9(10), 1397; https://doi.org/10.3390/biomedicines9101397 - 05 Oct 2021
Cited by 18 | Viewed by 3629
Abstract
Bilateral adrenal hyperplasia is a rare cause of Cushing’s syndrome. Micronodular adrenal hyperplasia, including the primary pigmented micronodular adrenal dysplasia (PPNAD) and the isolated micronodular adrenal hyperplasia (iMAD), can be distinguished from the primary bilateral macronodular adrenal hyperplasia (PBMAH) according to the size [...] Read more.
Bilateral adrenal hyperplasia is a rare cause of Cushing’s syndrome. Micronodular adrenal hyperplasia, including the primary pigmented micronodular adrenal dysplasia (PPNAD) and the isolated micronodular adrenal hyperplasia (iMAD), can be distinguished from the primary bilateral macronodular adrenal hyperplasia (PBMAH) according to the size of the nodules. They both lead to overt or subclinical CS. In the latter case, PPNAD is usually diagnosed after a systematic screening in patients presenting with Carney complex, while for PBMAH, the diagnosis is often incidental on imaging. Identification of causal genes and genetic counseling also help in the diagnoses. This review discusses the last decades’ findings on genetic and molecular causes of bilateral adrenal hyperplasia, including the several mechanisms altering the PKA pathway, the recent discovery of ARMC5, and the role of the adrenal paracrine regulation. Finally, the treatment of bilateral adrenal hyperplasia will be discussed, focusing on current data on unilateral adrenalectomy. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Adrenal Tumors)
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Other

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21 pages, 1002 KiB  
Systematic Review
The Diagnostic, Prognostic and Therapeutic Role of miRNAs in Adrenocortical Carcinoma: A Systematic Review
by Chrysoula Mytareli, Danae A. Delivanis, Fani Athanassouli, Vassiliki Kalotychou, Marina Mantzourani, Eva Kassi and Anna Angelousi
Biomedicines 2021, 9(11), 1501; https://doi.org/10.3390/biomedicines9111501 - 20 Oct 2021
Cited by 2 | Viewed by 2861
Abstract
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis and a high rate of recurrence and mortality. Therapeutic options are limited. In some cases, the distinction of ACCs from benign adrenal neoplasms with the existing widely available pathological and histopathological [...] Read more.
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis and a high rate of recurrence and mortality. Therapeutic options are limited. In some cases, the distinction of ACCs from benign adrenal neoplasms with the existing widely available pathological and histopathological tools is difficult. Thus, new biomarkers have been tested. We conducted a review of the recent literature on the advances of the diagnostic, prognostic and therapeutic role of miRNAs on ACC patients. More than 10 miRNAs validated by multiple studies were found to present a diagnostic and prognostic role for ACC patients, from which miR-483-5p and miR-195 were the most frequently met biomarkers. In particular, upregulation of miR-483-5p and downregulation of miR-195 were the most commonly validated molecular alterations. Unfortunately, data on the therapeutic role of miRNA are still scarce and limited mainly at the experimental level. Thus, the role of miRNA regulation in ACC remains an area of active research. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Adrenal Tumors)
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