{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:00:46Z","timestamp":1753891246583,"version":"3.41.2"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T00:00:00Z","timestamp":1749513600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Past studies on common mutant aldosterone-producing adenomas (APAs) had found genotype\u2013phenotype correlations associated with histological appearance. Most of these studies did not perform CYP11B2-guided sequencing of APAs or sequencing for all the currently known aldosterone-driver genes. Hence, misinterpretation of the genotype\u2013phenotype correlations could have occurred. Herein, we aimed to identify the genotype\u2013phenotype correlations associated with the histopathology of the different mutant APAs utilizing CYP11B2-guided sequencing. A total of 33 APAs with confirmed aldosterone-driver mutation (17 <jats:italic>KCNJ5<\/jats:italic> mutant APAs, 8 <jats:italic>ATP1A1<\/jats:italic> mutant APAs, 6 <jats:italic>CACNA1D<\/jats:italic> mutant APAs, and 2 <jats:italic>CTNNB1<\/jats:italic> mutant APAs) were immunohistochemically stained using H&amp;amp;E, CYP17A1, CYP11B2, KCNJ5, Ki67, \u03b2-catenin, and LHCGR antibody. Interestingly, APAs with a p.Thr41Ala <jats:italic>CTNNB1<\/jats:italic> mutation also harbored a p.Val1373Met <jats:italic>CACNA1D<\/jats:italic> mutation. The <jats:italic>CTNNB1<\/jats:italic> double mutant APAs had less expression of CYP17A1 and larger quantities of spironolactone bodies than a single mutant APA with a p.Ser45Phe <jats:italic>CTNNB1<\/jats:italic> mutation. However, both <jats:italic>CTNNB1<\/jats:italic> mutant APAs displayed diffuse active \u03b2-catenin expression with prominent nuclear staining that reflects the constitutive activation of the Wnt\/\u03b2-catenin signaling pathway (<jats:italic>p<\/jats:italic>\u202f=\u202f0.016 compared to other genotypes) but no significant increase in LHCGR. <jats:italic>KCNJ5<\/jats:italic> mutant APAs displayed distinct existence of atypical cells (6 of the 17 <jats:italic>KCNJ5<\/jats:italic> mutant APAs), whereas <jats:italic>CACNA1D<\/jats:italic> mutant APAs had frequent presentations of spironolactone bodies (4 of the 6 <jats:italic>CACNA1D<\/jats:italic> mutant APAs), and <jats:italic>ATP1A1<\/jats:italic> mutant APAs had significantly higher Ki67 score than <jats:italic>KCNJ5<\/jats:italic> mutant APAs (<jats:italic>p<\/jats:italic>\u202f=\u202f0.020). The results of this study support the notion that CYP11B2-guided sequencing of all currently known aldosterone-driver genes can fine-tune existing genotype\u2013phenotype correlations in histopathological profiles.<\/jats:p>","DOI":"10.3389\/fmed.2025.1569619","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T05:22:21Z","timestamp":1749532941000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Histopathological spectrum of common aldosterone-driver gene mutations in aldosterone-producing adenomas"],"prefix":"10.3389","volume":"12","author":[{"given":"Fatin Athirah","family":"Pauzi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muaatamarulain","family":"Mustangin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geok Chin","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ales","family":"Ryska","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiri","family":"Ceral","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miroslav","family":"Solar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena Aisha","family":"Azizan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,10]]},"reference":[{"key":"ref1","first-page":"2799","article-title":"Primary aldosteronism: JACC state-of-the-art review","volume-title":"J Am Coll 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