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Intratumoural Aldosterone and Heterogeneity in Genetic Subtypes of Aldosterone Producing Adenomas
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. (Experimentell kirurgi)
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(English)Manuscript (preprint) (Other academic)
Abstract [en]



Primary Aldosteronism is the most common endocrine cause of hypertension. Unilateral disease in the form of Aldosterone producing adenomas (APAs) is found in 1.5-3% of hypertensive. Determining the source of aldosteronism is necessary for correct diagnosis and further molecular analysis.


To evaluate tissue aldosterone as a marker of aldosterone production and correlate it to patient phenotype and tumour mutation status, and to explore molecular heterogeneity in APAs.


Forty-six frozen tumour samples from patients diagnosed with APAs were included. Tumours were derived from a single endocrine referral center, and had been stored from 1985 to 2015. Tissue aldosterone concentration was related to clinical characteristics, genotype and molecular phenotype. Genetic heterogeneity was investigated by biopsies and in situ sequencing. Immunohistochemical analysis of Nephronectin, CYP11B1 and CYP11B2 were performed. qRT-PCR and in situ mRNA expression were used to analyze CYP11B2 mRNA expression.


Tissue aldosterone content was specific for aldosterone producing tumours and proved stable after long-term storage at -70C. CYP11B2 expression and aldosterone concentrations were higher in tumours with ATP1A1, ATP2B3 and CACNA1D mutations compared to those with KCNJ5 mutations (p<0.0001 and p=0.0018 respectively). The tissue aldosterone content correlated with CYP11B2 protein expression (r2=0.48, p<0.0001), and both CYP11B2 expression and tissue aldosterone content were associated with the plasma level of aldosterone (r2=0.33, p=0.0002 and r2=0.75, p<0.0001 respectively). In four tumours with suspicion of genetic heterogeneity, sampling of DNA revealed a heterogeneous KCNJ5 mutation in one tumour. Using in situ sequencing we confirmed heterogeneous expression of mutated KCNJ5 cDNA in the others. In three tumours classified as APAs, no mutation nor any aldosterone or CYP11B2 were detected, suggesting non-functional tumours.


Tissue aldosterone content is specific for aldosterone producing lesions, correlates with plasma levels, and displays variable levels depending on tumour genotype. Genetic heterogeneity is evident in a subgroup of KCNJ5 mutated tumours. The present results show that CYP11B2 expression and tissue aldosterone measurement may be used to clarify the source of aldosterone secretion. 

National Category
Clinical Medicine Endocrinology and Diabetes
URN: urn:nbn:se:uu:diva-281039OAI: oai:DiVA.org:uu-281039DiVA: diva2:912575
Available from: 2016-03-16 Created: 2016-03-16 Last updated: 2016-04-21
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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