Evolutionary Characteristics in Primary Aldosteronism Patients.

IF 6.9 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Hypertension Pub Date : 2024-11-06 DOI:10.1161/HYPERTENSIONAHA.124.23398
Yinjie Gao, Yu Wang, Yue Zhou, Xiaoyan Chang, Yushi Zhang, Min Nie, Anli Tong
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Abstract

Background: Primary aldosteronism is predominantly caused by excessive aldosterone production from the adrenal cortex, and the aldosterone-producing structures could take many forms, like adenomas, nodules, micronodules, and so on. Most studies of primary aldosteronism were limited to the hotspot driver genes responsible for autonomous aldosterone production; however, the panoramic genetic architecture and genomic alterations of aldosterone-producing structures and their adjacent hyperplasia glands remain unknown.

Methods: In this study, whole-exome sequencing and transcriptome sequencing (RNA-seq) analyses were performed using functional nodules and matched hyperplasia tissues, which were microdissected guided by aldosterone synthase immunohistochemistry. Phylogenetic trees were constructed based on the shared and unique mutations, gene mutation spectrums, and clonal characteristics.

Results: The rates of mutations represented higher means of functional nodules than hyperplasia samples, and the little mutational overlap was shown between the 2 groups on phylogenetic trees. The mutations of the aldosterone driver gene (KCNJ5 or CACNA1D) were only observed in functional nodules and indicated almost the largest values of cancer cell fraction. Moreover, the functional nodules also harbored some potential variants related to cell proliferation, which were not detected in hyperplasia tissues. Transcriptome analysis suggested that only 25.5% upregulated and 23.3% downregulated genes overlapped between functional nodules and hyperplasia tissues.

Conclusions: This study demonstrated a genetic and transcriptome landscape of aldosterone-producing structures and adjacent hyperplasia glands in primary aldosteronism. The results indicated independent clonal origins on functional nodules and hyperplasia tissues, and little mutual evolutionary relationship was found on their phylogenetic trees.

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原发性醛固酮增多症患者的演变特征
背景:原发性醛固酮增多症主要由肾上腺皮质分泌过多醛固酮引起,醛固酮分泌结构有多种形式,如腺瘤、结节、小结节等。大多数原发性醛固酮增多症的研究仅限于负责自主醛固酮生成的热点驱动基因,然而,醛固酮生成结构及其邻近增生腺体的全景遗传结构和基因组改变仍不为人知:本研究使用功能性结节和匹配的增生组织(在醛固酮合成酶免疫组化的指导下进行显微解剖)进行了全外显子组测序和转录组测序(RNA-seq)分析。根据共有突变和独特突变、基因突变谱和克隆特征构建了系统发生树:结果:功能性结节样本的突变率高于增生样本,两组样本在系统发生树上的突变重叠较少。醛固酮驱动基因(KCNJ5 或 CACNA1D)的突变仅在功能性结节中观察到,并显示出几乎最大的癌细胞比例值。此外,功能性结节中还存在一些与细胞增殖有关的潜在变异,而增生组织中没有检测到这些变异。转录组分析表明,功能性结节和增生组织之间只有 25.5%的上调基因和 23.3%的下调基因重叠:本研究显示了原发性醛固酮增多症患者醛固酮分泌结构和邻近增生腺体的基因和转录组情况。结果表明,功能性结节和增生组织具有独立的克隆起源,在它们的系统发生树上几乎没有发现相互的进化关系。
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来源期刊
Hypertension
Hypertension 医学-外周血管病
CiteScore
15.90
自引率
4.80%
发文量
1006
审稿时长
1 months
期刊介绍: Hypertension presents top-tier articles on high blood pressure in each monthly release. These articles delve into basic science, clinical treatment, and prevention of hypertension and associated cardiovascular, metabolic, and renal conditions. Renowned for their lasting significance, these papers contribute to advancing our understanding and management of hypertension-related issues.
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