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Activating mutations in CTNNB1 in aldosterone producing adenomas
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 19546Article in journal (Refereed) Published
Abstract [en]

Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalenceof 5–10% in unreferred hypertensive patients. Aldosterone producing adenomas (APAs) constitutea large proportion of PA cases and represent a surgically correctable form of the disease. The WNTsignaling pathway is activated in APAs. In other tumors, a frequent cause of aberrant WNT signaling ismutation in the CTNNB1 gene coding for β-catenin. Our objective was to screen for CTNNB1 mutationsin a well-characterized cohort of 198 APAs. Somatic CTNNB1 mutations were detected in 5.1% of thetumors, occurring mutually exclusive from mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D. Allof 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, suggestingactivation of WNT signaling. By CYP11B2 mRNA expression, CYP11B2 protein expression, and directmeasurement of aldosterone in tumor tissue, we confirmed the ability for aldosterone production. Thisreport provides compelling evidence that aberrant WNT signaling caused by mutations in CTNNB1 occurin APAs. This also suggests that other mechanisms that constitutively activate the WNT pathway maybe important in APA formation.

Place, publisher, year, edition, pages
2016. Vol. 6, 19546
National Category
Endocrinology and Diabetes Medical and Health Sciences
URN: urn:nbn:se:uu:diva-277306DOI: 10.1038/srep19546ISI: 000368736400001PubMedID: 26815163OAI: oai:DiVA.org:uu-277306DiVA: diva2:904610
Swedish Cancer SocietySwedish Research Council
Available from: 2016-02-19 Created: 2016-02-19 Last updated: 2016-04-21Bibliographically approved
In thesis
1. Genetic Alterations and Molecular Signatures in Aldosterone Producing Adenomas
Open this publication in new window or tab >>Genetic Alterations and Molecular Signatures in Aldosterone Producing Adenomas
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Primary Aldosteronism (PA) is caused by autonomous overproduction of aldosterone. Aldosterone is necessary for fluid and ion homeostasis. Aberrant overproduction leads to hypertension and cardiovascular damage. With a prevalence of over 5% in the worlds’ hypertensive community, and with over a billion people worldwide having high blood pressure, PA represents a major contributor to health care costs and morbidity. Importantly, 30% of PA patients have a unilateral dominant secretion, an aldosterone producing adenoma (APA), making it possible to cure a substantial portion of patients with surgery. Unfortunately, there is a large underdiagnosis of PA, leading to delayed diagnosis in many patients, worsening their outcome after surgery. A need for better screening techniques, raised awareness and treatment options for PA is warranted.

Since 2011, the genetic understanding of APAs has revolutionized. Somatic mutations turning on an autonomous aldosterone production has been observed in up to 80% of tumors. In this thesis we have investigated the genetic landscape and phenotypes of APAs. By international collaborations we have collected one of the largest cohorts of APAs ever sequenced. We have confirmed and extended the understanding of KCNJ5 mutations, its associated phenotype and the specificity for APAs. We have confirmed a high rate of mutations in ATP1A1, ATP2B3 and CACNA1D, and noted distinct clinical and molecular phenotypes in these tumors. We describe a marker of Zona Glomerulosa cells, perhaps important for the normal regulation and function of these cells. We observe somatic mutations in CTNNB1, occurring in a mutually exclusive manner to the other mutations. Using in situ sequencing, we note genetic heterogeneity in APAs with KCNJ5 mutations. Finally, we evaluate intratumoral aldosterone measurement on a large cohort of tumors, validating a high specificity for APAs. Noting also a difference in the level of intratumoral aldosterone between APAs and a possible association with genotype. Remarkably, we also note a robust correlation between the intracellular concentrations and plasma-aldosterone. We hope that with gained knowledge of the genetic background, the understanding of both pathologic and normal states of the adrenals will increase, and hopefully benefit patients in the future.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 49 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1197
Aldosterone, aldosterone producing adenoma, KCNJ5, ATP1A1, ATP2B3, CACNA1D, CTNNB1
National Category
Endocrinology and Diabetes
urn:nbn:se:uu:diva-281042 (URN)978-91-554-9517-6 (ISBN)
Public defence
2016-05-07, Robergssalen, Akademiska sjukhuset, ingång 40, plan 4, Uppsala, 10:00 (English)
Available from: 2016-04-15 Created: 2016-03-16 Last updated: 2016-04-21

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