Genetic, Cellular, and Molecular Heterogeneity in Adrenals With Aldosterone-Producing Adenoma
Genetic, Cellular, and Molecular Heterogeneity in Adrenals With Aldosterone-Producing Adenoma
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DOI：
10.1161/hypertensionaha.119.14177
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发表时间：
2020-04-01
期刊：
影响因子：
8.3
通讯作者：
Zennaro, Maria-Christina
中科院分区：
文献类型：
--
作者：
De Sousa, Kelly;Boulkroun, Sheerazed;Zennaro, Maria-Christina
产生醛固酮的腺瘤（阿帕）引起原发性醛固酮增多症-继发性高血压的最常见形式。编码离子通道和ATP酶的基因的体细胞突变在阿帕和产生醛固酮的细胞簇中被发现。我们研究了阿帕患者肾上腺不同醛固酮生成结构的遗传、细胞和分子异质性，以深入了解其发展机制，并研究其临床和生化相关性。在CYP 11B 2免疫组化后，通过下一代测序对49例患者的肾上腺组织进行阿帕、醛固酮产生细胞簇和继发性结节的遗传分析。结果与患者的临床和生化特征、类固醇特征以及肿瘤和邻近肾上腺皮质的组织学特征相关。在93.75%的APA中鉴定出体细胞突变。与其他突变组相比，携带KCNJ 5突变的腺瘤具有更多的透明细胞和表达CYP 11B 1的细胞，而表达CYP 11B 2或活化的β-catenin的细胞较少。18-羟基皮质醇和18-氧代皮质醇在携带KCNJ 5突变的患者中更高，并且与腺瘤的组织学特征相关;然而，突变状态不能使用类固醇分析来预测。KCNJ 5突变腺瘤中CYP 11B 2表达的异质性与遗传异质性无关。不同的突变被确定在继发结节表达醛固酮合成酶和独立的醛固酮产生细胞群肾上腺腺瘤，已知KCNJ 5突变被确定在5个醛固酮产生细胞群。同一肾上腺不同醛固酮生成结构的遗传异质性提示阿帕发生的复杂机制。
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 beta-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.