ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 S24.1 | DOI: 10.1530/endoabs.63.S24.1

Adrenocortical tumors: new genes, new understanding, new therapy

Mr Guillaume Assie


For the last ten years, genomic approaches have led to important discoveries in adrenocortical tumors, unraveling mechanisms of tumorigenesis and autonomous hormone secretion. Autonomous aldosterone secretion in primary aldosteronism is now seen as induced by abnormal intra-cellular calcium signaling in glomerulosa cells, related to somatic mutations. The most common affects KCNJ5, coding for a membrane channel. A clinical trial with macrolides -impacting this channel- is ongoing. These mutations also impact primary aldosteronism nosography. Firstly, many ‘aldosterone producing adenomas’ correspond to diffuse adrenal diseases rather than focal alterations. Secondly, there seems to be a continuum between adrenal cortex aging and primary aldosteronism. These novelties should impact the screening and therapeutic strategies. Somatic mutations are found in one third of adrenocortical adenomas. Clinical impact is currently limited. Diffuse primitive adrenal cortex alterations are heterogenous. Discovering ectopic adrenal expression of hormone receptors permitted pharmacological treatment of a few patients with macronodular hyperplasia. Germline mutations of PRKAR1A and ARMC5, respectively associated to primary pigmented nodular adrenocortical dysplasia and to multinodular primary macronodular hyperplasia, helped to better classify these lesions. These mutations also improved our mechanistic understanding. Clinical impact is major for mutations carriers and their relatives, enabling early and efficient treatment of potentially deadly conditions. In adrenocortical carcinoma, recurrent somatic mutations mostly affect Wnt/beta-catenin (CTNNB1 and ZNRF3) and cell-cycle (TP53). Therapeutic targeting of these mutations is limited. Few cases with high mutation burden or microsatellite instability -potentially related to germline MUTHY or Mismatch repair genes mutations respectively-, may orient towards immune checkpoint inhibitors. Finally, genomic screening of these carcinomas identified two main molecular classes, associated with major differences in outcome. Early prognostic stratification may impact the decision of adjuvant therapy after complete surgery. Taken together, genomic accelerated adrenal research pace, with clinical implications now coming to bedside. Clinical evaluation is now needed.

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