Supplemental Digital Content is available in the text. Aldosterone-producing adenoma (APA) cause primary aldosteronism—the most frequent form of secondary hypertension. Somatic mutations in genes coding for ion channels and ATPases are found in APA and in aldosterone-producing cell clusters. We investigated the genetic, cellular, and molecular heterogeneity of different aldosterone-producing structures in adrenals with APA, to get insight into the mechanisms driving their development and to investigate their clinical and biochemical correlates. Genetic analysis of APA, aldosterone-producing cell clusters, and secondary nodules was performed in adrenal tissues from 49 patients by next-generation sequencing following CYP11B2 immunohistochemistry. Results were correlated with clinical and biochemical characteristics of patients, steroid profiles, and histological features of the tumor and adjacent adrenal cortex. Somatic mutations were identified in 93.75% of APAs. Adenoma carrying KCNJ5 mutations had more clear cells and cells expressing CYP11B1, and fewer cells expressing CYP11B2 or activated β-catenin, compared with other mutational groups. 18-hydroxycortisol and 18-oxocortisol were higher in patients carrying KCNJ5 mutations and correlated with histological features of adenoma; however, mutational status could not be predicted using steroid profiling. Heterogeneous CYP11B2 expression in KCNJ5-mutated adenoma was not associated with genetic heterogeneity. Different mutations were identified in secondary nodules expressing aldosterone synthase and in independent aldosterone-producing cell clusters from adrenals with adenoma; known KCNJ5 mutations were identified in 5 aldosterone-producing cell clusters. Genetic heterogeneity in different aldosterone-producing structures in the same adrenal suggests complex mechanisms underlying APA development.

中文翻译：

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具有醛固酮产生腺瘤的肾上腺的遗传、细胞和分子异质性

补充数字内容在文本中可用。醛固酮腺瘤 (APA) 会导致原发性醛固酮增多症——继发性高血压的最常见形式。在 APA 和产生醛固酮的细胞簇中发现了编码离子通道和 ATP 酶的基因的体细胞突变。我们研究了 APA 肾上腺中不同醛固酮产生结构的遗传、细胞和分子异质性，以深入了解驱动它们发展的机制并研究它们的临床和生化相关性。在 49 名患者的肾上腺组织中通过 CYP11B2 免疫组化后的下一代测序对 APA、产生醛固酮的细胞簇和继发性结节进行了遗传分析。结果与患者的临床和生化特征、类固醇谱、以及肿瘤和邻近肾上腺皮质的组织学特征。在 93.75% 的 APA 中发现了体细胞突变。与其他突变组相比，携带 KCNJ5 突变的腺瘤具有更多的透明细胞和表达 CYP11B1 的细胞，而表达 CYP11B2 或活化 β-连环蛋白的细胞较少。携带 KCNJ5 突变的患者的 18-羟基皮质醇和 18-氧皮质醇较高，并且与腺瘤的组织学特征相关；然而，使用类固醇分析无法预测突变状态。KCNJ5 突变腺瘤中的异质 CYP11B2 表达与遗传异质性无关。在表达醛固酮合酶的次级结节和来自具有腺瘤的肾上腺的独立产生醛固酮的细胞簇中发现了不同的突变；在 5 个产生醛固酮的细胞簇中发现了已知的 KCNJ5 突变。同一肾上腺中不同醛固酮产生结构的遗传异质性表明 APA 发展的复杂机制。