Review of Markers of Zona Glomerulosa and Aldosterone-Producing Adenoma Cells

Seccia, Teresa Maria; Caroccia, Brasilina; Gómez-Sánchez, Elise P.; Vanderriele, Paul-Emmanuel; Gómez-Sánchez, Celso E.; Rossi, Gian Paolo

doi:10.1161/hypertensionaha.117.09991

Cited by 14 publications

(4 citation statements)

References 62 publications

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“…Understanding the functional and cellular correlates of the previously discussed ion channel-related molecular alterations has transformed the field of primary aldosteronism by expanding the role of biomarkers including but not limited to CYP11B2, CD56, and Dab2 (Table 1 ) ( 26 – 28 ). Several lines of evidence suggest that there is strong genotype ( KCNJ5, ATP1A1, ATP2B3 , and CACNA1D ) and phenotype correlation with respect to patient demographics ( 16 , 22 , 29 ), degree of aldosteronism ( 29 ), tumor size ( 16 – 18 , 22 , 29 ) and focality ( 11 , 22 ), tumor cytomorphology ( 11 , 14 – 18 , 29 ), proliferative capacity ( 15 ), and expression for CYP11B1, CYP17, and CYP11B2 in aldosterone-producing adenomas ( 14 – 18 ), as well as in APCCs (as discussed above).…”

Section: Heterogeneity In Aldosterone-producing Benign Adrenal Corticmentioning

confidence: 99%

“…Some tumors also showed CYP11B2-positive and negative regions ( 14 ) or diffuse CYP11B1 positivity with low CYP11B2 expression ( 31 , 32 ). Several researchers have hypothesized that CTNNB1 mutations likely play a role in tumorigenesis rather than in aldosterone production ( 31 ); however, others have proposed that CTNNB1 mutations play a role in aldosterone overproduction through aberrant activation of beta-catenin that can result in overexpression of AT1 receptor, as well as certain nuclear receptors (e.g., NURR1 and NURR7) and conversion of progesterone into 11β-deoxycorticosterone ( 26 ). The MAPK and PI3K/AKT signaling pathways were also reported to be involved in a proportion of sporadic aldosterone-producing adenomas ( 27 ).…”

Section: Heterogeneity In Aldosterone-producing Benign Adrenal Corticmentioning

confidence: 99%

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The Many Faces of Primary Aldosteronism and Cushing Syndrome: A Reflection of Adrenocortical Tumor Heterogeneity

Mete

Duan

2018

Front. Med.

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Adrenal cortical tumors constitute a heterogeneous group of neoplasms with distinct clinical, morphological, and molecular features. Recent discoveries of specific genotype–phenotype correlations in adrenal cortical adenomas have transformed our understanding of their respective endocrine syndromes. Indeed, a proportion of patients with primary aldosteronism are now known to harbor adrenal cortical adenomas with heterogeneous molecular alterations (KCNJ5, ATP1A1, ATP2B3, and CACNA1D) involving the calcium/calmodulin kinase signaling pathway. Several lines of evidence suggest that KCNJ5-mutant aldosterone-producing adenomas have distinct clinicopathological phenotype compared to those harboring ATP1A1, ATP2B3, and CACNA1D mutations. Benign adrenal cortical tumors presenting with Cushing syndrome often have diverse mutations (PRKACA, PRKAR1A, GNAS, PDE11A, and PDE8B) involving the cyclic AMP signaling pathway. In addition to cortisol-producing adenomas, bilateral micronodular adrenocortical disease and primary bilateral macronodular adrenal hyperplasia (PBMAH) have also expanded the spectrum of benign neoplasms causing adrenal Cushing disease. The recent discovery of inactivating ARMC5 germline mutations in PBMAH has challenged the old belief that this disorder is mainly a sporadic disease. Emerging evidence suggests that PBMAH harbors multiple distinct clonal proliferations, reflecting the heterogeneous genomic landscape of this disease. Although most solitary adrenal cortical tumors are sporadic, there is an increasing recognition that inherited susceptibility syndromes may also play a role in their pathogenesis. This review highlights the molecular and morphological heterogeneity of benign adrenal cortical neoplasms, reflected in the diverse presentations of primary aldosteronism and adrenal Cushing syndrome.

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Section: Heterogeneity In Aldosterone-producing Benign Adrenal Corticmentioning

confidence: 99%

Section: Heterogeneity In Aldosterone-producing Benign Adrenal Corticmentioning

confidence: 99%

The Many Faces of Primary Aldosteronism and Cushing Syndrome: A Reflection of Adrenocortical Tumor Heterogeneity

Mete

Duan

2018

Front. Med.

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“…IHC revealed diffuse immunoreactivity of CYP11B2 in tumor cells suggestive of neoplastic production of aldosterone ( Figures 3A, B ). VSNL1, a marker for the normal zona glomerulosa (ZG) ( 29 ), was also abundant in the tumor ( Figures 3C, D ). Consistent with normal suppression of cortisol after 1 mg dexamethasone suppression test, immunoreactivity of CYP17A1 and CYP11B1, both required for cortisol biosynthesis, was markedly low ( Figures 3E–H ).…”

Section: Resultsmentioning

confidence: 99%

Double somatic mutations in CTNNB1 and GNA11 in an aldosterone-producing adenoma

Nanba,

Blinder,

Udager

et al. 2024

Front. Endocrinol.

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Double somatic mutations in CTNNB1 and GNA11/Q have recently been identified in a small subset of aldosterone-producing adenomas (APAs). As a possible pathogenesis of APA due to these mutations, an association with pregnancy, menopause, or puberty has been proposed. However, because of its rarity, characteristics of APA with these mutations have not been well characterized. A 46-year-old Japanese woman presented with hypertension and hypokalemia. She had two pregnancies in the past but had no history of pregnancy-induced hypertension. She had regular menstrual cycle at presentation and was diagnosed as having primary aldosteronism after endocrinologic examinations. Computed tomography revealed a 2 cm right adrenal mass. Adrenal venous sampling demonstrated excess aldosterone production from the right adrenal gland. She underwent right laparoscopic adrenalectomy. The resected right adrenal tumor was histologically diagnosed as adrenocortical adenoma and subsequent immunohistochemistry (IHC) revealed diffuse immunoreactivity of aldosterone synthase (CYP11B2) and visinin like 1, a marker of the zona glomerulosa (ZG), whereas 11β-hydroxylase, a steroidogenic enzyme for cortisol biosynthesis, was mostly negative. CYP11B2 IHC-guided targeted next-generation sequencing identified somatic CTNNB1 (p.D32Y) and GNA11 (p.Q209H) mutations. Immunofluorescence staining of the tumor also revealed the presence of activated β-catenin, consistent with features of the normal ZG. The expression patterns of steroidogenic enzymes and related proteins indicated ZG features of the tumor cells. PA was clinically and biochemically cured after surgery. In conclusion, our study indicated that CTNNB1 and GNA11-mutated APA has characteristics of the ZG. The disease could occur in adults with no clear association with pregnancy or menopause.

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“…Often underdiagnosed, PA is prevalent in 5–10% of hypertensive patients and reaches more than 20% prevalence in patients suffering of resistant hypertension [ 6 , 77 ]. Genetic somatic alterations were identified in aldosterone-producing tumours and adrenocortical carcinoma and linked to aberrant intracellular calcium signalling and altered ATPase function leading to enhanced CYP11B 2 expression and increased aldosterone production [ 62 , 77 ]. Patients with the familial form 3 of hyperaldosteronism presented with massive adrenal hyperplasia, severe hypokalaemia and high concentrations of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol in urine [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Role of glucocorticoid receptor mutations in hypertension and adrenal gland hyperplasia

Verouti

Hummler

Vanderriele

2022

Pflugers Arch - Eur J Physiol

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Hypertension is one of the leading causes of premature death in humans and exhibits a complex aetiology including environmental and genetic factors. Mutations within the glucocorticoid receptor (GR) can cause glucocorticoid resistance, which is characterized by several clinical features like hypercortisolism, hypokalaemia, adrenal hyperplasia and hypertension. Altered glucocorticoid receptor signalling further affects sodium and potassium homeostasis as well as blood pressure regulation and cell proliferation and differentiation that influence organ development and function. In salt-sensitive hypertension, excessive renal salt transport and sympathetic nervous system stimulation may occur simultaneously, and, thus, both the mineralocorticoid receptor (MR) and the GR-signalling may be implicated or even act interdependently. This review focuses on identified GR mutations in human primary generalized glucocorticoid resistance (PGGR) patients and their related clinical phenotype with specific emphasis on adrenal gland hyperplasia and hypertension. We compare these findings to mouse and rat mutants harbouring genetically engineered mutations to further dissect the cause and/or the consequence of clinical features which are common or different.

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Review of Markers of Zona Glomerulosa and Aldosterone-Producing Adenoma Cells

Cited by 14 publications

References 62 publications

The Many Faces of Primary Aldosteronism and Cushing Syndrome: A Reflection of Adrenocortical Tumor Heterogeneity

The Many Faces of Primary Aldosteronism and Cushing Syndrome: A Reflection of Adrenocortical Tumor Heterogeneity

Double somatic mutations in CTNNB1 and GNA11 in an aldosterone-producing adenoma

Role of glucocorticoid receptor mutations in hypertension and adrenal gland hyperplasia

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