ESPE Abstracts (2016) 86 PL2

Recent Advances in the Genetics of Adrenal Hyperfunction and Tumours

Jérôme Bertherat


Paris, France


There is a variety of unilateral adrenocortical tumors (ACT) and bilateral nodular adrenal hyperplasias that can be responsible for Cushing’ syndrome. Before puberty the most frequent are adrenocortical cancer (ACC) or micronodular adrenocortical hyperplasia (MiAH). The most classic form of MiAH is primary pigmented nodular adrenocortical dysplasia (PPNAD), diagnosed in more than two-third of Carney Complex patients. In adults adrenocortical adenomas (ACA) and primary bilateral macronodular adrenal hyperplasia (PBMAH) along with ACC can causes various level of cortisol dysregulation, ranging from non secreting tumors to overt-Cushing. Recently, genomics led to spectacular and fast progress in the identification of genetic and epigenetic alterations of all type of ACT. Exome sequencing identified somatic activating mutations of the catalytic subunit of PKA (PRKACA) in ACA responsible for overt-Cushing. Combining pangenomic snp analysis and whole genome sequencing led to the identification of inactivating germline mutations of a new tumor suppressor gene, ARMC5, in PBMAH. The identification of ARMC5 as a gene frequently altered in adults with PBMAH revealed the hereditary nature of this disease. The use of combined genomics in ACC has shown alterations of key driver genes like CTNNB1 (β-catenin), TP53, ZNRF3, and demonstrated frequent epigenetic changes at 11p15 (IGF2 locus). With these progress the alterations of the cAMP and the Wnt/β-catenin signaling pathways are now clearly described. Interestingly, activation of the cAMP pathway lead to benign and small unilateral or bilateral tumors with a very high steroid synthesis capacity causing overt-Cushing. On the other hand activation of the Wnt/β-catenin signaling pathways seems to be mostly observed in more aggressive tumors with a lower secretion capacity. These progress offer not only new molecular tools for genetic predisposition screening and molecular classification of adrenal causes of cortisol excess, but also open new perspectives for therapeutic development.

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