Activating mutations in CTNNB1 in aldosterone producing adenomas

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.

Maharjan, RajaniUppsala universitet,Experimentell kirurgi(Swepub:uu)mahra921 (author)
Willenberg, Holger Sven (author)
Cupisti, Kenko (author)
Ip, Julian (author)
Moser, Ana (author)
Stålberg, PeterUppsala universitet,Endokrinkirurgi(Swepub:uu)petestah (author)
Robinson, Bruce (author)
Iwen, Alexander K (author)
Dralle, Henning (author)
Walz, Martin K. (author)
Lehnert, Hendrik (author)
Sidhu, Stan (author)
Gomez-Sanchez, Celso (author)
Hellman, PerUppsala universitet,Endokrinkirurgi(Swepub:uu)perhellm (author)
Björklund, PeymanUppsala universitet,Experimentell kirurgi(Swepub:uu)pebjo957 (author)
Uppsala universitetExperimentell kirurgi (creator_code:org_t)

By the author/editor: Åkerström, Tobia ...; Maharjan, Rajani; Willenberg, Holg ...; Cupisti, Kenko; Ip, Julian; Moser, Ana; show more...; Stålberg, Peter; Robinson, Bruce; Iwen, Alexander ...; Dralle, Henning; Walz, Martin K.; Lehnert, Hendrik; Sidhu, Stan; Gomez-Sanchez, C ...; Hellman, Per; Björklund, Peyma ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

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