Wnt/beta-catenin pathway deregulation in childhood adrenocortical tumors

Area of Science:

• Endocrinology
• Oncology
• Molecular Biology

Background:

• Wnt/β-catenin pathway activation is common in adult adrenocortical tumors (ACT).
• Data on Wnt/β-catenin pathway involvement in childhood ACT is limited.
• Investigating these pathways is crucial for understanding pediatric adrenocortical tumorigenesis.

Purpose of the Study:

• To investigate abnormalities in the Wnt/β-catenin pathway in childhood ACT.
• To analyze the frequency of CTNNB1 mutations and Wnt-related gene expression.
• To correlate genetic findings with clinicopathological features and patient outcomes.

Main Methods:

• Analysis of clinicopathological data and outcomes from 62 childhood ACT patients.
• Assessment of CTNNB1 mutations and expression of Wnt pathway genes (ligands, inhibitors, target genes) using quantitative PCR and immunohistochemistry.
• Evaluation of β-catenin accumulation and TP53 mutations.

Main Results:

• CTNNB1-activating mutations were infrequent (6%) in childhood ACT, often co-occurring with TP53 mutations and associated with mortality.
• Diffuse β-catenin accumulation was observed in 71% of ACT, irrespective of CTNNB1 mutation status.
• Childhood ACT showed increased CTNNB1 and WISP2 expression, alongside decreased expression of Wnt inhibitors (DKK3, SFRP1, AXIN1) and MYC, compared to normal adrenals. Lower expression of SFRP1, WNT4, and TCF7 correlated with higher survival.

Conclusions:

• While CTNNB1 mutations are uncommon in childhood ACT, they indicate a poor prognosis.
• Most childhood ACTs display altered Wnt/β-catenin pathway signaling, including increased β-catenin and WISP2 expression and reduced Wnt inhibitor levels.
• These findings suggest that genetic events beyond CTNNB1 mutations contribute to the development of childhood adrenocortical tumors.