The molecular genetics of adrenal cushing

• Published in: Hormones (Athens, Greece) Vol. 23; no. 4; pp. 601 - 610
• Main Authors: Vaduva, Patricia, Bertherat, Jerome
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2024
• Subjects: Endocrinology; Medicine; Medicine & Public Health; Metabolic Diseases; Review Article; Cortisol-producing adenoma; Primary pigmented nodular adrenal disease; Molecular genetics; Adrenal cushing; Primary bilateral macronodular adrenal hyperplasia; Adrenocortical carcinoma
• ISSN: 1109-3099; 2520-8721; 2520-8721
• DOI: 10.1007/s42000-024-00608-0

Adrenal Cushing represents 20% of cases of endogenous hypercorticism. Unilateral cortisol-producing adenoma (CPA), a benign tumor, and adrenocortical carcinoma (ACC), a malignant tumor, are more frequent than bilateral adrenal nodular diseases (primary bilateral macronodular adrenal hyperplasia (PBMAH) and primary pigmented nodular adrenal disease (PPNAD)). In cortisol-producing adrenal tumors, the signaling pathways mainly altered are the protein kinase A and Wnt/β-catenin pathways. Studying components of these pathways and exploring syndromic and familial cases of these tumors has historically enabled identification of many of the predisposing genes. More recently, pangenomic sequencing revealed alterations in sporadic tumors. In ACC, mainly due to TP53 alterations causing Li-Fraumeni syndrome, germline predisposition is frequent in children, while it is rare in adults. Pathogenic variants in the DNA mismatch repair genes MLH1 , MSH2 , MSH6 , and PMS2 , which cause Lynch syndrome or alterations of IGF2 and CDKN1C (11p15 locus) in Beckwith-Wiedemann syndrome, can also cause ACC. Rarely, ACC is described in other hereditary tumor syndromes due to germline pathogenic variants in MEN1 or APC and, in very rare cases, NF1 , SDH , PRKAR1A , or BRCA2 . Concerning ACC somatic alterations, TP53 and genetic or epigenetic alterations at the 11p15 locus are also frequently described, as well as CTNNB1 and ZNRF3 pathogenic variants. CPAs mainly harbor somatic pathogenic variants in PRKACA and CTNNB1 and, less frequently, PRKAR1A , PRKACB , or GNAS1 pathogenic variants. Isolated PBMAH is due to ARMC5 inactivating pathogenic variants in 20 to 25% of cases and to KDM1A pathogenic variants in food-dependent Cushing. Syndromic PBMAH may be due to germline pathogenic variants in MEN1 , APC , or FH , causing type 1 multiple endocrine neoplasia, familial adenomatous polyposis, or hereditary leiomyomatosis-kidney cancer syndrome, respectively. PRKAR1A germline pathogenic variants are the main alteration causing PPNAD (isolated or part of Carney complex).