Genomics of benign adrenocortical tumors

Benign adrenocortical adenomas and hyperplasia are relatively common and include a spectrum of distinct entities, which diagnosis depends on the macroscopic aspect and the secretion profile. Recent advances in genomics have proposed high-throughput molecular characterization of adrenal tumors, thereby improving our knowledge on the pathophysiology and tumorigenesis of these tumors. Genomic (exome and chromosome alteration profiles), epigenomic (micro-RNAs expression and methylation profiles) and transcriptomic (gene expression profiles) studies highlighted the major roles of intracellular calcium signaling in aldosterone-producing adenomas (APA), of protein kinase A (PKA)/cAMP pathway in cortisol-producing tumors, and of Wnt/beta-catenin pathway in non-secreting tumors. Exome sequencing revealed new major drivers in all tumor types, including KCNJ5, ATP1A1, ATP2B3, CACNA1D and CACNA1H mutations in APA, PRKACA mutations in cortisol-producing adenomas (CPA) and ARMC5 mutations in primary macronodular adrenocortical hyperplasia (PMAH). The clinical impact of these findings is just starting to evolve. The identification of genetic syndromes, such as germline ARMC5 mutations in PMAH, has allowed genetic counseling. Key molecular alterations could serve as a basis for the development of targeted medical treatments for benign adrenal tumors. The recent developments in genomics, including single-cell technologies, and in proteomics and metabolomics will probably offer new perspectives for characterizing benign adrenal tumorigenesis.