Activating mutations in CTNNB1 in aldosterone producing adenomas

Tobias Åkerström; Rajani Maharjan; Holger Sven Willenberg; Kenko Cupisti; Julian Ip; Ana Moser; Peter Stålberg; Bruce Robinson; K. Alexander Iwen; Henning Dralle; Martin K. Walz; Hendrik Lehnert; Stan Sidhu; Celso Gomez-Sanchez; Per Hellman; Peyman Björklund

doi:10.1038/srep19546

journal article Open Access Jan 27, 2016

Activating mutations in CTNNB1 in aldosterone producing adenomas

Tobias Åkerström Rajani Maharjan Holger Sven Willenberg Kenko Cupisti Julian Ip Ana Moser Peter Stålberg Bruce Robinson K. Alexander Iwen Henning Dralle Martin K. Walz Hendrik Lehnert Stan Sidhu Celso Gomez-Sanchez Per Hellman Peyman Björklund

Scientific Reports Vol. 6 No. 1 · Springer Science and Business Media LLC

View at Publisher Save 10.1038/srep19546

Abstract

AbstractPrimary 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 theCTNNB1gene coding for β-catenin. Our objective was to screen forCTNNB1mutations in a well-characterized cohort of 198 APAs. SomaticCTNNB1mutations were detected in 5.1% of the tumors, occurring mutually exclusive from mutations inKCNJ5, ATP1A1, ATP2B3andCACNA1D. 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 inCTNNB1occur in APAs. This also suggests that other mechanisms that constitutively activate the WNT pathway may be important in APA formation.

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References

53

[1]

Hamlet, S. M., Tunny, T. J., Woodland, E. & RD., G. Is aldosterone/renin ratio useful to screen a hypertensive population for primary aldosteronism? Clin Exp Pharmacol Physiol. 12, 249–252 (1985). 10.1111/j.1440-1681.1985.tb02641.x

[2]

Conn, J. W., Knopf, R. F. & Nesbit, R. Clinical characteristics of primary aldosteronism from an analysis of 145 cases. Am J Surg 107, 159–172 (1964). 10.1016/0002-9610(64)90252-1

[3]

Mulatero P. et al. Increased Diagnosis of Primary Aldosteronism, Including Surgically Correctable Forms, in Centers from Five Continents. Journal of Clinical Endocrinology & Metabolism 89, 1045–1050 (2004). 10.1210/jc.2003-031337

[4]

Fogari, R. et al. Prevalence of primary aldosteronism among unselected hypertensive patients: A prospective study based on the use of an aldosterone/renin ratio above 25 as a screening test. Hypertension Research 30, 111–117 (2007). 10.1291/hypres.30.111

[5]

Rossi, G. P. et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 48, 2293–2300 (2006). 10.1016/j.jacc.2006.07.059

[6]

Hannemann, A. et al. Screening for primary aldosteronism in hypertensive subjects: results from two German epidemiological studies. Eur J Endocrinol 167, 7–15 (2012). 10.1530/eje-11-1013

[7]

Funder, J. W. et al. Case detection, diagnosis and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. The Journal of clinical endocrinology and metabolism 93, 3266–3281 (2008). 10.1210/jc.2008-0104

[8]

Stowasser, M. et al. Evidence for abnormal left ventricular structure and function in normotensive individuals with familial hyperaldosteronism type I. The Journal of clinical endocrinology and metabolism 90, 5070–5076 (2005). 10.1210/jc.2005-0681

[9]

Rossi, G. P. et al. Changes in Left Ventricular Anatomy and Function in Hypertension and Primary Aldosteronism. Hypertension 27, 1039–1045 (1996). 10.1161/01.hyp.27.5.1039

[10]

Milliez, P. et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 45, 1243–1248 (2005). 10.1016/j.jacc.2005.01.015

[11]

Cardiovascular Complications Associated With Primary Aldosteronism

Sébastien Savard, Laurence Amar, Pierre-Francois Plouin et al.

Hypertension 2013 10.1161/hypertensionaha.113.01060

[12]

Heikkila, M. Wnt-4 Deficiency Alters Mouse Adrenal Cortex Function, Reducing Aldosterone Production. Endocrinology 143, 4358–4365 (2002). 10.1210/en.2002-220275

[13]

Kim, A. C. et al. Targeted disruption of beta-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex. Development 135, 2593–2602 (2008). 10.1242/dev.021493

[14]

Klinensmith, J. & Nusse, A. R. Signaling by wingless in Drosophilia. Developmental biology 166, 396–414 (1994). 10.1006/dbio.1994.1325

[15]

Liu C. et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108, 837–847 (2002). 10.1016/s0092-8674(02)00685-2

[16]

Morin, P. J. Activation of beta -Catenin-Tcf Signaling in Colon Cancer by Mutations in beta -Catenin or APC. Science 275, 1787–1790 (1997). 10.1126/science.275.5307.1787

[17]

Rubinfeld, B. Stabilization of beta -Catenin by Genetic Defects in Melanoma Cell Lines. Science 275, 1790–1792 (1997). 10.1126/science.275.5307.1790

[18]

Bjorklund, P., Lindberg, D., Akerstrom, G. & Westin, G. Stabilizing mutation of CTNNB1/beta-catenin and protein accumulation analyzed in a large series of parathyroid tumors of Swedish patients. Mol Cancer 7, 53 (2008). 10.1186/1476-4598-7-53

[19]

Polakis, P. Wnt signaling and cancer. Genes Dev., 1837–1851 (2000). 10.1101/gad.14.15.1837

[20]

Iwao K. et al. Activation of the beta-catenin gene by interstitial deletions involving exon 3 in primary colorectal carcinomas without adenomatous polyposis coli mutations. Cancer Research 58, 1021–1026 (1998).

[21]

Annabel Berthon et al. WNT/beta-catenin Signalling is Activated in Aldosterone Producing Adenomas and Controls Aldosterone Production. Hum. Mol. Genet 23, 889–905 (2014). 10.1093/hmg/ddt484

[22]

Aldosterone-Producing Adenoma Formation in the Adrenal Cortex Involves Expression of Stem/Progenitor Cell Markers

Sheerazed Boulkroun, Benoit Samson-Couterie, José-Felipe Golib-Dzib et al.

Endocrinology 2011 10.1210/en.2011-1205

[23]

Berthon, A. et al. Constitutive beta-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development. Hum Mol Genet 19, 1561–1576 (2010). 10.1093/hmg/ddq029

[24]

Wawrzak, D. et al. Wnt3a binds to several sFRPs in the nanomolar range. Biochem Biophys Res Commun 357, 1119–1123 (2007). 10.1016/j.bbrc.2007.04.069

[25]

Heaton J. H. et al. Progression to Adrenocortical Tumorigenesis in Mice and Humans through Insulin-Like Growth Factor 2 and Beta-Catenin. Am J Pathol. 181, 1017–1033 (2012). 10.1016/j.ajpath.2012.05.026

[26]

Durand, J., Lampron, A., Mazzuco, T. L., Chapman, A. & Bourdeau, I. Characterization of differential gene expression in adrenocortical tumors harboring beta-catenin (CTNNB1) mutations. The Journal of clinical endocrinology and metabolism 96, E1206–1211 (2011). 10.1210/jc.2010-2143

[27]

Tissier, F. et al. Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res 65, 7622–7627 (2005). 10.1158/0008-5472.can-05-0593

[28]

Scholl, U. I. et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet 45, 1050–1054 (2013). 10.1038/ng.2695

[29]

Azizan, E. A. et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet 45, 1055–1060 (2013). 10.1038/ng.2716

[30]

Akerstrom, T. et al. Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter. PloS one 7, e41926 (2012). 10.1371/journal.pone.0041926

[31]

Tobias Åkerström et al. Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas. Endocr Relat Cancer. 5, 735–744 (2015). 10.1530/erc-15-0321

[32]

Chen, X., Yang, J., Evans, P. M. & Liu, C. Wnt signaling: the good and the bad. Acta Biochimica et Biophysica Sinica 40, 577–594 (2008). 10.1111/j.1745-7270.2008.00440.x

[33]

Brunner, E., Peter, O., Schweizer, L. & Basler, K. Pangolin encodes a LEF-1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophilia. Nature 385, 829–833 (1997). 10.1038/385829a0

[34]

Armadillo Coactivates Transcription Driven by the Product of the Drosophila Segment Polarity Gene dTCF

Marc van de Wetering, Robert Cavallo, Dennis Dooijes et al.

Cell 1997 10.1016/s0092-8674(00)81925-x

[35]

Tadjine, M., Lampron, A., Ouadi, L. & Bourdeau, I. Frequent mutations of beta-catenin gene in sporadic secreting adrenocortical adenomas. Clin Endocrinol (Oxf) 68, 264–270 (2008). 10.1111/j.1365-2265.2007.03033.x

[36]

Silvia Monticone et al. Immunohistochemical, genetic and clinical characterization of sporadic aldosterone-producing adenomas. Molecular and Cellular Endocrinology 411, 146–154 (2015). 10.1016/j.mce.2015.04.022

[37]

Dekkers, T. et al. Adrenal Nodularity and Somatic Mutations in Primary Aldosteronism: One Node Is the Culprit? The Journal of clinical endocrinology and metabolism 99, E1341–1351 (2014). 10.1210/jc.2013-4255

[38]

F. Fallo et al. Quantitative assessment of CYP11B1 and CYP11B2 expression in aldosterone-producing adenomas. Eur J Endocrinol. 147, 795–802 (2012).

[39]

A. M. Neville, C. & Symington, T. Pathology of primary aldosteronism. Cancer 19, 1854–1868 (1966). 10.1002/1097-0142(196612)19:12<1854::aid-cncr2820191213>3.0.co;2-l

[40]

Azizan, E. A. et al. Microarray, qPCR and KCNJ5 sequencing of aldosterone-producing adenomas reveal differences in genotype and phenotype between zona glomerulosa- and zona fasciculata-like tumors. The Journal of clinical endocrinology and metabolism 97, E819–829 (2012). 10.1210/jc.2011-2965

[41]

Fernandes-Rosa, F. L. et al. Genetic Spectrum and Clinical Correlates of Somatic Mutations in Aldosterone-Producing Adenoma. Hypertension 64, 354–361 (2014). 10.1161/hypertensionaha.114.03419

[42]

Cao, Y. et al. Activating hotspot L205R mutation in PRKACA and adrenal Cushing’s syndrome. Science 344, 913–917 (2014). 10.1126/science.1249480

[43]

Beuschlein, F. et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing’s syndrome. N Engl J Med 370, 1019–1028 (2014). 10.1056/nejmoa1310359

[44]

Goh, G. et al. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat Genet 46, 613–617 (2014). 10.1038/ng.2956

[45]

Sato, Y. et al. Recurrent somatic mutations underlie corticotropin-independent Cushing’s syndrome. Science 344, 917–920 (2014). 10.1126/science.1252328

[46]

A genetic model for colorectal tumorigenesis

Eric R. Fearon, Bert Vogelstein

Cell 1990 10.1016/0092-8674(90)90186-i

[47]

Phelps, R. A. et al. A two-step model for colon adenoma initiation and progression caused by APC loss. Cell 137, 623–634 (2009). 10.1016/j.cell.2009.02.037

[48]

Marie-Hélène Bernard et al. A Case Report in Favor of a Multistep Adrenocortical Tumorigenesis JCEM 88, 998–1001 (2003). 10.1210/jc.2002-021117

[49]

Rossella Libé et al. Adrenocortical Tumor with Two Distinct Elements Revealed by Combined 18F-Fluorodeoxyglucose Positron Emission Tomography and 131I Nor-Cholesterol Scintigraphy JCEM 94, 3631–3632 (2009). 10.1210/jc.2009-1025

[50]

Gaujoux, S. et al. Wnt/beta-catenin and 3′,5′-cyclic adenosine 5′-monophosphate/protein kinase A signaling pathways alterations and somatic beta-catenin gene mutations in the progression of adrenocortical tumors. The Journal of clinical endocrinology and metabolism 93, 4135–4140 (2008). 10.1210/jc.2008-0631

Showing 50 of 53 references

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Published: Jan 27, 2016
Vol/Issue: 6(1)
License: View

Authors

T

Tobias Åkerström

Department of Surgical Sciences, Uppsala University , 75185 Uppsala ,

R

Rajani Maharjan

H

Holger Sven Willenberg

Department of Surgical Sciences University Hospital Uppsala University 75185 Uppsala Sweden

Section of Endocrine Surgery, Department of General, Visceral and Transplantation Surgery, Medical Center, University Essen-Duisburg, Duisburg, Germany

M

Martin K. Walz

From the Departments of Medical Oncology and Hematology and Surgery, Kliniken Essen-Mitte; Institute for Medical Informatics, Biometry and Epidemiology, Department of Radiation Oncology, and Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Essen; Department of Surgery, Klinikum Solingen, Solingen; Departments of Gastorenterology, Radiation Oncology, and Surgery, University Clinic, Tübingen; and Departments of Gastroenterology, Radiation...

H

Hendrik Lehnert

First Department of Medicine University Hospital Schleswig‐Holstein (UKSH), Campus Lübeck, and University of Lübeck Lübeck Germany

Department of Surgical Sciences University Hospital Uppsala University 75185 Uppsala Sweden

P

Peyman Björklund

Cite This Article

Tobias Åkerström, Rajani Maharjan, Holger Sven Willenberg, et al. (2016). Activating mutations in CTNNB1 in aldosterone producing adenomas. Scientific Reports, 6(1). https://doi.org/10.1038/srep19546

Activating mutations in CTNNB1 in aldosterone producing adenomas

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