Microarray, qPCR, and<i>KCNJ5</i>Sequencing of Aldosterone-Producing Adenomas Reveal Differences in Genotype and Phenotype between Zona Glomerulosa- and Zona Fasciculata-Like Tumors

Azizan, Elena; Lam, Brian Y.H.; Newhouse, Stephen J.; Zhou, Junhua; Kuc, Rhoda E.; Clarke, Jennifer; Happerfield, Lisa; Marker, Alison; Hoffman, Gary J.; Brown, Morris J.

doi:10.1210/jc.2011-2965

Cited by 165 publications

(139 citation statements)

References 33 publications

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“…There have been several reports that find cellular histologic correlations with aldosterone-stimulating mutations (9,13,17,27). Therefore, we examined the cell histology of APCC samples that were captured for sequence analysis (Fig.…”

Section: Resultsmentioning

confidence: 99%

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

Nishimoto

Tomlins

Kuick

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

263

273

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Primary aldosteronism (PA) represents the most common cause of secondary hypertension, but little is known regarding its adrenal cellular origins. Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue. PA-causing aldosteroneproducing adenomas (APAs) harbor mutations in genes encoding ion channels/pumps that alter intracellular calcium homeostasis and cause renin-independent aldosterone production through increased CYP11B2 expression. Herein, we hypothesized that APCCs have APArelated aldosterone-stimulating somatic gene mutations. APCCs were studied in 42 normal adrenals from kidney donors. To clarify APCC molecular characteristics, we used microarrays to compare the APCC transcriptome with conventional adrenocortical zones [zona glomerulosa (ZG), zona fasciculata, and zona reticularis]. The APCC transcriptome was most similar to ZG but with an enhanced capacity to produce aldosterone. To determine if APCCs harbored APA-related mutations, we performed targeted next generation sequencing of DNA from 23 APCCs and adjacent normal adrenal tissue isolated from both formalin-fixed, paraffin-embedded, and frozen tissues. Known aldosterone driver mutations were identified in 8 of 23 (35%) APCCs, including mutations in calcium channel, voltage-dependent, L-type, α1D-subunit (CACNA1D; 6 of 23 APCCs) and ATPase, Na + /K + transporting, α1-polypeptide (ATP1A1; 2 of 23 APCCs), which were not observed in the adjacent normal adrenal tissue. Overall, we show three major findings: (i) APCCs are common in normal adrenals, (ii) APCCs harbor somatic mutations known to cause excess aldosterone production, and (iii) the mutation spectrum of aldosteronedriving mutations is different in APCCs from that seen in APA. These results provide molecular support for APCC as a precursor of PA.primary aldosteronism | aldosterone | adrenal | somatic mutations | aldosterone-producing cell cluster P rimary aldosteronism (PA) accounts for 8% of hypertension and is the most common adrenal disease (1-4). PA patients can be classified into those with aldosterone-producing adenomas (APAs), idiopathic hyperaldosteronism, or familial hyperaldosteronism (FH), which is further divided into FH types 1-3 (FHI-FHIII) (5). In 1992, FHI was shown to result from a gene fusion of cytochrome P450, family 11, subfamily B, polypeptide 2 (CYP11B2: aldosterone synthase) and cytochrome P450, family 11, subfamily B, polypeptide 1 (CYP11B1; cortisol synthase) that resulted in zona fasciculata (ZF) expression of CYP11B2 and excess aldosterone production (6). For almost two decades after the original report, no other genetic abnormalities were identified in the other forms of PA.First reported in 2011, exome sequencing identified a series of germ-line and somatic mutations in genes that altered adrenal cell intracellular Ca 2+ in PA. The most common mutations are somatic mutations of the gene encoding the potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5)...

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Section: Resultsmentioning

confidence: 99%

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

Nishimoto

Tomlins

Kuick

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

263

273

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“…Nevertheless, despite their morphological appearance, ZF-like cells still express markers of the ZG cells such as CYP11B2, DAB2, or CD56, suggesting that adenoma cells derive from ZG (Boulkroun et al 2010(Boulkroun et al , 2011. In different studies, mutational status of the tumor has been shown to be correlated with its cellular composition and size: KCNJ5 mutations were associated with large ZF-like APA, while ATP1A1 and CACNA1D mutations were associated with small ZG-like APA, suggesting that adenoma size is associated with cellular composition (Azizan et al 2012, Dekkers et al 2014. Nevertheless, these associations were not replicated in a recent study investigating a large cohort of patients (Fernandes-Rosa et al 2014), probably due to differences in the investigated population with a large proportion of ZF-like APA in the latter cohort.…”

Section: Familial Hyperaldosteronism Type IImentioning

confidence: 99%

“…The question on the origin of cells composing APA is still a matter of debate. Transcriptome analysis allowed researchers to identify a small set of differentially expressed genes between ZG-and ZF-like APA that in addition to CYP17A1 and CYP11B1 and the proportion of clear or compact cells (ZG-like APA are composed of at least 50% of compact cells) distinguish those tumors; it is interesting to note however that CYP11B2 expression does not allow discrimination between ZG-and ZF-like APA (Azizan et al 2012).…”

Section: Familial Hyperaldosteronism Type IImentioning

confidence: 99%

“…Our actual knowledge does not allow explanation of the mechanisms involved in APA formation and their histological variability. Different hypotheses have been formulated: i) if APA derive from ZG cells, the ZF-like phenotype would be due to greater metabolic activity or induction of lipid uptake (Boulkroun et al 2010(Boulkroun et al , 2011; ii) if APA derive from ZF cells, AS expression would be due to the presence of a somatic mutation in identified or not yet identified genes (Azizan et al 2012(Azizan et al , 2013; iii) APA derive from aldosteroneproducing cell clusters (APCCs; Nishimoto et al 2010). APCCs are AS-positive cell clusters of cuneiform or trapezoid shape located in the ZG and outer ZF that were reported recently in addition to the conventional adrenal cortex zonation (Nishimoto et al 2010).…”

Section: Familial Hyperaldosteronism Type IImentioning

confidence: 99%

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An update on novel mechanisms of primary aldosteronism

Zennaro¹,

Boulkroun²,

Fernandes-Rosa³

2014

Journal of Endocrinology

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Primary aldosteronism (PA) is the most common and curable form of secondary hypertension. It is caused in the majority of cases by either unilateral aldosterone overproduction due to an aldosterone-producing adenoma (APA) or by bilateral adrenal hyperplasia. Recent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities underlying the development of APA and familial hyperaldosteronism. Recurrent somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and ATPases (ATP1A1 and ATP2B3) regulating intracellular ionic homeostasis and cell membrane potential have been identified in APA. Similar germline mutations of KCNJ5 were identified in a severe familial form of PA, familial hyperaldosteronism type 3 (FH3), whereas de novo germline CACNA1D mutations were found in two cases of hyperaldosteronism associated with a complex neurological disorder. These results have allowed a pathophysiological model of APA development to be established. This model involves modifications in intracellular ionic homeostasis and membrane potential, accounting for w50% of all tumors, associated with specific gender differences and severity of PA. In this review, we describe the different genetic abnormalities associated with PA and discuss the mechanisms whereby they lead to increased aldosterone production and cell proliferation. We also address some of the foreseeable consequences that genetic knowledge may contribute to improve diagnosis and patient care.

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“…34,36 A very recent transcriptome study further demonstrated the tumor heterogeneity of CYP11B2 expression and the correlation of high versus low CYP17A1 expression in APA with morphological features, that is, adenomas composed of zona fasciculata-like cells versus tumors composed of ZG-like cells, respectively. 39 One possible reason for different studies reporting varying results in terms of the heterogeneity of CYP11B2 expression in APA samples may relate to the small number of samples investigated, the different technical approaches used, and/or the different screening procedures for selecting patients for surgery. In addition, in some studies APAs were compared with adrenal cortices obtained from nephroadrenalectomies for renal cancer, whereas others used adjacent adrenal cortex as a control, with both tissues having their own pitfalls (see below).…”

Section: From Physiological To Pathological Aldosterone Productionmentioning

confidence: 99%

Integrating Genetics and Genomics in Primary Aldosteronism

2012

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Microarray, qPCR, andKCNJ5Sequencing of Aldosterone-Producing Adenomas Reveal Differences in Genotype and Phenotype between Zona Glomerulosa- and Zona Fasciculata-Like Tumors

Abstract: KCNJ5 mutations are common in APA, particularly those arising from ZF. The long-recognized heterogeneity among APA may have a genetic basis.

Cited by 165 publications

References 33 publications

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

An update on novel mechanisms of primary aldosteronism

Integrating Genetics and Genomics in Primary Aldosteronism

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