Abstract
Adrenocortical tumors (ACTs) are typically unilateral and can be classified as benign adrenocortical adenomas (ACAs) or malignant adrenocortical cancers (ACCs). In rare cases, tumors may occur in both adrenal glands as micronodular hyperplasia (primary pigmented nodular adrenal dysplasia) or as macronodular hyperplasia (primary bilateral macronodular adrenal hyperplasia, PBMAH). The study of certain tumor predisposition syndromes has improved our understanding of sporadic ACTs. Most ACAs are associated with abnormalities of the cAMP signaling pathway, whereas most ACCs are linked to alterations in IGF2, TP53, or the Wnt/βcatenin pathways. Over the past year, single-nucleotide polymorphism array technology and next-generation sequencing have identified novel genetic alterations in ACTs that shed new light on the molecular mechanisms of oncogenesis. Among these are somatic mutations of PKA catalytic subunit alpha gene (PRKACA) in ACA, germline, and somatic mutations of armadillo repeat containing 5 gene (ARMC5) in primary bilateral macronodular adrenal hyperplasia and somatic alterations of the E3 ubiquitin ligase gene ZNRF3 in ACC. This review focuses on the recent discoveries and their diagnostic, prognostic, and therapeutic implications.
Highlights
The pathogenic mechanisms underlying adrenocortical tumors (ACTs) are complex and heterogeneous
A hotspot somatic mutation in the PKA catalytic subunit alpha gene (PRKACA) has been identified in adrenocortical adenomas (ACAs) [14], germline, and somatic mutations of armadillo repeat containing 5 gene (ARMC5) have been described in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) [15], and somatic alterations in the E3 ubiquitin ligase gene ZNRF3 were recently identified in adrenocortical cancers (ACCs) [16]
A somatic mutation in ARMC5 gene has been found in a meningioma in patients with an ARMC5 germline mutation and a PBMAH [30]. These data suggest that genetic alterations of the ARMC5 gene may cause the development of different associated tumors with PBMAH
Summary
The pathogenic mechanisms underlying adrenocortical tumors (ACTs) are complex and heterogeneous. Somatic mutations in the CTNNB1 gene have been reported in both benign and malignant ACTs [13] Alterations in these several genes are identified only in subgroups of ACA and ACC. Over the last 5 years, the development of high-throughput sequencing has revealed several frequent alterations in genes not previously described, underlying new insights in the pathogenesis of benign and malignant forms of ACT. A hotspot somatic mutation in the PKA catalytic subunit alpha gene (PRKACA) has been identified in ACA [14], germline, and somatic mutations of armadillo repeat containing 5 gene (ARMC5) have been described in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) [15], and somatic alterations in the E3 ubiquitin ligase gene ZNRF3 were recently identified in ACC [16]. We aim to give an overview of recent advances in the genetics of ACT, focusing on the latest driver genes identified, and improving our understanding of the pathophysiology of these tumors
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