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Wnt/β-Catenin and 3′,5′-Cyclic Adenosine 5′-Monophosphate/Protein Kinase A Signaling Pathways Alterations and Somatic β-Catenin Gene Mutations in the Progression of Adrenocortical Tumors
Abstract
BACKGROUND: The Wnt/beta-catenin and cAMP signaling pathways play an important role in adrenal cortex tumorigenesis. Somatic activating mutations of the beta-catenin gene (CTNNB1) are the most frequent genetic defects identified both in adrenocortical adenomas (ACAs) and adrenocortical cancers (ACCs). PRKAR1A mutations leading to cAMP pathway dysregulation are observed in primary pigmented nodular adrenocortical diseases (PPNADs) and some sporadic ACAs. OBJECTIVE: The objective of the investigation was to study Wnt/beta-catenin dysregulation in adrenocortical tumors (ACTs) with cAMP pathway genetic alteration and search for secondary CTNNB1 somatic mutations in heterogeneous tumors. PATIENTS AND METHODS: Nine PPNADs, including five with macronodules, three ACAs with PRKAR1A somatic mutations, and one heterogeneous tumor with ACC developed within an ACA, were studied by immunohistochemistry and DNA sequencing. RESULTS: beta-Catenin accumulation was observed in all PPNADs, ACAs with PRKAR1A mutations, and the ACC component of the heterogeneous tumor. CTNNB1 somatic activating mutations were found in the macronodule of two of the five macronodular PPNADs, in one ACA with a PRKAR1A somatic mutation, and in the malignant part of the heterogeneous ACT. CONCLUSIONS: The Wnt/beta-catenin pathway is activated in PPNADs and ACAs with PRKAR1A mutations, suggesting a cross talk between the cAMP and Wnt/beta-catenin pathways in ACT development. In addition, the occurrence as an additional hit of a CTNNB1 somatic mutation is associated with larger or more aggressive ACTs. This underlines the importance of the Wnt/beta-catenin pathway in adrenal cortex tumorigenesis and the importance of genetic accumulation in the progression of ACTs.
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“mutational analysis of the effector of the canonical Wnt pathway, the β-catenin gene, CTNNB1, has identified activating point mutations in over 25% of both ACAs and ACCs in children and adults (149, 206–208).”
From Adrenocortical carcinoma (2014) · cites this paper as [206]
In the citing paper
“Furthermore, mutational analysis of the β-catenin gene CTNNB1 identified activating point mutations in both ACAs and ACCs (149, 206–208).”
From Adrenocortical carcinoma (2014) · cites this paper as [206]
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Antonini, S. R. R., Leal, L. F., & Cavalcanti, M. M. (2014) · Expert Review of Endocrinology & Metabolism · doi:10.1586/17446651.2014.941813 · Cited by 16
Rubin, B., Pilon, C., Pezzani, R., Rebellato, A., & Fallo, F. (2019) · Journal of Endocrinological Investigation · doi:10.1007/s40618-019-01127-1 · Cited by 15
Update on primary micronodular bilateral adrenocortical diseases
Maillet, M., Bourdeau, I., & Lacroix, A. (2020) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000538 · Cited by 17
Wnt/β-catenin signaling pathway in the tumor progression of adrenocortical carcinoma
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Insights into the role of genetic alterations in adrenocortical tumorigenesis
Herbet, M., Feige, J., & Thomas, M. (2008) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.10.010 · Cited by 13
Molecular markers and targeted therapies for adrenocortical carcinoma
Xu, Y., Qi, Y., Zhu, Y., Ning, G., & Huang, Y. (2013) · Clinical Endocrinology · doi:10.1111/cen.12358 · Cited by 13
Seidel, E., & Scholl, U. I. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00075 · Cited by 14
Disorders of the adrenal cortex: Genetic and molecular aspects
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Azevedo, M. F., & Stratakis, C. A. (2011) · Endocrine Practice · doi:10.4158/ep10412.ra · Cited by 15
AXIN genetic analysis in adrenocortical carcinomas updated.
Guimier, A., Ragazzon, B., Assié, G., Tissier, F., Dousset, B. E., Bertherat, J. Y., & Gaujoux, S. (2013) · PubMed · doi:10.3275/9022 · Cited by 12
Self-citationKamilaris, C. D. C., Faucz, F. R., Andriessen, V. C., Nilubol, N., Lee, C. R., Ahlman, M. A., Hannah‐Shmouni, F., & Stratakis, C. A. (2021) · Journal of the Endocrine Society · doi:10.1210/jendso/bvab007 · Cited by 10
Soon, P. S. H., & Sidhu, S. B. (2009) · Cancer treatment and research · doi:10.1007/978-1-4419-0857-5_11 · Cited by 9
Classification of adrenal cortical tumors: Promise of the ‘molecular’ approach
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Pusantisampan, T., Sangkhathat, S., Kayasut, K., Kanngurn, S., Jaruratanasirikul, S., Chotsampancharoen, T., & Kritsaneepaiboon, S. (2009) · Pediatric and Developmental Pathology · doi:10.2350/09-07-0683-cr.1 · Cited by 9
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Pathogenesis of benign adrenocortical tumors
Vezzosi, D., Bertherat, J. Y., & Groussin, L. (2010) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2010.10.005 · Cited by 7
Self-citationAdrenocortical tumors and hereditary syndromes
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Wu, L., Xie, J., Qi, Y., Su, T., Jiang, L., Zhou, W., Jiang, Y., Zhang, C., Zhong, X., Cao, Y., et al. (2022) · Endocrine Related Cancer · doi:10.1530/erc-21-0410 · Cited by 6
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Self-citationAdenosine receptors on the immuno-oncology expressway: TIME, perspectives, and translation
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Metadata
- Authors
- Gaujoux, S., Tissier, F., Groussin, L., Libé, R., Ragazzon, B., Launay, P., Audebourg, A., Dousset, B., Bertagna, X., & Bertherat, J.
- Affiliations
- Hôpital Cochin (FR)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2008-10
- Volume
- 93
- Issue
- 10
- Pages
- 4135-4140
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2170487994
- Cited by
- 142
- References
- 20
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 7 · 2019: 4 · 2018: 6 · 2017: 4 · 2016: 14 · 2015: 6 · 2014: 5 · 2013: 11 · 2012: 11
- FWCI
- 17.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- Wnt/β-catenin signaling, cAMP/PKA signaling, CTNNB1 mutation, PRKAR1A mutation, adrenal adenoma, adrenocortical carcinoma, primary pigmented nodular adrenocortical disease, tumor progression, pathway crosstalk, somatic mutations
- MeSH terms
- Adenoma, Cyclic AMP, Adolescent, Adrenal Cortex Neoplasms, Adult, Aged, Aged, 80 and over, Child, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Mutation, Neoplasm Invasiveness, Signal Transduction, Gene Expression Regulation, Neoplastic, Disease Progression, Tumor Burden, Wnt Proteins, beta Catenin, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
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