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

Area of Science:

• Endocrinology
• Oncology
• Genetics

Background:

• Aldosterone-producing adenomas (APAs) are classified as posture-responsive (approx. 40%) or posture-unresponsive (approx. 60%).
• Somatic gene mutations are identified in about 90% of APAs, driving aldosterone production.

Purpose of the Study:

• To characterize the biochemical, histopathologic, and genetic differences between posture-responsive and posture-unresponsive APAs.
• To investigate the role of specific gene mutations and enzyme expression in APA subtypes.

Main Methods:

• Plasma analysis of aldosterone and hybrid steroids (18-oxocortisol, 18-hydroxycortisol) using liquid chromatography-tandem mass spectrometry.
• Immunohistochemistry for CYP11B2 and CYP17A1 on APA tissues.
• Deoxyribonucleic acid sequencing (Sanger and next-generation) to identify somatic mutations.

Main Results:

• Posture-unresponsive APAs had higher hybrid steroids, aldosterone, cortisol, and larger zona fasciculata (ZF)-like tumors with increased CYP17A1 expression compared to posture-responsive APAs.
• Somatic mutations were found in 92.5% of APAs, with KCNJ5 (35.0%) and CACNA1D (32.5%) being the most common.
• Posture-responsive APAs were more frequently associated with CACNA1D mutations (64.7%), while posture-unresponsive APAs were more often linked to KCNJ5 mutations (56.5%).

Conclusions:

• Elevated hybrid steroid production in posture-unresponsive APAs may stem from ZF-like tumor composition and CYP17A1 expression, facilitating cortisol production used in hybrid steroid synthesis.
• Distinct mutation profiles (CACNA1D in posture-responsive, KCNJ5 in posture-unresponsive) correlate with APA subtypes and biochemical characteristics.