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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

Department of Endocrinology, Metabolism, and Cancer, Institut National de la Santé et de la Recherche Médicale Unit 567, Centre National de la Recherche Scientifique Unit Mixté de Recherche 8104, Institut Cochin (S.G., F.T., L.G., R.L., B.R., X.B., J.B.), Université Paris Descartes (S.G., F.T., L.G., R.L., B.D., X.B., J.B.), Department of Endocrinology, Center for Rare Adrenal Diseases (L.G., R.L., X.B., J.B.), Department of Pathology (F.T., P.L., A.A.) and Department of Digestive and Endocrine Surgery (S.G., B.D.), Assistance Publique Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France; and COMETE (COrtico-MEdullosurrénale Tumeurs Endocrines)-INCa (Institut National du Cancer)-Rare Adrenal Cancer Network (F.T., L.G., R.L., B.D., X.B., J.B.), 75014 Paris, France

Address all correspondence and requests for reprints to: Professor Jérôme Bertherat, Service des Maladies Endocriniennes et Métaboliques, Hôpital Cochin, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France. E-mail: jerome.bertherat{at}cch.aphp.fr.

Background: The Wnt/β-catenin and cAMP signaling pathways play an important role in adrenal cortex tumorigenesis. Somatic activating mutations of the β-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/β-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: β-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/β-catenin pathway is activated in PPNADs and ACAs with PRKAR1A mutations, suggesting a cross talk between the cAMP and Wnt/β-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/β-catenin pathway in adrenal cortex tumorigenesis and the importance of genetic accumulation in the progression of ACTs.