Biochemical, Histopathological, and Genetic Characterization of Posture-Responsive and Unresponsive APAs

• Published in: The journal of clinical endocrinology and metabolism Vol. 105; no. 9; pp. e3224 - e3235
• Main Authors: Guo, Zeng, Nanba, Kazutaka, Udager, Aaron, McWhinney, Brett C, Ungerer, Jacobus P J, Wolley, Martin, Thuzar, Moe, Gordon, Richard D, Rainey, William E, Stowasser, Michael
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.09.2020
• Subjects: Adrenal Cortex Neoplasms - genetics; Adrenal Cortex Neoplasms - metabolism; Adrenal Cortex Neoplasms - pathology; Adrenocortical Adenoma - genetics; Adrenocortical Adenoma - metabolism; Adrenocortical Adenoma - pathology; Adult; Aged; Aldosterone; Aldosterone - metabolism; Aldosterone synthase; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cohort Studies; Corticosteroids; Cortisol; Cytochrome P-450; Deoxyribonucleic acid; DNA; DNA Mutational Analysis; Endocrine disorders; Female; Gene mutations; Genetic aspects; Humans; Hydroxylase; Hyperaldosteronism - genetics; Hyperaldosteronism - metabolism; Hyperaldosteronism - pathology; Immunohistochemistry; Liquid chromatography; Male; Mass spectrometry; Mass spectroscopy; Middle Aged; Mutation; Next-generation sequencing; Nucleic acids; Online Only; Plasma levels; Point mutation; Posture; Posture - physiology; Steroid hormones; Steroids; Tumors; Young Adult; Australia; APA; IHC; aldosterone-producing Adenoma; posture responsiveness; immunohistochemistry; hybrid steroids; somatic gene mutations
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgaa367

Abstract Context and Objective Posture-responsive and posture-unresponsive aldosterone-producing adenomas (APAs) account for approximately 40% and 60% of APAs, respectively. Somatic gene mutations have been recently reported to exist in approximately 90% of APAs. This study was designed to characterize the biochemical, histopathologic, and genetic properties of these 2 types of APA. Methods Plasma levels of aldosterone and hybrid steroids (18-oxocortisol and 18-hydroxycortisol) were measured by liquid chromatography-tandem mass spectrometry. Immunohistochemistry for CYP11B2 (aldosterone synthase) and CYP17A1 (17α-hydroxylase) and deoxyribonucleic acid sequencing (Sanger and next-generation sequencing) were performed on APA tissue collected from 23 posture-unresponsive and 17 posture-responsive APA patients. Results Patients with posture-unresponsive APA displayed higher (P < 0.01) levels of hybrid steroids, recumbent aldosterone and cortisol, larger (P < 0.01) zona fasciculata (ZF)-like tumors with higher (P < 0.01) expression of CYP17A1 (but not of CYP11B2) than patients with posture-responsive APA (most of which were not ZF-like). Of 40 studied APAs, 37 (92.5%) were found to harbor aldosterone-driving somatic mutations (KCNJ5 = 14 [35.0%], CACNA1D = 13 [32.5%], ATP1A1 = 8 [20.0%], and ATP2B3 = 2 [5.0%]), including 5 previously unreported mutations (3 in CACNA1D and 2 in ATP1A1). Notably, 64.7% (11/17) of posture-responsive APAs carried CACNA1D mutations, whereas 56.5% (13/23) of posture-unresponsive APAs harbored KCNJ5 mutations. Conclusions The elevated production of hybrid steroids by posture-unresponsive APAs may relate to their ZF-like tumor cell composition, resulting in expression of CYP17A1 (in addition to somatic gene mutation-driven CYP11B2 expression), thereby allowing production of cortisol, which acts as the substrate for CYP11B2-generated hybrid steroids.