The Role of gsp Mutations on the Development of Adrenocortical Tumors and Adrenal Hyperplasia

Fragoso, Maria Candida Barisson Villares; Wanichi, Ingrid Quevedo; Cavalcante, Isadora Pontes; Mariani, Beatriz Marinho de Paula

doi:10.3389/fendo.2016.00104

Cited by 8 publications

(4 citation statements)

References 42 publications

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“…Historical terms of primary bilateral micronodular or macronodular adrenocortical hyperplasia are no longer used as the nodules are independent clonal proliferations and referred to as bilateral micro-or macro-nodular adrenal cortical disease and classified among benign adrenal cortical tumors [1][2][3][4][5]. Virtually all bilateral micronodular and a significant fraction of bilateral macronodular adrenal cortical diseases are caused by genetic susceptibility [4][5][6][7][8][9][10][11][12][13][14]. These findings have resulted in redefining the clinicopathologic spectrum of adrenal cortical nodular disease.…”

Section: Question 1: Are There Any Nomenclature Changes or Any New Di...mentioning

confidence: 99%

“…Moreover, germline variants in MEN1 (causing the multiple endocrine neoplasia type 1 syndrome) [7,13,91], FH (causing the hereditary leiomyomatosis and renal cell cancer syndrome) [12,92], and APC (causing familial adenomatosis polyposis) [11,12] have also been reported in individuals with bilateral macronodular adrenocortical disease. Moreover, additional somatic and/or germline gene variants have also been identified in a subset of individuals with this condition [5,7,8,12,14,93]. Intricate molecular mechanisms, for example aberrant G-protein-coupled receptor expression or dysregulation of the ACTH receptor may explain subsets of cases [94][95][96][97][98].…”

Section: Question 4: What Are the Pathological Correlates Of Adrenoco...mentioning

confidence: 99%

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Overview of the 2022 WHO Classification of Adrenal Cortical Tumors

et al. 2022

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The new WHO classification of adrenal cortical proliferations reflects translational advances in the fields of endocrine pathology, oncology and molecular biology. By adopting a question–answer framework, this review highlights advances in knowledge of histological features, ancillary studies, and associated genetic findings that increase the understanding of the adrenal cortex pathologies that are now reflected in the 2022 WHO classification. The pathological correlates of adrenal cortical proliferations include diffuse adrenal cortical hyperplasia, adrenal cortical nodular disease, adrenal cortical adenomas and adrenal cortical carcinomas. Understanding germline susceptibility and the clonal-neoplastic nature of individual adrenal cortical nodules in primary bilateral macronodular adrenal cortical disease, and recognition of the clonal-neoplastic nature of incidentally discovered non-functional subcentimeter benign adrenal cortical nodules has led to redefining the spectrum of adrenal cortical nodular disease. As a consequence, the most significant nomenclature change in the field of adrenal cortical pathology involves the refined classification of adrenal cortical nodular disease which now includes (a) sporadic nodular adrenocortical disease, (b) bilateral micronodular adrenal cortical disease, and (c) bilateral macronodular adrenal cortical disease (formerly known primary bilateral macronodular adrenal cortical hyperplasia). This group of clinicopathological entities are reflected in functional adrenal cortical pathologies. Aldosterone producing cortical lesions can be unifocal or multifocal, and may be bilateral with no imaging-detected nodule(s). Furthermore, not all grossly or radiologically identified adrenal cortical lesions may be the source of aldosterone excess. For this reason, the new WHO classification endorses the nomenclature of the HISTALDO classification which uses CYP11B2 immunohistochemistry to identify functional sites of aldosterone production to help predict the risk of bilateral disease in primary aldosteronism. Adrenal cortical carcinomas are subtyped based on their morphological features to include conventional, oncocytic, myxoid, and sarcomatoid subtypes. Although the classic histopathologic criteria for diagnosing adrenal cortical carcinomas have not changed, the 2022 WHO classification underscores the diagnostic and prognostic impact of angioinvasion (vascular invasion) in these tumors. Microscopic angioinvasion is defined as tumor cells invading through a vessel wall and forming a thrombus/fibrin-tumor complex or intravascular tumor cells admixed with platelet thrombus/fibrin. In addition to well-established Weiss and modified Weiss scoring systems, the new WHO classification also expands on the use of other multiparameter diagnostic algorithms (reticulin algorithm, Lin–Weiss–Bisceglia system, and Helsinki scoring system) to assist the workup of adrenal cortical neoplasms in adults. Accordingly, conventional carcinomas can be assessed using all multiparameter diagnostic scheme...

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Section: Question 1: Are There Any Nomenclature Changes or Any New Di...mentioning

confidence: 99%

Section: Question 4: What Are the Pathological Correlates Of Adrenoco...mentioning

confidence: 99%

Overview of the 2022 WHO Classification of Adrenal Cortical Tumors

et al. 2022

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“…There are several types of G protein α subunits (Gα), and different α subunits show distinct specificities. In the PKA signaling pathway, the stimulatory G protein known as G S activates membrane (m)-bound adenylyl cyclase [AC, denoted (4)] ( 7 ).The mACs produce cAMP from ATP, and can increase the intracellular cAMP-concentration by more than twentyfold in seconds after stimulation ( 8 ). Free cAMP [denoted (5)] can bind to and stimulate several proteins, including popeye domain-containing [POPDC, denoted (6)] proteins, cyclic nucleotide-gated ion channels [CNGs, denoted (7)], exchange protein directly activated by cAMP [Epac, denoted (8)], and PKA holoenzymes [denoted (9)] ( 3 , 4 ).…”

Section: The Camp and Pka Signaling Pathway And Camp Receptorsmentioning

confidence: 99%

The Molecular Basis for Specificity at the Level of the Protein Kinase a Catalytic Subunit

Søberg

Skålhegg

2018

Front. Endocrinol.

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Assembly of multi enzyme complexes at subcellular localizations by anchoring- and scaffolding proteins represents a pivotal mechanism for achieving spatiotemporal regulation of cellular signaling after hormone receptor targeting [for review, see (1)]. In the 3′ 5′-cyclic adenosine monophosphate (cAMP) dependent protein kinase (PKA) signaling pathway it is generally accepted that specificity is secured at several levels. This includes at the first level stimulation of receptors coupled to heterotrimeric G proteins which through stimulation of adenylyl cyclase (AC) forms the second messenger cAMP. Cyclic AMP has several receptors including PKA. PKA is a tetrameric holoenzyme consisting of a regulatory (R) subunit dimer and two catalytic (C) subunits. The R subunit is the receptor for cAMP and compartmentalizes cAMP signals through binding to cell and tissue-specifically expressed A kinase anchoring proteins (AKAPs). The current dogma tells that in the presence of cAMP, PKA dissociates into an R subunit dimer and two C subunits which are free to phosphorylate relevant substrates in the cytosol and nucleus. The release of the C subunit has raised the question how specificity of the cAMP and PKA signaling pathway is maintained when the C subunit no longer is attached to the R subunit-AKAP complex. An increasing body of evidence points toward a regulatory role of the cAMP and PKA signaling pathway by targeting the C subunits to various C subunit binding proteins in the cytosol and nucleus. Moreover, recent identification of isoform specific amino acid sequences, motifs and three dimensional structures have together provided new insight into how PKA at the level of the C subunit may act in a highly isoform-specific fashion. Here we discuss recent understanding of specificity of the cAMP and PKA signaling pathway based on C subunit subcellular targeting as well as evolution of the C subunit structure that may contribute to the dynamic regulation of C subunit activity.

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“…These point mutations (R201H and R201S) represent a rare cause of PBMAH as their deleterious effect has been demonstrated. Indeed, they increase cAMP level and therefore, activate cAMP/PKA pathway in adrenocortical cells [46].…”

Section: Mccune-albright Syndromementioning

confidence: 99%

Update of Genetic and Molecular Causes of Adrenocortical Hyperplasias Causing Cushing Syndrome

Berthon

Bertherat

2020

Horm Metab Res

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Bilateral hyperplasias of the adrenal cortex are rare causes of chronic endogenous hypercortisolemia also called Cushing syndrome. These hyperplasias have been classified in two categories based on the adrenal nodule size: the micronodular types include Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and isolated Micronodular Adrenal Disease (iMAD) and the macronodular also named Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH). This review discusses the genetic and molecular causes of these different forms of hyperplasia that involve mutations and dysregulation of various regulators of the cAMP/protein kinase A (PKA) pathway. PKA signaling is the main pathway controlling cortisol secretion in adrenocortical cells under ACTH stimulation. Although mutations of the regulatory subunit R1α of PKA (PRKAR1A) is the main cause of familial and sporadic PPNAD, inactivation of two cAMP-binding phosphodiesterases (PDE11A and PDE8B) are associated with iMAD even if they are also found in PPNAD and PBMAH cases. Interestingly, PBMAH that is observed in multiple familial syndrome such as APC, menin, fumarate hydratase genes, has initially been associated with the aberrant expression of G-protein coupled receptors (GPCR) leading to an activation of cAMP/PKA pathway. However, more recently, the discovery of germline mutations in Armadillo repeat containing protein 5 (ARMC5) gene in 25–50% of PBMAH patients highlights its importance in the development of PBMAH. The potential relationship between ARMC5 mutations and aberrant GPCR expression is discussed as well as the potential other causes of PBMAH.

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The Role of gsp Mutations on the Development of Adrenocortical Tumors and Adrenal Hyperplasia

Cited by 8 publications

References 42 publications

Overview of the 2022 WHO Classification of Adrenal Cortical Tumors

Overview of the 2022 WHO Classification of Adrenal Cortical Tumors

The Molecular Basis for Specificity at the Level of the Protein Kinase a Catalytic Subunit

Update of Genetic and Molecular Causes of Adrenocortical Hyperplasias Causing Cushing Syndrome

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