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Identification of genetic alterations of AXIN2 gene in adrenocortical tumors
Audrey Chapman1, Julien Durand, Lydia Ouadi
1Division of Endocrinology, Department of Medicine, Centre Hospitalier de l'Université de Montréal, Hôtel-Dieu, 3850 Saint Urbain Street, Montréal, Québec, Canada H2W 1T7.
Background:
Mutations of the β-catenin gene (CTNNB1), which lead to constitutive activation of Wnt signaling, have recently been described in adrenocortical adenomas (AA) and carcinomas (ACC). However, somatic CTNNB1 mutations may explain only about 50% of β-catenin accumulation observed in adrenocortical tumors, indicating that other components of the Wnt pathway may be involved.
Objective:
The objective of the study was to investigate whether alterations in AXIN2 may be present in adrenocortical tumors.
Methods:
We studied 49 human adrenocortical samples: 30 AA, six ACC, five primary pigmented nodular adrenocortical disease five ACTH-independent macronodular adrenal hyperplasias (AIMAH), and three ACTH-dependent hyperplasias in addition to the human ACC cell lines SW13 and H295R. Samples were screened for somatic genetic alterations in exon 3 of CTNNB1 and exons 5, 7, and 9 of AXIN2.
Results:
We found an in-frame, 12-bp deletion beginning at coding nucleotide 2013 in exon 7 of the AXIN2 gene, c.2013_2024del12 (p.Arg671_Pro674del), in two of 30 AA (7%), one of six ACC (17%), and the ACC H295R cell line. Immunohistochemistry revealed that tumors with AXIN2 genetic defects showed nuclear/cytoplasmic accumulation of β-catenin, indicating the activation of Wnt signaling. In addition, the ACC and H295R cells with AXIN2 deletion (c.2013_2024del12) harbored p.Ser45del and p.Ser45Pro CTNNB1 mutations, respectively. Two single-nucleotide polymorphisms were identified in exon 7 of AXIN2, c.2351C>T in 2 AA, and one AIMAH and c.2342A>G in an AIMAH tissue.
Conclusion:
The present study reports, for the first time, that AXIN2 genetic defects may be found in adrenocortical tumors. However, the functional consequence of this genetic alteration remains to be determined.
Insights
Genetic defects in AXIN2 were identified in adrenocortical tumors, contributing to Wnt signaling activation. This finding expands our understanding of the molecular basis of adrenocortical neoplasms.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Mutations in the beta-catenin gene (CTNNB1) activate Wnt signaling in adrenocortical tumors.
- CTNNB1 mutations explain only half of beta-catenin accumulation, suggesting other pathway involvement.
Purpose of the Study:
- Investigate potential alterations in the AXIN2 gene within adrenocortical tumors.
Main Methods:
- Screened 49 human adrenocortical samples (adenomas, carcinomas, hyperplasias) and two cell lines.
- Analyzed somatic genetic alterations in CTNNB1 exon 3 and AXIN2 exons 5, 7, and 9.
Main Results:
- Identified an AXIN2 deletion (c.2013_2024del12) in 7% of adrenocortical adenomas and 17% of adrenocortical carcinomas.
- AXIN2 defects correlated with nuclear/cytoplasmic beta-catenin accumulation, indicating Wnt pathway activation.
- Found single-nucleotide polymorphisms in AXIN2 exon 7 in some samples.
Conclusions:
- This study is the first to report genetic defects in AXIN2 within adrenocortical tumors.
- The functional impact of these AXIN2 genetic alterations requires further investigation.
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