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Bruno Ragazzon, Guillaume Assié, and Jérôme Bertherat

Transcriptome analysis has been successfully used to study the gene profile expression of adrenocortical tumors (ACT) for 7 years. The various studies reported to date have produced an abundance of new information on adrenocortical cancer (ACC), underlying the validity of this approach to study the molecular genetics and pathogenesis of these tumors. The gene expression profile of ACC clearly differs from that of benign adrenocortical adenomas (ACA). Interestingly, transcriptome analysis has the ability to establish a subclassification of ACC based on the gene expression profile. In particular, it is able to identify two groups of tumors with different outcomes (i.e. good prognosis and poor prognosis). This approach has been used to develop molecular markers for ACC diagnosis and prognostication. An IGF2 cluster of genes up-regulated in ACC has been identified. Transcriptome analysis has shown that, in comparison with ACA, IGF2 is indeed the gene most overexpressed in ACC. By contrast, genes associated with steroidogenesis are down-regulated in ACC. Genes controlling the cell cycle are dysregulated in ACC, and several are dramatically overexpressed. Analysis regarding the level of expression of Wnt/β-catenin and p53 signaling has shown alterations, in keeping with the known molecular somatic genetic defects of these pathways that are observed in ACC. This review summarizes the main findings of studies reporting ACC transcriptome analysis, demonstrating its power for ACT classification, and examines the resulting progress in understanding the pathogenesis of ACC. The potential for both ACC diagnosis and the identification of new therapeutic targets will be discussed.

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Isadora Pontes Cavalcante, Anna Vaczlavik, Ludivine Drougat, Claudimara Ferini Pacicco Lotfi, Karine Perlemoine, Christopher Ribes, Marthe Rizk-Rabin, Eric Clauser, Maria Candida Barisson Villares Fragoso, Jérôme Bertherat, and Bruno Ragazzon

ARMC5 (Armadillo repeat containing 5 gene) was identified as a new tumor suppressor gene responsible for hereditary adrenocortical tumors and meningiomas. ARMC5 is ubiquitously expressed and encodes a protein which contains a N-terminal Armadillo repeat domain and a C-terminal BTB (Bric-a-Brac, Tramtrack and Broad-complex) domain, both docking platforms for numerous proteins. At present, expression regulation and mechanisms of action of ARMC5 are almost unknown. In this study, we showed that ARMC5 interacts with CUL3 requiring its BTB domain. This interaction leads to ARMC5 ubiquitination and further degradation by the proteasome. ARMC5 alters cell cycle (G1/S phases and cyclin E accumulation) and this effect is blocked by CUL3. Moreover, missense mutants in the BTB domain of ARMC5, identified in patients with multiple adrenocortical tumors, are neither able to interact and be degraded by CUL3/proteasome nor alter cell cycle. These data show a new mechanism of regulation of the ARMC5 protein and open new perspectives in the understanding of its tumor suppressor activity.