Genetic, Cellular, and Molecular Heterogeneity in Adrenals With Aldosterone-Producing Adenoma.

Abstract

Aldosterone-producing adenoma (APA) cause primary aldosteronism-the most frequent form of secondary hypertension. Somatic mutations in genes coding for ion channels and ATPases are found in APA and in aldosterone-producing cell clusters. We investigated the genetic, cellular, and molecular heterogeneity of different aldosterone-producing structures in adrenals with APA, to get insight into the mechanisms driving their development and to investigate their clinical and biochemical correlates. Genetic analysis of APA, aldosterone-producing cell clusters, and secondary nodules was performed in adrenal tissues from 49 patients by next-generation sequencing following CYP11B2 immunohistochemistry. Results were correlated with clinical and biochemical characteristics of patients, steroid profiles, and histological features of the tumor and adjacent adrenal cortex. Somatic mutations were identified in 93.75% of APAs. Adenoma carrying KCNJ5 mutations had more clear cells and cells expressing CYP11B1, and fewer cells expressing CYP11B2 or activated β-catenin, compared with other mutational groups. 18-hydroxycortisol and 18-oxocortisol were higher in patients carrying KCNJ5 mutations and correlated with histological features of adenoma; however, mutational status could not be predicted using steroid profiling. Heterogeneous CYP11B2 expression in KCNJ5-mutated adenoma was not associated with genetic heterogeneity. Different mutations were identified in secondary nodules expressing aldosterone synthase and in independent aldosterone-producing cell clusters from adrenals with adenoma; known KCNJ5 mutations were identified in 5 aldosterone-producing cell clusters. Genetic heterogeneity in different aldosterone-producing structures in the same adrenal suggests complex mechanisms underlying APA development.

• Authors: Kelly De Sousa, Sheerazed Boulkroun, Stéphanie Baron, Kazutaka Nanba, Maxime Wack, William E Rainey, Angélique Rocha, Isabelle Giscos-Douriez, Tchao Meatchi, Laurence Amar, Simon Travers, Fabio L Fernandes-Rosa, Maria-Christina Zennaro
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 75 Issue 4 Pg. 1034-1044 (04 2020) ISSN: 1524-4563 [Electronic] United States
• PMID: 32114847 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• G Protein-Coupled Inwardly-Rectifying Potassium Channels
• KCNJ5 protein, human
• Aldosterone
• Cytochrome P-450 CYP11B2
• Steroid 11-beta-Hydroxylase

Topics

• Adrenal Cortex Neoplasms (genetics, metabolism, pathology)
• Adrenal Glands (metabolism, pathology)
• Adrenocortical Adenoma (genetics, metabolism, pathology)
• Adult
• Aged
• Aldosterone (metabolism)
• Cytochrome P-450 CYP11B2 (genetics, metabolism)
• Female
• G Protein-Coupled Inwardly-Rectifying Potassium Channels (genetics, metabolism)
• Humans
• Hyperaldosteronism (genetics, metabolism, pathology)
• Immunohistochemistry
• Male
• Middle Aged
• Mutation
• Steroid 11-beta-Hydroxylase (genetics, metabolism)