Genetic Spectrum and Clinical Correlates of Somatic Mutations in Aldosterone-Producing Adenoma

Fernandes-Rosa, Fábio Luiz; Williams, Tracy Ann; Riester, Anna; Steichen, Olivier; Beuschlein, Felix; Boulkroun, Sheerazed; Strom, Tim M.; Monticone, Silvia; Amar, Laurence; Méatchi, Tchao; Mantero, Franco; Cicala, Maria-Verena; Quinkler, Marcus; Fallo, Francesco; Allolio, Bruno; Bernini, Giampaolo; Maccario, Mauro; Giacchetti, Gilberta; Jeunemaı̂tre, Xavier; Mulatero, Paolo; Reincke, Martín; Zennaro, Maria-Christina

doi:10.1161/hypertensionaha.114.03419

Cited by 263 publications

(324 citation statements)

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“…To assess whether APCCs harbored somatic mutations seen in APA, we developed a custom Ion Torrent AmpliSeq Panel (APA_v1) with 310 multiplexed amplicons targeting the entire coding sequences of genes with described somatic mutations in APA (ATP1A1, ATP2B3, CACNA1D, and KCNJ5) as well as genes shown to harbor germ-line or somatic variants associated with adrenal hyperplasia [phosphodiesterase 11A (PDE11A), phosphodiesterase 8B (PDE8B), and protein kinase, cAMP-dependent, regulatory, type Iα (PRKAR1A)] (7,10,13,(18)(19)(20)(21)(22)(23)(24)(25)(26). NGS was performed on APCCs and paired control adrenal tissue (adjacent ZF and/or medulla), both of which were isolated from formalin-fixed, paraffin-embedded (FFPE) adrenal samples (marked P in Table 1).…”

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.

270

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.

270

273

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“…Ainsi, deux études multicentriques consécutives réalisées au sein du réseau européen d'étude des tumeurs de la surrénales 4 ont éva-lué l'éventail génétique et les corrélations cliniques des mutations somatiques chez les patients porteurs d'adénomes produisant de l'aldostérone [14,15]. L'analyse de 474 patients issus de sept centres différents a identifié des mutations somatiques chez 54 % des patients porteurs d'adénomes ; cette prévalence varie de 27,2 % à 56,8 % selon les centres.…”

Section: Anomalies De Kcnj5 Dans L'hyperaldostéronisme Primaire Familialunclassified

“…La fréquence de ces mutations concorde avec celle rapportée à partir d'autres cohortes [9,11,16], bien que les mutations KCNJ5 soient plus ou moins fréquentes dans certaines populations et selon les procédures diagnostiques utilisées [14,17,18]. Les mutations du gène CACNA1D sont les secondes mutations les plus fréquentes après les mutations KCNJ5 et leur prévalence est de 9,3 % [15]. L'analyse de la corrélation entre les données génétiques et les paramètres cliniques et biologiques a montré que les mutations KCNJ5 étaient plus fréquentes chez les femmes, et diagnostiquées plus précocement que les mutations CACNA1D [15] ; les mutations CACNA1D sont, quant à elles, présentes dans des adénomes plus petits.…”

Section: Anomalies De Kcnj5 Dans L'hyperaldostéronisme Primaire Familialunclassified

“…Les mutations du gène CACNA1D sont les secondes mutations les plus fréquentes après les mutations KCNJ5 et leur prévalence est de 9,3 % [15]. L'analyse de la corrélation entre les données génétiques et les paramètres cliniques et biologiques a montré que les mutations KCNJ5 étaient plus fréquentes chez les femmes, et diagnostiquées plus précocement que les mutations CACNA1D [15] ; les mutations CACNA1D sont, quant à elles, présentes dans des adénomes plus petits. Il n'y a pas d'association entre le statut mutationnel et les taux plasmatiques d'aldostérone, de rénine, ni avec le rapport aldostérone sur rénine en préopératoire, ou le nombre de médicaments pris avant la chirurgie.…”

Section: Anomalies De Kcnj5 Dans L'hyperaldostéronisme Primaire Familialunclassified

“…Le vérapamil n'agirait donc pas uniquement sur la production d'aldostérone en inhibant les canaux Ca 2+ dépendants du voltage activés par la dépolarisation, mutation germinale a été identifiée dans l'exon 8B du gène CACNA1D sous la forme de la substitution d'une glycine par une asparagine en position 403 (p.Gly403Asp). Des mutations somatiques du même résidu du gène CACNA1D (p.Gly403Arg) ont été identifiées dans les adénomes produisant de l'aldostérone [9,10,15]. L'analyse fonctionnelle du canal porteur de cette mutation a montré une activation à des potentiels plus bas que le canal sauvage [10].…”

Section: Des Mutations Constitutionnelles De Kcnj5 Et Cacna1d Dans L'unclassified

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Progrès récents dans la génétique de l’hyperaldostéronisme primaire

2015

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Molecular Genetics of Hyperaldosteronism

Scholl

2017

Encyclopedia of Life Sciences

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In primary aldosteronism, the adrenal gland produces excessive amounts of the steroid hormone aldosterone, which causes hypertension. Common causes are aldosterone‐producing adenomas (benign tumours) and bilateral adrenal hyperplasia. The majority of aldosterone‐producing adenomas carry somatic mutations in known disease genes. These include KCNJ5 (a potassium channel), CACNA1D (a calcium channel) and ATP1A1 and AT2B3 (ATPase subunits). These mutations either directly or indirectly cause increased intracellular calcium levels, which lead to increased aldosterone production and proliferation. Mutations in CTNNB1 (beta‐catenin) are rare. The molecular mechanisms underlying bilateral adrenal hyperplasia are largely unknown, with the exception of rare forms of familial hyperaldosteronism (FH). FH‐I, ‐III and ‐IV are caused by germ line mutations in CYP11B2 (aldosterone synthase), KCNJ5 and CACNA1H (another calcium channel), respectively, and a syndrome that includes neurologic abnormalities is due to germ line mutations in CACNA1D . These observations suggest pathways for the development of novel diagnostic and therapeutic strategies in primary aldosteronism. Key Concepts Primary aldosteronism is the most common cause of secondary hypertension, caused by aldosterone‐producing adenoma or bilateral adrenal hyperplasia. Recent exome sequencing studies have identified the genetic basis of the majority of aldosterone‐producing adenomas. Somatic mutations in the potassium channel KCNJ5 explain about 40% of aldosterone‐producing adenomas. Mutations in KCNJ5 are associated with female gender, early onset and larger tumour size. Other somatic mutations in aldosterone‐producing adenomas affect the CACNA1D , ATP1A1 , ATP2B3 and CTNNB1 genes. The shared common final pathway of somatic mutations in aldosterone‐producing adenomas is increased calcium signalling, which causes excessive aldosterone production and proliferation. The pathophysiology of sporadic bilateral adrenal hyperplasia is largely unknown. Rare forms of familial hyperaldosteronism (FH) include FH‐I, ‐III and ‐IV, caused by germ line mutations in CYP11B2 , KCNJ5 and CACNA1H , respectively, and FH‐II, whose genetic basis remains unknown. The identification of the molecular mechanisms of primary aldosteronism suggests pathways for the development of novel diagnostic and therapeutic strategies.

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Genetic Spectrum and Clinical Correlates of Somatic Mutations in Aldosterone-Producing Adenoma

Cited by 263 publications

References 30 publications

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

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

Progrès récents dans la génétique de l’hyperaldostéronisme primaire

Molecular Genetics of Hyperaldosteronism

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