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.

中文翻译：

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原发性醛固酮增多症患者的进化特征。


背景 原发性醛固酮增多症主要由肾上腺皮质产生过多醛固酮引起，醛固酮产生结构可有多种形式，如腺瘤、结节、微结节等。大多数关于原发性醛固酮增多症的研究仅限于负责自主醛固酮产生的热点驱动基因;然而，醛固酮产生结构及其邻近增生腺体的全景遗传结构和基因组改变仍然未知。方法 在本研究中，使用功能性结节和匹配的增生组织进行全外显子组测序和转录组测序 （RNA-seq） 分析，并在醛固酮合酶免疫组化的引导下进行显微解剖。系统发育树是根据共享和独特的突变、基因突变谱和克隆特征构建的。结果 突变率代表功能性结节的均值高于增生样本，并且在系统发育树上 2 组之间显示出很少的突变重叠。醛固酮驱动基因 （KCNJ5 或 CACNA1D） 的突变仅在功能性结节中观察到，并且表明癌细胞分数几乎最大。此外，功能性结节还携带一些与细胞增殖相关的潜在变异，这些变异在增生组织中未检测到。转录组分析表明，功能性结节和增生组织之间只有 25.5% 的上调和 23.3% 的下调基因重叠。结论 本研究证明了原发性醛固酮增多症中醛固酮产生结构和邻近增生腺体的遗传和转录组景观。 结果表明，功能性结节和增生组织具有独立的克隆起源，在它们的系统发育树上几乎没有相互进化关系。