Aldosterone and cortisol, the main mineralocorticoid and glucocorticoid hormones in humans, are produced in the adrenal cortex, which is composed of three concentric zones with specific functional characteristics. Adrenocortical adenomas (ACAs) can lead to the autonomous secretion of aldosterone responsible for primary aldosteronism, the most frequent form of secondary arterial hypertension. In the case of cortisol production, ACAs lead to overt or subclinical Cushing syndrome. Genetic analysis driven by next-generation sequencing technology has enabled the discovery, during the past 7 years, of the genetic causes of a large subset of ACAs. In particular, somatic mutations in genes regulating intracellular ionic homeostasis and membrane potential have been identified in aldosterone-producing adenomas. These mutations all promote increased intracellular calcium concentrations, with activation of calcium signaling, the main trigger for aldosterone production. In cortisol-producing adenomas, recurrent somatic mutations in PRKACA (coding for the cyclic adenosine monophosphate-dependent protein kinase catalytic subunit α) affect cyclic adenosine monophosphate-dependent protein kinase A signaling, leading to activation of cortisol biosynthesis. In addition to these specific pathways, the Wnt/β-catenin pathway appears to play an important role in adrenal tumorigenesis, because β-catenin mutations have been identified in both aldosterone- and cortisol-producing adenomas. This, together with different intermediate states of aldosterone and cortisol cosecretion, raises the possibility that the two conditions share a certain degree of genetic susceptibility. Alternatively, different hits might be responsible for the diseases, with one hit leading to adrenocortical cell proliferation and nodule formation and the second specifying the hormonal secretory pattern.

中文翻译：

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功能性肾上腺皮质腺瘤的遗传原因

醛固酮和皮质醇是人体内主要的盐皮质激素和糖皮质激素，在肾上腺皮质中产生，肾上腺皮质由三个具有特定功能特征的同心区组成。肾上腺皮质腺瘤（ACA）可导致负责原发性醛固酮增多症的醛固酮的自主分泌，醛固酮增多症是继发性高血压的最常见形式。如果生产皮质醇，ACA会导致明显或亚临床的库欣综合症。在过去的7年中，由下一代测序技术驱动的遗传分析使发现ACA很大一部分的遗传原因成为可能。特别是，在产生醛固酮的腺瘤中已经发现调节细胞内离子稳态和膜电位的基因中的体细胞突变。这些突变都促进细胞内钙浓度的升高，并激活钙信号传导，这是醛固酮生产的主要诱因。在产生皮质醇的腺瘤中，反复发生体细胞突变PRKACA（编码环状单磷酸腺苷依赖性蛋白激酶催化亚基α）影响环状单磷酸腺苷依赖性蛋白激酶A信号传导，导致皮质醇生物合成的激活。除了这些特定的途径外，Wnt / β -catenin途径似乎在肾上腺肿瘤发生中起重要作用，因为β在产生醛固酮和皮质醇的腺瘤中均已发现β-catenin突变。这与醛固酮和皮质醇的不同中间状态一起分泌，增加了这两种条件共有一定程度的遗传易感性的可能性。或者，不同的命中可能是造成这种疾病的原因，其中一个命中导致肾上腺皮质细胞增殖和结节形成，第二个命中表明了激素的分泌方式。