Activating mutations in CTNNB1 in aldosterone producing adenomas

Area of Science:

• Endocrinology
• Oncology
• Molecular Biology

Background:

• Primary aldosteronism (PA) is the most frequent cause of secondary hypertension, with aldosterone-producing adenomas (APAs) being a surgically correctable subtype.
• The WNT signaling pathway is known to be activated in APAs, contributing to disease development.

Purpose of the Study:

• To investigate the role of CTNNB1 gene mutations in the aberrant WNT signaling observed in APAs.
• To screen a cohort of 198 APAs for somatic CTNNB1 mutations.

Main Methods:

• Screening of 198 APAs for CTNNB1 mutations.
• Analysis of mutation location and impact on β-catenin stability and WNT signaling.
• Assessment of aldosterone production via CYP11B2 expression and direct measurement.

Main Results:

• Somatic CTNNB1 mutations were identified in 5.1% of APAs, occurring independently of other known APA gene mutations.
• Mutations were located in the GSK3β binding domain of exon 3, leading to β-catenin stabilization and increased AXIN2 expression, indicative of WNT pathway activation.
• Tumor tissues confirmed aldosterone production capabilities.

Conclusions:

• Aberrant WNT signaling due to CTNNB1 mutations is a significant factor in APA development.
• These findings suggest that other mechanisms activating the WNT pathway may also contribute to APA formation, highlighting potential therapeutic avenues.