Genetic Causes of Functional Adrenocortical Adenomas

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.