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Biochemical, Histopathological, and Genetic Characterization of Posture-Responsive and Unresponsive APAs
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Biochemical, Histopathological, and Genetic Characterization of Posture-Responsive and Unresponsive APAs
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Journal Article
Biochemical, Histopathological, and Genetic Characterization of Posture-Responsive and Unresponsive APAs
2020
Overview
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.
Publisher
Oxford University Press
Subject
Adrenal Cortex Neoplasms - genetics
/ Adrenal Cortex Neoplasms - metabolism
/ Adrenal Cortex Neoplasms - pathology
/ Adrenocortical Adenoma - genetics
/ Adrenocortical Adenoma - metabolism
/ Adrenocortical Adenoma - pathology
/ Adult
/ Aged
/ Biomarkers, Tumor - genetics
/ Biomarkers, Tumor - metabolism
/ Cortisol
/ DNA
/ Female
/ Humans
/ Hyperaldosteronism - genetics
/ Hyperaldosteronism - metabolism
/ Hyperaldosteronism - pathology
/ Male
/ Mutation
/ Posture
/ Steroids
/ Tumors
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