Genetic Alterations in Benign Adrenal Tumors

Abstract

The genetic basis of most types of adrenal adenomas has been elucidated over the past decade, leading to the association of adrenal gland pathologies with specific molecular defects. Various genetic studies have established links between variants affecting the protein kinase A (PKA) signaling pathway and benign cortisol-producing adrenal lesions. Specifically, genetic alterations in GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B have been identified. The PKA signaling pathway was initially implicated in the pathogenesis of Cushing syndrome in studies aiming to understand the underlying genetic defects of the rare tumor predisposition syndromes, Carney complex, and McCune-Albright syndrome, both affected by the same pathway. In addition, germline variants in ARMC5 have been identified as a cause of primary bilateral macronodular adrenal hyperplasia. On the other hand, primary aldosteronism can be subclassified into aldosterone-producing adenomas and bilateral idiopathic hyperaldosteronism. Various genes have been reported as causative for benign aldosterone-producing adrenal lesions, including KCNJ5, CACNA1D, CACNA1H, CLCN2, ATP1A1, and ATP2B3. The majority of them encode ion channels or pumps, and genetic alterations lead to ion transport impairment and cell membrane depolarization which further increase aldosterone synthase transcription and aldosterone overproduction though activation of voltage-gated calcium channels and intracellular calcium signaling. In this work, we provide an overview of the genetic causes of benign adrenal tumors.

Keywords: Cushing syndrome; PKA; PRKAR1A; adrenal tumors; genetics.

Figure 1

Algorithm for the diagnosis of primary cortisol-producing adrenocortical hyperplasias based on the underlying genetic etiology. APC adenomatous polyposis coli gene, ARMC5 armadillo repeat-containing protein 5, c-PPNAD CNC-associated primary pigmented nodular adrenocortical disease, CNC Carney complex, FH fumarate hydratase, GNAS gene coding for the stimulatory subunit α of the G-protein (Gsα), i-MAD isolated micronodular adrenocortical disease, i-PPNAD isolated PPNAD, MAS McCune–Albright syndrome, MEN1 multiple endocrine neoplasia type 1, PBAD primary bimorphic adrenocortical disease, PBMAH primary bilateral macronodular adrenocortical hyperplasia, PDE8B phosphodiesterase 8B gene, PDE11A phosphodiesterase 11A gene, PPNAD primary pigmented nodular adrenocortical disease, PRKACA protein kinase cAMP-dependent catalytic, alpha, PRKAR1A protein kinase cAMP-dependent regulatory type Iα gene. Adapted from Kamilaris CDC, Stratakis CA, Hannah-Shmouni F, 2020 [23].

Figure 2

Schematic representation of cyclic adenosine monophosphate (cAMP) signaling pathway in primary adrenal neoplasms. C catalytic subunit of PKA, GDP guanosine diphosphate, GNAS gene coding for the stimulatory subunit α of the G-protein (Gsα), GPCR G-protein coupled receptor, GTP guanosine triphosphate, PDE phosphodiesterase, PDE11A/8B phosphodiesterase 11A and 8B respectively, PKA protein kinase, R regulatory subunit of PKA, α, β, γ subunits, PRKACA protein kinase cAMP-dependent catalytic, alpha PRKAR1A protein kinase cAMP-dependent regulatory type Iα gene.

Figure 3

Cellular mechanisms leading to aldosterone production in aldosterone-producing adenoma and familial hyperaldosteronism. Genetic alterations in CLCN2, ATP1A1, and KCNJ5 result in defective ion transport and thus membrane depolarization, which in turn activates voltage-gated Ca²⁺ channels and increases Ca²⁺ levels. Genetic alterations in ATP2B3 decrease export of Ca²⁺, while in CACNA1D and CACNA1H directly increase Ca²⁺ levels. Increased intracellular Ca²⁺ enhances expression of aldosterone synthase (CYP11B2) and promotes aldosterone production. APA aldosterone-producing adenoma, CLC2 chloride channel 2, FH familial hyperaldosteronism, GIRK4 G-protein coupled inward rectifying potassium channel 4, PMCA3 Ca²⁺ ATPase type 3.