Adrenocortical tumorigenesis: Lessons from genetics

Abstract

Advances in genomics over the past two decades have allowed for elucidation of the genetic alterations leading to the development of adrenocortical tumors and/or hyperplasias. These molecular changes were initially discovered through the study of rare familial tumor syndromes such as McCune-Albright Syndrome, Carney complex, Li-Fraumeni syndrome, and Beckwith-Wiedemann syndrome, with the identification of alterations in genes and molecular pathways that subsequently led to the discovery of aberrations in these or related genes and pathways in sporadic tumors. Genetic alterations in GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B, that lead to aberrant cyclic adenosine monophosphate-protein (cAMP) kinase A signaling, were found to play a major role in the development of benign cortisol-producing adrenocortical tumors and/or hyperplasias, whereas genetic defects in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2 were implicated in the development of benign aldosterone-producing tumors and/or hyperplasias through modification of intracellular calcium signaling. Germline ARMC5 defects were found to cause the development of primary bilateral macronodular adrenocortical hyperplasia with glucocorticoid and/or mineralocorticoid oversecretion. Adrenocortical carcinoma was linked primarily to aberrant p53 signaling and/or Wnt-β-catenin signaling, as well as IGF2 overexpression, with frequent genetic alterations in TP53, ZNRF3, CTNNB1, and 11p15. This review focuses on the genetic underpinnings of benign cortisol- and aldosterone-producing adrenocortical tumors/hyperplasias and adrenocortical carcinoma.

Keywords: adrenocortical adenoma; adrenocortical carcinoma; adrenocortical hyperplasia; cushing's syndrome; primary aldosteronism.

Figure 1.. Gene-based diagnostic algorithm for primary cortisol-producing adrenocortical hyperplasias.

Abbreviations: APC, adenomatous polyposis coligene; ARMC5, armadillo repeat-containing protein 5; c-PPNAD, CNC-associated primary pigmented nodular adrenocortical disease; 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 I, α gene.