Research of ARMC5 in Patients with Bilateral Macronodular Adrenocortical Disease (BMAD): influence of somatic variants in the prognosis

• Grant number: 25/01662-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2025
• End date: March 31, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Maria Candida Barisson Villares Fragoso
• Grantee: João Tomás de Camargo Silva
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Bilateral Macronodular Adrenocortical Disease (BMAD), first described in 1964 by Kirshner et al (1), is a rare (less than 2%) heterogeneous condition associated with endogenous Cushing's Syndrome (CS). BMAD is characterized by the formation of adrenal macronodules, usually bilateral, which secrete mainly cortisol in a variable manner and consequently greatly influence the phenotypic expression of the disease. BMAD may be associated with genetic syndromes, or isolated in its familial or apparently sporadic form. BMAD pathophysiology mainly involves germline pathogenic variants of tumor suppressor genes (ARMC5 and KDM1A) associated with the presence of the second molecular event in hyperplastic adrenal glands. Molecular mechanisms that are not yet fully elucidated lead to the activation of the cAMP-PKA pathway, corroborating adrenocortical hyperplasia and hypercortisolism. Pathogenic variants of the ARMC5 gene are the most prevalent in familial and apparently sporadic cases, and are associated with cell cycle dysregulation and irregular proliferation of adrenocortical cells. ARMC5 is a tumor suppressor gene and its loss of function results in increased cortisol production as well as increased adrenal glands distributed in nodules of different sizes. The KDM1A gene, also a tumor suppressor, is associated with a specific pattern of BMAD-associated hypercortisolism due to aberrant overexpression of the GIP receptor in macronodule cells.Pathogenic variants of ARMC5, both germline and somatic, are associated with variable clinical progression of the disease. Families with common germline and distinct somatic variants present variable hormone concentrations, indicating the importance of the somatic event in the hormonal pattern and consequently in the clinical progression of patients. Some authors have identified multiple somatic events of PMAH, however, in the cases already studied, this pattern was not identified in the Brazilian cohort, which may be justified by the methodology applied.To date, approximately 119 distinct pathogenic variants have been identified. In short, ARMC5 is the main genetic component of BMAD, and the study of somatic variants can better clarify its mechanism of action, contributing to the genotype-phenotype understanding of this type of BMAD, and carry out targeted and more appropriate clinical monitoring of patients.