Microarray, qPCR, andKCNJ5Sequencing of Aldosterone-Producing Adenomas Reveal Differences in Genotype and Phenotype between Zona Glomerulosa- and Zona Fasciculata-Like Tumors
| Autor: | Elena A.B. Azizan, Gary J. Hoffman, Brian Y.H. Lam, Junhua Zhou, Alison Marker, Rhoda E. Kuc, Jennifer Clarke, Morris J. Brown, Lisa Happerfield, Stephen Newhouse |
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| Rok vydání: | 2012 |
| Předmět: |
Adenoma
Adult Male Familial hyperaldosteronism medicine.medical_specialty Genotype Endocrinology Diabetes and Metabolism education Clinical Biochemistry Adrenal Gland Neoplasms Biology Biochemistry chemistry.chemical_compound Endocrinology Zona fasciculata Internal medicine Hyperaldosteronism mental disorders medicine Humans Aldosterone Aged Laser capture microdissection Adrenal gland Biochemistry (medical) Middle Aged medicine.disease Molecular biology Phenotype medicine.anatomical_structure G Protein-Coupled Inwardly-Rectifying Potassium Channels chemistry Zona glomerulosa Female Zona Glomerulosa Zona Fasciculata psychological phenomena and processes |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 97:E819-E829 |
| ISSN: | 1945-7197 0021-972X |
| Popis: | Aldosterone-producing adenomas (APA) are heterogeneous. The recent finding of somatic KCNJ5 mutations suggests a genetic explanation.The objectives of this study were the following: 1) to compare transcriptional profiles in APA and adjacent adrenal gland (AAG); 2) to test whether gene expression profile clusters with different cell histology; and 3) to measure the frequency of KCNJ5 mutations and determine the genotype-phenotype relationship.The design of the study included laboratory analyses of 46 unselected APA.The patients in this study had primary hyperaldosteronism with unilateral APA.The objectives of this study were the following: 1) Illumina beadchip analysis of RNA from eight paired APA-AAG; 2) a blinded review of cell histology for 46 APA; 3) laser capture microdissection of zona glomerulosa (ZG) and zona fasciculata (ZF) cells; and 4) sequencing of KCNJ5 in 46 APA.The main outcome measures of this study were the following: 1) a difference in gene expression profile and a correlation with histological markers of ZF; 2) a frequency of KCNJ5 mutations and phenotypic comparisons of wild type with mutant APA.The results of the study were the following: 1) a cluster analysis of microarray data separated APA from AAG. APA at opposite ends of the APA cluster had an approximately 800-fold difference in CYP17A1 mRNA expression, whereas histology showed 0% ZF-like cells in one vs. 100% in the other. A heat map ranking APA by CYP17A1 expression correctly predicted several genes (e.g. KCNK1, SLC24A3) to be enriched in laser capture microdissection samples of ZG; 2) known or novel mutations of KCNJ5 were found in 20 of 46 consecutive APA [43% (95% confidence interval [CI] (29, 58)%)]. The APA with KCNJ5 gene mutations were larger compared with tumors harboring the wild type, 1.63 [95% CI (1.37, 1.88)] vs. 1.14 [0.97, 1.30] cm (P = 0.0013), had predominantly ZF-like cells, and their CYP17A1 (log(2)-fold change) was higher than in wild type: -0.96 [95% CI (-0.07, -1.85)] vs. -2.54 [-1.61, -3.46], (P = 0.017).KCNJ5 mutations are common in APA, particularly those arising from ZF. The long-recognized heterogeneity among APA may have a genetic basis. |
| Databáze: | OpenAIRE |
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