SY 03-3 OVERVIEW OF SOMATIC MUTATIONS AND EPIGENETIC REGULATION OF ALDOSTERONE PRODUCING ADENOMA (APA)

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Abstract

Primary aldosteronism (PA) is a heterogeneous group of disorders including both sporadic and familial forms (familial hyperaldosteronism type I, II and III). PA is the most frequent endocrine cause of secondary hypertension and associated with a higher rate of cardiovascular complications, compared with essential hypertension.

Here I review the recent progress in understanding of the genetic and molecular mechanisms leading to autonomous aldosterone production in PA.

Systematic screening detects primary aldosteronism in 5 to 10% of all patients with hypertension and in approximately 20% of patients with resistant hypertension. A unilateral APA is the most common curable cause of hypertension. Early detection of an APA is important both to cure of hypertension by means of adenoma removal and to prevent the onset of resistant hypertension and the risk of long-term cardiovascular complications, such as left ventricular hypertrophy, coronary artery disease, myocardial infarction, heart failure, and atrial fibrillation. (Hypertens 2013; 62: 331)

(1) Novel somatic mutations in APA

Recent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities underlying the development of APA. Pathogenic mechanisms of APA by the somatic mutation are as follows.

The majority of the GIRK4 APA mutations (KCNJ5) lie in or within the close proximity of the ion selectivity filter of the K+ channel and result in the indiscriminate conductance of Na+ that causes membrane depolarization, Ca2+ influx, and increased aldosterone biosynthesis.

Mutations in the Na+/K+- ATPase 1 (ATP1A1) produce a decrease in K+ binding that results in the reduced import of K+ and export of Na+ and also causes cell depolarization. This in turn results in the opening of voltage- gated Ca2+-channels.

In contrast, the Ca2+-ATPase mutations (ATP2B3) were proposed to affect the clearance of cytoplasmic calcium ions. The net result of mutations in both ATPases is therefore likely to cause an increase in the intracellular Ca2+ concentration and as a consequence, an upregulation of aldosterone biosynthesis.

The Cav1.3 mutations (CACNA1D) have been reported to result in channel activation at less depolarized potentials and cause calcium influx and aldosterone production.

Women in pregnancy and after menopause, the APA harbored activating mutations of CTNNB1 was reported, which encoded β-catenin in the Wnt cell-differentiation pathway, and expressed LHCGR and GNRHR, encoding gonadal receptors, at levels that were more than 100 times as high as the levels in other APA. The mutations stimulate Wnt activation and cause adrenocortical cells to de-differentiate toward their common adrenal– gonadal precursor cell type. (Science 2011; 331: 768. Nat Genet 2013; 45: 440, 1050, 1055 NEJM 2015; 373: 1429, Hypertens 2015;66:248 )

The prevalence of somatic mutations in APA has been extensively investigated in many studies. KCNJ5 mutations are the most frequent genetic abnormalities reported in APA with a prevalence of ∼40% in Caucasian population, and as high as 70% in series from Japan. Mutations in the CACNA1D gene are the second most frequent genetic alterations observed in APA with a prevalence comprised about 5∼10 %. The mutations affecting ATP1A1 and ATP2B3 genes are less frequent with a reported prevalence of around 5 and 2%, respectively. (J Endo. 2015; 224: R63. Hypertens. 2015; 65: 507)

(2) Clinical, radiological and pathological relationship of these mutations

Genotype–phenotype correlations have been reported that patients with KCNJ5 mutations are more frequently female, diagnosed younger and with higher minimal plasma potassium concentrations,and larger than those with non- KCNJ5 mutations or without mutations. KCNJ5-mutant APA are lower average Hounsfield units (H.U.) reading in CT scans. Most of KCNJ5 mutations are solitary uninodular APAs. Most tumors exhibiting KCNJ5 mutations demonstrated the classic histological pattern of APAs, comprising of large clear cells with abundant microvesicular cytoplasm with numerous lipid droplets (‘fasciculata-like’). The histological pattern of tumors with CACNA1D and ATPase mutations was still controversial (Clin Endo 2015; 83: 779, JCEM 2016;101:494)

(3) Epigenetics in APA

Integrated analysis of genome-wide methylation and gene expression shows epigenetic regulation of CYP11B2 in aldosteronomas. APA were hypomethylated compared with normal, nonfunctioning adrenocortical tumors and APA-adjacent adrenal gland samples from the same patient. CYP11B2 was upregulated and hypomethylated, suggesting that dysregulated methylation preferentially upregulates CYP11B2 with commensurate inhibition of other key genes involved in steroid biosynthesis. Comparing the methylation status of CYP11B2 CpG islands in paired DNA samples from aldosteronomas and blood from the same patients showed CpG hypomethylation was found in aldosteronomas but not in peripheral blood DNA in all cases. These results may suggest the involvement of these DNA hypomethylation in aldosterone production. (J Clin Endocrinol Metab 2014; 99: E536. Eur J Endocrinol 2015; 173: 185)

(4) Aldosterone-producing cell clusters (APCCs) with high expression of CYP11B2 in both normal and PA adrenal tissue

Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue. Known aldosterone driver mutations were identified in some of APCCs, including CACNA1D and ATP1A1, which were not observed in the adjacent normal adrenal tissue. These studies suggest that APCCs are common in normal adrenals, and APCCs harbor somatic mutations known to cause excess aldosterone production. Furthermore, the mutation spectrum of aldosterone-driving mutations is different in APCCs from that seen in APA. The mutations in KCNJ5 were not detected in those APCCs. The frequency of somatic mutations in CACNA1D in APCCs from normal adrenals increases with age. These results may suggest the APCC as a precursor of PA. (PNAS 2015; 112: E4591)

Recurrent somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1 are found in more than half of APA, and these genetic mutations may lead to increased aldosterone production in APA. The roles of epigenetic change in APA and APCC in the normal adrenal gland as potential precursors of APA need to be evaluated further.

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