ENDOCRINE TUMOURS: The genomics of adrenocortical tumors

Abstract

The last decade witnessed the emergence of genomics, a set of high-throughput molecular measurements in biological samples. These pan-genomic and agnostic approaches have revolutionized the molecular biology and genetics of malignant and benign tumors. These techniques have been applied successfully to adrenocortical tumors. Exome sequencing identified new major drivers in all tumor types, including KCNJ5, ATP1A1, ATP2B3 and CACNA1D mutations in aldosterone-producing adenomas (APA), PRKACA mutations in cortisol-producing adenomas (CPA), ARMC5 mutations in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) and ZNRF3 mutations in adrenocortical carcinomas (ACC). Moreover, the various genomic approaches -including exome sequencing, transcriptome, miRNome, genome and methylome -converge into a single molecular classification of adrenocortical tumors. Especially for ACC, two main molecular groups have emerged, showing major differences in outcomes. These ACC groups differ by their gene expression profiles, but also by recurrent mutations and specific DNA hypermethylation patterns in the subgroup of poor outcome. The clinical impact of these findings is just starting. The main altered signaling pathways now become therapeutic targets. The molecular groups of diseases individualize robust subtypes within diseases such as APA, CPA, PBMAH and ACC. A revised nosology of adrenocortical tumors should impact the clinical research. Obvious consequences also include genetic counseling for the new genetic diseases such as ARMC5 mutations in PBMAH, and a better prognostication of ACC based on targeted measurements of a few discriminant molecular alterations. Identifying the main molecular groups of adrenocortical tumors by extensively gathering the molecular variations is a significant step forward towards precision medicine.

European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors

“…In recent years, several multicenter studies have shed light on the pathogenesis of ACC (5,6,7,8), but 'multi-omic' studies (9,10,11) reveal that only a minority of ACC cases have pathogenic driver mutations. For details on this topic, we refer to recent reviews (12,13,14).…”

Identification of hub genes and pathways in adrenocortical carcinoma by integrated bioinformatic analysis

“…These results can help us to further understand the role of DEGs in the development and progress of ACC. The additional KEGG pathway analysis showed that up‐regulated DEGs were significantly enriched in cell cycle, cell senescence, progesterone‐mediated oocyte maturation, oocyte, p53 signalling pathway and folic acid resistance, further confirmed the important roles of p53 signalling pathway in ACC …”

De Novo Development Of A Cortisol-Producing Adrenocortical Carcinoma In A Patient With Primary Adrenal Insufficiency

“…Mutations in the TP53 tumor suppressor gene, abnormal Wnt activation, and insulin-like growth factor 2 overexpression have been reported in ACCs (11). Analysis of mRNA expression, DNA methylation, and microRNA expression profiles in ACC delineates 2 main subgroups with differences in overall survival rate (12). Multistep tumorigenesis models are well-documented in many solid tumors, such as colorectal carcinoma, but it is still a matter of debate whether multistep tumorigenesis occurs in ACC.…”