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Primary Aldosteronism: Spatial Multiomics Mapping of Genotype-Dependent Heterogeneity and Tumor Expansion of Aldosterone-Producing Adenomas

ABSTRACT: Primary Aldosteronism: Spatial Multiomics Mapping of Genotype-Dependent Heterogeneity and Tumor Expansion of Aldosterone-Producing Adenomas

PROVIDER: PRJNA1145938 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30174100_1.fastq.gz	Fastqsanger.gz
	SRR30174100_2.fastq.gz	Fastqsanger.gz
	SRR30174101_1.fastq.gz	Fastqsanger.gz
	SRR30174101_2.fastq.gz	Fastqsanger.gz
	SRR30174102_1.fastq.gz	Fastqsanger.gz

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Primary Aldosteronism: Spatial Multiomics Mapping of Genotype-Dependent Heterogeneity and Tumor Expansion of Aldosterone-Producing Adenomas

Project description:Primary aldosteronism is frequently caused by an adrenocortical aldosterone-producing adenoma (APA) carrying a somatic mutation that drives aldosterone overproduction. APAs with a mutation in KCNJ5 (APA-KCNJ5MUT) are characterized by heterogeneous CYP11B2 (aldosterone synthase) expression, a particular cellular composition and larger tumor diameter than those with wild-type KCNJ5 (APA-KCNJ5WT). Here, we used spatial transcriptomics profiling of adrenal tissue cryosections to define the role of transcriptomic reprogramming in APA pathophysiology. Our findings advance the understanding of the transcriptional context of inter- and intra-tumoral APA heterogeneity and provide novel insight into the genotype-dependent tumor expansion capabilities of APAs.

2024-08-13 | GSE274314 | GEO

Somatic mutations in SLC30A1 lead to aldosterone-producing adenomas and primary aldosteronism

Project description:Primary aldosteronism (PA), the most common form of endocrine hypertension, is characterized by inappropriately elevated aldosterone production via renin-independent mechanisms. Driver somatic mutations for aldosterone excess have been found in approximately 90% of aldosterone-producing adenomas (APAs) using an aldosterone synthase (CYP11B2)-guided sequencing approach. Herein, using CYP11B2-guided whole-exome sequencing (WES) and targeted amplicon sequencing, we detected two closely-stationed somatic variants in SLC30A1 in five APAs (p.L51_A57del, n=3; p.L49_L55del, n=2) that were devoid of any of the known aldosterone-driver mutations. SLC30A1 encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). PA cases with SLC30A1 mutations showed male dominance and demonstrated increased serum aldosterone concentration compared with age-matched male controls. We tested functional effects of the variant SLC30A1L51_A57del in a doxycycline-inducible system using the human adrenocortical HAC15 cell line. Functional in vitro studies following doxycycline treatment indicated increased adrenal cell aldosterone production, CYP11B2 mRNA expression, CYP11B2 promoter activity, depolarization of the resting membrane potential and increased cytosolic Ca2+ levels in the SLC30A1L51_A57del cells. Collectively, these data support a pathological role for mutant SLC30A1 on the development of PA.

2023-07-03 | GSE236437 | GEO

Somatic mutations in SLC30A1 lead to aldosterone-producing adenomas and primary aldosteronism

Project description:Somatic mutations in SLC30A1 lead to aldosterone-producing adenomas and primary aldosteronism

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Microarray study of human adrenal zona glomerulosa (ZG), zona fasciculata (ZF) and aldosterone-producing adenomas (APA)

Project description:Learn about the transcriptome profiling of zona glomerulosa (ZG), zona fasciculata (ZF) and aldosterone-producing adenomas (APA) in human adrenals

2015-09-15 | GSE64957 | GEO

Microarray study of aldosterone-producing adenomas (APA) and their adjacent normal adrenal glands

Project description:Aldosterone-producing adenomas (APA) are heterogeneous. The objectives of this study were to compare the transcriptional profiles in APA and normal adjacent adrenal gland (AAG). This was done through the Illumina beadchip analysis of RNA from eight paired APA-AAG. Other tissues (phaeochromocytoma, cushing, and hyperplastic adrenals) were included as controls.

2020-12-01 | GSE156931 | GEO

Microarray study of human adrenal zona glomerulosa (ZG), zona fasciculata (ZF) and aldosterone-producing adenomas (APA)

Project description:Learn about the transcriptome profiling of zona glomerulosa (ZG), zona fasciculata (ZF) and aldosterone-producing adenomas (APA) in human adrenals 21 pairs of zona fasciculata (ZF) and zona glomerulosa (ZG), and 14 paired aldosterone-producing adenomas (APAs) from 14 Conn’s syndrome patients and 7 phaeochromocytoma patients were assayed on the Affymetrix Human Genome U133 Plus 2.0 Array. Laser capture microdissection was used to acquire samples of ZF, ZG and APA as previously described (Azizan EA, et al. J Clin Endocrinol Metab. 2012;97:E819-E829). For differentiation of ZG from ZF, sections were stained with cresyl violet using the LCM Staining Kit (AM1935, Ambion, USA). Data processing and analysis was performed using AffymetrixGeneChip Command Console Software and PartekGenomicSuite 6.5 (Partek Inc., St. Louis, MO). Gene expressions were portrayed as the summarized log-signal of the Robust Multichip Average (RMA) with quantilenormalisation and median polish for probe set summarisation. Validation by qPCR was performed on genes >10 fold up-regulated in zona glomerulosa (compared to zona fasciculata) and >10 fold up-regulated in aldosterone-producing adenomas (compared to zona glomerulosa).

2015-09-15 | E-GEOD-64957 | biostudies-arrayexpress

Expression data from aldosterone-producing adenomas (APAs) with a somatic mutation in either KCNJ5, CACNA1D, or ATP1A1

2013-07-14 | GSE48303 | GEO

Molecular characteristics of the KCNJ5 mutated aldosterone-producing adenomas.

Project description:The pathophysiology of aldosterone-producing adenomas (APAs) has been investigated via genetic approaches and the pathogenic significance of a series of somatic mutations, including KCNJ5, has been uncovered. However, how the mutational status of an APA is associated with its molecular characteristics, including its transcriptome and methylome, has not been fully understood. This study was undertaken to explore the molecular characteristics of APAs, specifically focusing on APAs with KCNJ5 mutations as opposed to those without KCNJ5 mutations, by comparing their transcriptome and methylome status. Cortisol-producing adenomas (CPAs) were used as reference. We conducted transcriptome and methylome analyses of 29 APAs with KCNJ5 mutations, 8 APAs without KCNJ5 mutations and 5 CPAs. Genome-wide gene expression and CpG methylation profiles were obtained from RNA and DNA samples extracted from these 42 adrenal tumors. Cluster analysis of the transcriptome and methylome revealed molecular heterogeneity in APAs depending on their mutational status. DNA hypomethylation and gene expression changes in Wnt signaling and inflammatory response pathways were characteristic of APAs with KCNJ5 mutations. Comparisons between transcriptome data from our APAs and that from normal adrenal cortex obtained from the Gene Expression Omnibus suggested similarities between APAs with KCNJ5 mutations and zona glomerulosa. The present study, which is based on transcriptome and methylome analyses, indicates the molecular heterogeneity of APAs depends on their mutational status. Here, we report the unique characteristics of APAs with KCNJ5 mutations.

2018-01-08 | GSE90867 | GEO

Expression data from aldosterone-producing adenomas (APAs) with a somatic mutation in either KCNJ5, CACNA1D, or ATP1A1

Project description:Analysis of aldosterone-producing adenoma (APA) samples from patients with primary hyperaldosteronism. These APAs have a somatic mutation in either KCNJ5, CACNA1D, or ATP1A1. Results provide insight into the different mechanisms each mutation may cause leading to elevated aldosterone production in APA. In this dataset, we include expression data from aldosterone-producing adenomas (APAs) with a somatic mutation in either KCNJ5, CACNA1D, or ATP1A1. These data are used to obtain differentially expressed genes between KCNJ5 mutant APAs and CACNA1D/ATP1A1 mutant APAs. A total of 13 samples were analyzed (8 KCNJ5 mutant APAs and 5 CACNA1D/ATP1A1 mutant APAs). 43 genes had a false discovery rate (FDR) <0.5% and were >2-fold different between KCNJ5 mutant APAs and 5 CACNA1D/ATP1A1 mutant APAs. The two sets of genotypes were separated on unsupervised hierarchical clustering of 1475 genes correlating >0.6 with CYP11B2.

2013-07-14 | E-GEOD-48303 | biostudies-arrayexpress

Primary Aldosteronism: Metabolic Reprogramming and the Pathogenesis of Aldosterone-Producing Adenomas.

Project description:Aldosterone-producing adenomas (APAs) are characterized by aldosterone hypersecretion and deregulated adrenocortical cell growth. Increased energy consumption required to maintain cellular tumorigenic properties triggers metabolic alterations that shape the tumor microenvironment to acquire necessary nutrients, yet our knowledge of this adaptation in APAs is limited. Here, we investigated adrenocortical cell-intrinsic metabolism and the tumor immune microenvironment of APAs and their potential roles in mediating aldosterone production and growth of adrenocortical cells. Using multiple advanced bioinformatics methods, we analyzed gene expression datasets to generate distinct metabolic and immune cell profiles of APAs versus paired adjacent cortex. APAs displayed activation of lipid metabolism, especially fatty acid β-oxidation regulated by PPARα, and glycolysis. We identified an immunosuppressive microenvironment in APAs, with reduced infiltration of CD45+ immune cells compared with adjacent cortex, validated by CD45 immunohistochemistry (3.45-fold, p < 0.001). APAs also displayed an association of lipid metabolism with ferroptosis and upregulation of antioxidant systems. In conclusion, APAs exhibit metabolic reprogramming towards fatty acid β-oxidation and glycolysis. Increased lipid metabolism via PPARα may serve as a key mechanism to modulate lipid peroxidation, a hallmark of regulated cell death by ferroptosis. These findings highlight survival advantages for APA tumor cells with metabolic reprogramming properties.

| S-EPMC8345059 | biostudies-literature

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