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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 64; no. 2; pp. 354 - 361
• Main Authors: Fernandes-Rosa, Fabio Luiz, Williams, Tracy Ann, Riester, Anna, Steichen, Olivier, Beuschlein, Felix, Boulkroun, Sheerazed, Strom, Tim M, Monticone, Silvia, Amar, Laurence, Meatchi, Tchao, Mantero, Franco, Cicala, Maria-Verena, Quinkler, Marcus, Fallo, Francesco, Allolio, Bruno, Bernini, Giampaolo, Maccario, Mauro, Giacchetti, Gilberta, Jeunemaitre, Xavier, Mulatero, Paolo, Reincke, Martin, Zennaro, Maria-Christina
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.08.2014; Lippincott Williams & Wilkins
• Subjects: Adrenal Cortex Neoplasms - complications; Adrenal Cortex Neoplasms - genetics; Adrenal Cortex Neoplasms - metabolism; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Adrenocortical Adenoma - complications; Adrenocortical Adenoma - genetics; Adrenocortical Adenoma - metabolism; Adult; Age Factors; Aldosterone - metabolism; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Calcium Channels, L-Type - genetics; Cardiology. Vascular system; Endocrinopathies; Female; G Protein-Coupled Inwardly-Rectifying Potassium Channels - genetics; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hyperaldosteronism - etiology; Hyperaldosteronism - genetics; Male; Medical sciences; Middle Aged; Mutation; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Plasma Membrane Calcium-Transporting ATPases - genetics; Potassium - blood; Sex Factors; Sodium-Potassium-Exchanging ATPase - genetics; Endocrinopathy; Hypertension; Adrenal cortex diseases; Hyperaldosteronism; Steroid hormone; Mineralocorticoid; Adrenal cortex; Cardiovascular disease; Hyperadrenocorticism; Ionic channel; Adenoma; Aldosterone; Inorganic element; Somatic mutation; mutation; potassium channels; Adrenal hormone; Adrenal gland diseases; aldosteronism; Genetics; Benign neoplasm; Circulatory system; Potassium; mineralocorticoids; adrenal cortex; aldosterone
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.114.03419

Primary aldosteronism is the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D have been described in aldosterone-producing adenomas (APAs). Our aim was to investigate the prevalence of somatic mutations in these genes in unselected patients with APA (n=474), collected through the European Network for the Study of Adrenal Tumors. Correlations with clinical and biochemical parameters were first analyzed in a subset of 199 patients from a single center and then replicated in 2 additional centers. Somatic heterozygous KCNJ5 mutations were present in 38% (180/474) of APAs, whereas ATP1A1 mutations were found in 5.3% (25/474) and ATP2B3 mutations in 1.7% (8/474) of APAs. Previously reported somatic CACNA1D mutations as well as 10 novel CACNA1D mutations were identified in 44 of 474 (9.3%) APAs. There was no difference in the cellular composition of APAs or in CYP11B2, CYP11B1, KCNJ5, CACNA1D, or ATP1A1 gene expression in APAs across genotypes. Patients with KCNJ5 mutations were more frequently female, diagnosed younger, and with higher minimal plasma potassium concentrations compared with CACNA1D mutation carriers or noncarriers. CACNA1D mutations were associated with smaller adenomas. These associations were largely dependent on the population structure of the different centers. In conclusion, recurrent somatic mutations were identified in 54% of APAs. Young women with APAs are more likely to be KCNJ5 mutation carriers; identification of specific characteristics or surrogate biomarkers of mutation status may lead to targeted treatment options.