title: Activating mutations in CTNNB1 in aldosterone producing adenomas.
abstract: Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalence of 5-10% in unreferred hypertensive patients. Aldosterone producing adenomas (APAs) constitute a large proportion of PA cases and represent a surgically correctable form of the disease. The WNT signaling pathway is activated in APAs. In other tumors, a frequent cause of aberrant WNT signaling is mutation in the CTNNB1 gene coding for β-catenin. Our objective was to screen for CTNNB1 mutations in a well-characterized cohort of 198 APAs. Somatic CTNNB1 mutations were detected in 5.1% of the tumors, occurring mutually exclusive from mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D. All of the observed mutations altered serine/threonine residues in the GSK3β binding domain in exon 3. The mutations were associated with stabilized β-catenin and increased AXIN2 expression, suggesting activation of WNT signaling. By CYP11B2 mRNA expression, CYP11B2 protein expression, and direct measurement of aldosterone in tumor tissue, we confirmed the ability for aldosterone production. This report provides compelling evidence that aberrant WNT signaling caused by mutations in CTNNB1 occur in APAs. This also suggests that other mechanisms that constitutively activate the WNT pathway may be important in APA formation.
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Åkerström
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Rajani
authors.initials: R
authors.lastname: Maharjan
authors.affiliation: Department of Endocrinology and Metabolism, Rostock University Medical Center, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Sven Willenberg
authors.affiliation: General, Visceral and Pediatric Surgery University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Kenko
authors.initials: K
authors.lastname: Cupisti
authors.affiliation: University of Sydney, Endocrine Surgical Unit and Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia.
authors.forename: Julian
authors.initials: J
authors.lastname: Ip
authors.affiliation: Department of Medicine I, University of Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Moser
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Stålberg
authors.affiliation: University of Sydney, Endocrine Surgical Unit and Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia.
authors.forename: Bruce
authors.initials: B
authors.lastname: Robinson
authors.affiliation: Department of Medicine I, University of Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Alexander Iwen
authors.affiliation: Department of General, Visceral and Vascular Surgery, University Hospital, University of Halle-Wittenberg, Halle/Saale, Germany. Sweden.
authors.forename: Henning
authors.initials: H
authors.lastname: Dralle
authors.affiliation: Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Kliniken Essen-Mitte, Essen, Germany.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Walz
authors.affiliation: Department of Medicine I, University of Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Lehnert
authors.affiliation: University of Sydney, Endocrine Surgical Unit and Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia.
authors.forename: Stan
authors.initials: S
authors.lastname: Sidhu
authors.affiliation: Endocrine Section, Department of Medicine, G.V. (Sonny) Montgomery VA Medical Center and University of Mississippi Medical Center, Jackson, USA.
authors.forename: Celso
authors.initials: C
authors.lastname: Gomez-Sanchez
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hellman
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Peyman
authors.initials: P
authors.lastname: Björklund
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018246:Adrenocortical Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000450:Aldosterone / Q000096:biosynthesis* / Q000235:genetics; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D009363:Neoplasm Proteins; D051176:beta Catenin; D000450:Aldosterone
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