Format

Send to

Choose Destination
Sci Rep. 2016 Jan 27;6:19546. doi: 10.1038/srep19546.

Activating mutations in CTNNB1 in aldosterone producing adenomas.

Author information

1
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
2
Department of Endocrinology and Metabolism, Rostock University Medical Center, Germany.
3
General, Visceral and Pediatric Surgery University Hospital Düsseldorf, Düsseldorf, Germany.
4
University of Sydney, Endocrine Surgical Unit and Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia.
5
Department of Medicine I, University of Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany.
6
Department of General, Visceral and Vascular Surgery, University Hospital, University of Halle-Wittenberg, Halle/Saale, Germany. Sweden.
7
Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Kliniken Essen-Mitte, Essen, Germany.
8
Endocrine Section, Department of Medicine, G.V. (Sonny) Montgomery VA Medical Center and University of Mississippi Medical Center, Jackson, USA.

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.

PMID:
26815163
PMCID:
PMC4728393
DOI:
10.1038/srep19546
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center