Genetics of Adrenocortical Development and Tumors

Abstract

This article links the understanding of developmental physiology of the adrenal cortex to adrenocortical tumor formation. Many molecular mechanisms that lead to formation of adrenocortical tumors have been discovered via next-generation sequencing approaches. The most frequently mutated genes in adrenocortical tumors are also factors in normal adrenal development and homeostasis, including those that alter the p53 and Wnt/β-catenin pathways. In addition, dysregulated protein kinase A signaling and ARMC5 mutations have been identified as key mediators of adrenocortical tumorigenesis. The growing understanding of genetic changes that orchestrate adrenocortical development and disease pave the way for potential targeted treatment strategies.

Keywords: Adrenal development; Adrenocortical carcinoma; Driver mutation; Genetic; Ontogenesis; Pathway; Signaling; Zonation.

Fig. 1

The anatomy and structure of the adrenal glands. The adrenal glands are located at the upper poles of the kidneys. In humans, the adrenal gland has three distinct cortical zones (1) the zona glomerulosa, (2) the zona fasiculata, and (3) the zona reticularis. The inner part of the adrenal gland is the medulla, responsible for catecholamine synthesis. ZF, zona fasiculata; ZG, zona glomerulosa; ZR, zona reticularis.

Fig. 2

Early adrenal development. The adrenal cortex develops from a thickening of the coelomic epithelium at the intersection of the urogenital ridge and the dorsal mesentery. This group of cells is called the adrenogonadal primordium, and these cells express the transcription factors SF-1 and NR5A1. The chromaffin cells form the medulla, and the adrenal primordium cells form the fetal adrenal gland, which is surrounded by the definitive adrenal gland. The fetal adrenal cortex differentiates into a definitive zone and a fetal zone after 9 weeks’ gestation. The transitional zone appears after 24 weeks’ gestation. After birth the fetal adrenals involute, and the adult adrenals form. By 6 months of age the adult adrenal cortex consists of the zona glomerulosa and the zona fasciculata. During adrenarche (age 6–7) the zona reticularis is formed. ZF, zona fasiculata; ZG, zona glomerulosa; ZR, zona reticularis.

Fig. 3

cAMP/PKA signaling in adrenocortical tumors. (A) In the resting state, PKA exists as an inactive tetramer comprising a dimer of regulatory subunits bound to catalytic subunits. PDEs act as inhibitors of the pathway by degrading cAMP to regulate signal transduction. Adenylyl cyclase catalyzes the conversion of ATP to cAMP, and elevation in cellular cAMP levels leads to activation of PKA, release of the catalytic subunits, and phosphorylation of downstream targets, including the transcription factor cAMP response-element binding protein (CREB). (B) In McCune-Albright syndrome, activating mutations in the GNAS gene, which encodes the stimulatory guanine nucleotide-binding protein (Gsα) subunit, lead to constitutive activation of the Gsα protein subunit that couples hormone receptors to intracellular generation of cAMP. Mutations in Gsα lead to prolonged activation of Gsα and its downstream effectors. In Carney complex, inactivating mutations in the regulatory subunit 1α of PKA (R1α) subunit of PKA lead to suppression of its inhibitory action, release of the catalytic subunits, and transcription of downstream targets. Inactivating mutations in PDEs lead to accumulation of cAMP and dysregulated activation of the cAMP-PKA pathway. Activating mutations in the catalytic subunit of PKA result in up-regulation of the PKA pathway and phosphorylation of downstream targets. AC, adenylyl cyclase; Cα, catalytic subunit of PKA; GPCR, G-protein-coupled receptor.