Identification of Somatic Mutations in CLCN2 in Aldosterone-Producing Adenomas

Rege, Juilee; Nanba, Kazutaka; Blinder, Amy R; Plaska, Samuel; Udager, Aaron M.; Vats, Pankaj; Kumar‐Sinha, Chandan; Giordano, Thomas J.; Rainey, William E.; Else, Tobias

doi:10.1210/jendso/bvaa123

Cited by 28 publications

(30 citation statements)

References 34 publications

(50 reference statements)

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“…ACAs harboring ATP1A1, ATP2B3, and CACNA1D mutations often feature higher levels of mRNA transcripts for CYP11B2 when compared with KCNJ5-dependent primary aldosteronism [17,33,37,63,64,69]. KCNJ5-driven APAs show abundant CYP17A1 and CYP11B1 mRNA transcripts among all APAs [37]. These findings help explain variations in cytomorphology and immunohistochemical staining patterns for steroidogenic enzymes [63,68,69].…”

Section: Genotype-phenotype Correlations In Sporadic Forms Of Primary Aldosteronismmentioning

confidence: 83%

“…For this reason, the pathogenesis of benign aldosterone-producing adrenal cortical disease (e.g., APA, APM/ APCC, APN) is typically linked to somatic mutations in several ion channels (Fig. 3) including the potassium channel mutation-KCNJ5 (encodes G-protein activated inward rectifier potassium channel 4; GIRK4) [30,31], sodium/ potassium ATPase mutation-ATP1A1 (encodes alpha-1 subunit of the sodium/potassium ATPase) [31][32][33], calcium ATPase mutation-ATP2B3 (encodes the plasma cell membrane calcium ATPase isoform; PMCA3) [31,32], voltagedependent calcium channel subunit mutations including the high-voltage activated L-type subunit-CACNA1D (encodes Ca v 1.3) [33][34][35] and the low-voltage activated T-type subunit-CACNA1H (encodes Ca v 3.2) [35,36], and the recently described voltage-gated chloride channel mutation-CLCN2 (encodes CIC-2) [37].…”

Section: Molecular Pathogenesis Of Primary Aldosteronism: a Disease Of Ion Channelsmentioning

confidence: 99%

“…From a steroidogenic enzyme expression perspective, all aldosterone-producing lesions show variable expression for CYP11B2 [37,63,68,69]. ACAs harboring ATP1A1, ATP2B3, and CACNA1D mutations often feature higher levels of mRNA transcripts for CYP11B2 when compared with KCNJ5-dependent primary aldosteronism [17,33,37,63,64,69]. KCNJ5-driven APAs show abundant CYP17A1 and CYP11B1 mRNA transcripts among all APAs [37].…”

Section: Genotype-phenotype Correlations In Sporadic Forms Of Primary Aldosteronismmentioning

confidence: 99%

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What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics

et al. 2021

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Approximately one-tenth of the general population exhibit adrenal cortical nodules, and the incidence has increased. Afflicted patients display a multifaceted symptomatology-sometimes with rather spectacular features. Given the general infrequency as well as the specific clinical, histological, and molecular considerations characterizing these lesions, adrenal cortical tumors should be investigated by endocrine pathologists in high-volume tertiary centers. Even so, to distinguish specific forms of benign adrenal cortical lesions as well as to pinpoint malignant cases with the highest risk of poor outcome is often challenging using conventional histology alone, and molecular genetics and translational biomarkers are therefore gaining increased attention as a possible discriminator in this context. In general, our understanding of adrenal cortical tumorigenesis has increased tremendously the last decade, not least due to the development of next-generation sequencing techniques. Comprehensive analyses have helped establish the link between benign aldosterone-producing adrenal cortical proliferations and ion channel mutations, as well as mutations in the protein kinase A (PKA) signaling pathway coupled to cortisol-producing adrenal cortical lesions. Moreover, molecular classifications of adrenal cortical tumors have facilitated the distinction of benign from malignant forms, as well as the prognostication of the individual patients with verified adrenal cortical carcinoma, enabling high-resolution diagnostics that is not entirely possible by histology alone. Therefore, combinations of histology, immunohistochemistry, and next-generation multi-omic analyses are all needed in an integrated fashion to properly distinguish malignancy in some cases. Despite significant progress made in the field, current clinical and pathological challenges include the preoperative distinction of non-metastatic low-grade adrenal cortical carcinoma confined to the adrenal gland, adoption of individualized therapeutic algorithms aligned with molecular and histopathologic risk stratification tools, and histological confirmation of functional adrenal cortical disease in the context of multifocal adrenal cortical proliferations. We herein review the histological, genetic, and epigenetic landscapes of benign and malignant adrenal cortical neoplasia from a modern surgical endocrine pathology perspective and highlight key mechanisms of value for diagnostic and prognostic purposes.

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Section: Genotype-phenotype Correlations In Sporadic Forms Of Primary Aldosteronismmentioning

confidence: 83%

Section: Molecular Pathogenesis Of Primary Aldosteronism: a Disease Of Ion Channelsmentioning

confidence: 99%

Section: Genotype-phenotype Correlations In Sporadic Forms Of Primary Aldosteronismmentioning

confidence: 99%

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What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics

et al. 2021

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“…The morphology of the adrenal glands varied from normal to unilateral nodules on CT scan, but aldosterone production was bilateral in the three cases that underwent adrenal venous sampling [ 11 ]. Recently, somatic mutations of CLCN2 were reported in sporadic APA, but the frequency is rare [ 95 , 96 ].…”

Section: Clcn2mentioning

confidence: 99%

Update on Genetics of Primary Aldosteronism

et al. 2021

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Primary aldosteronism (PA) is the most common form of secondary hypertension, with a prevalence of 5–10% among patients with hypertension. PA is mainly classified into two subtypes: aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism. Recent developments in genetic analysis have facilitated the discovery of mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, CLCN2, and CTNNB1 in sporadic or familial forms of PA in the last decade. These findings have greatly advanced our understanding of the mechanism of excess aldosterone synthesis, particularly in APA. Most of the causative genes encode ion channels or pumps, and their mutations lead to depolarization of the cell membrane due to impairment of ion transport. Depolarization activates voltage-gated Ca2+ channels and intracellular calcium signaling and promotes the transcription of aldosterone synthase, resulting in overproduction of aldosterone. In this article, we review recent findings on the genetic and molecular mechanisms of PA.

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“…Recently somatic CACNA1H pathogenic variants were identified as a cause of APAs, however the prevalence of these pathogenic variants in APAs is low (41). Somatic pathogenic variants in CLCN2 were also recently described in APAs with a prevalence of 1.74% in one small study (42). The histologic classification of PA is a spectrum, ranging from BAH to PBMAH, as shown in Figure 2 (43).…”

Section: Aldosterone-producing Adrenocortical Adenomasmentioning

confidence: 99%

Molecular Genetic and Genomic Alterations in Cushing’s Syndrome and Primary Aldosteronism

2021

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The genetic alterations that cause the development of glucocorticoid and/or mineralocorticoid producing benign adrenocortical tumors and hyperplasias have largely been elucidated over the past two decades through advances in genomics. In benign aldosterone-producing adrenocortical tumors and hyperplasias, alteration of intracellular calcium signaling has been found to be significant in aldosterone hypersecretion, with causative defects including those in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2. In benign cortisol-producing adrenocortical tumors and hyperplasias abnormal cyclic adenosine monophosphate-protein kinase A signaling has been found to play a central role in tumorigenesis, with pathogenic variants in GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B being implicated. The role of this signaling pathway in the development of Cushing’s syndrome and adrenocortical tumors was initially discovered through the study of the underlying genetic defects causing the rare multiple endocrine neoplasia syndromes McCune-Albright syndrome and Carney complex with subsequent identification of defects in genes affecting the cyclic adenosine monophosphate-protein kinase A pathway in sporadic tumors. Additionally, germline pathogenic variants in ARMC5, a putative tumor suppressor, were found to be a cause of cortisol-producing primary bilateral macronodular adrenal hyperplasia. This review describes the genetic causes of benign cortisol- and aldosterone-producing adrenocortical tumors.

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Identification of Somatic Mutations in CLCN2 in Aldosterone-Producing Adenomas

Cited by 28 publications

References 34 publications

What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics

What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics

Update on Genetics of Primary Aldosteronism

Molecular Genetic and Genomic Alterations in Cushing’s Syndrome and Primary Aldosteronism

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