OBJECTIVE: Aldosterone-producing adenoma (APA) is a common curable cause of hypertension. Somatic mutations in five genes (KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1) have been found to cause the excess aldosterone production of two thirds of APAs [1-4]. KCNJ5 mutant APAs, the most common and largest, had explicit genotype-phenotype relationship - a low protein expression of KCNJ5 relative to their peritumoural zona glomerulosa (ZG) and a zona fasciculata-like composition [5-6]. Conversely for the other genes, controversy arises on whether they have the opposite cell phenotype [4,7-8]. This prospective study aim to to characterize the histopathological-specific mutation spectrum of APAs. DESIGN AND METHOD: Targeted sequencing of 'hotspots' for mutations associated with primary aldosteronism were performed on all APAs. Diagnosis of APA was confirmed through CYP11B2 expression as measured by immunohistochemistry. Immunohistochemical staining using KCNJ5 as a ZG cell marker and CYP17A1 as a ZF cell marker was used to characterize the APAs in addition to hematoxylin and eosin staining. The relationship between genotype and phenotype was then compared. RESULTS: APAs with intense staining of KCNJ5 frequently had a mutation in ATP1A1 or CACNA1D. APAs with intense staining of CYP17A1 frequently had a mutation in KCNJ5. In addition to previously reported mutations, a new causal mutation in exon 28 of CACNA1D was identified. CONCLUSIONS: ATP1A1 and CACNA1D mutant APAs comprise of ZG-like cell composition with intense staining of KCNJ5 whereas KCNJ5 mutant APAs comprise of ZF-like cell composition with intense staining of CYP17A1. As ZG-like APAs have been reported to be small [4], diagnosis of an APA in these patients could be made easier through identification of the causal mutation through genotyping the free-circulating ZG-like APA DNA pre-adrenalectomy.

• Publikační typ
• časopisecké články MeSH

Mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 are thought to cause the excessive autonomous aldosterone secretion of aldosterone-producing adenomas (APAs). The histopathology of KCNJ5 mutant APAs, the most common and largest, has been thoroughly investigated and shown to have a zona fasciculata-like composition. This study aims to characterize the histopathologic spectrum of the other genotypes and document the proliferation rate of the different sized APAs. Adrenals from 39 primary aldosteronism patients were immunohistochemically stained for CYP11B2 to confirm diagnosis of an APA. Twenty-eight adenomas had sufficient material for further analysis and were target sequenced at hot spots in the 5 causal genes. Ten adenomas had a KCNJ5 mutation (35.7%), 7 adenomas had an ATP1A1 mutation (25%), and 4 adenomas had a CACNA1D mutation (14.3%). One novel mutation in exon 28 of CACNA1D (V1153G) was identified. The mutation caused a hyperpolarizing shift of the voltage-dependent activation and inactivation and slowed the channel's inactivation kinetics. Immunohistochemical stainings of CYP17A1 as a zona fasciculata cell marker and Ki67 as a proliferation marker were used. KCNJ5 mutant adenomas showed a strong expression of CYP17A1, whereas ATP1A1/CACNA1D mutant adenomas had a predominantly negative expression (P value =1.20×10(-4)). ATP1A1/CACNA1D mutant adenomas had twice the nuclei with intense staining of Ki67 than KCNJ5 mutant adenomas (0.7% [0.5%-1.9%] versus 0.4% [0.3%-0.7%]; P value =0.04). Further, 3 adenomas with either an ATP1A1 mutation or a CACNA1D mutation had >30% nuclei with moderate Ki67 staining. In summary, similar to KCNJ5 mutant APAs, ATP1A1 and CACNA1D mutant adenomas have a seemingly specific histopathologic phenotype.

• MeSH
• adenom * genetika   patologie   MeSH
• aldosteron metabolismus   MeSH
• dospělí MeSH
• dovnitř usměrňující draslíkové kanály spřažené s G proteiny genetika   MeSH
• genetická predispozice k nemoci MeSH
• hyperaldosteronismus * genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nadledviny patologie   MeSH
• nádory nadledvin * genetika   patologie   MeSH
• sodíko-draslíková ATPasa genetika   MeSH
• vápníkové kanály - typ L genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH