Tumor suppressor gene ARMC5 controls adrenal redox state through NRF1 turnover.

ARMC5: is a tumor suppressor gene frequently mutated in primary bilateral macronodular adrenal hyperplasia (PBMAH), an adrenal cause of Cushing's syndrome. The function of ARMC5 is poorly understood, aside from the fact that it regulates cell viability and adrenal steroidogenesis by mechanisms still unknown. Tumor suppressor genes play an important role in modifying intracellular redox response, which in turn regulates diverse cell signaling pathways. In this study, we demonstrated that inactivation in adrenocortical cells increased the expression of actors scavenging reactive oxygen species, such as superoxide dismutases (SOD) and peroxiredoxins (PRDX) by increasing the transcriptional regulator NRF1. Moreover, ARMC5 is involved in the NRF1 ubiquitination and in its half-life. Finally, inactivation alters adrenocortical steroidogenesis through the activation of p38 pathway and decreases cell sensitivity to ferroptosis participation to increase cell viability. Altogether, this study uncovers a function of ARMC5 as a regulator of redox homeostasis in adrenocortical cells, controlling steroidogenesis and cell survival.

Primary bilateral macronodular adrenal hyperplasia: definitely a genetic disease.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is an adrenal cause of Cushing syndrome. Nowadays, a PBMAH diagnosis is more frequent than previously, as a result of progress in the diagnostic methods for adrenal incidentalomas, which are widely available. Although some rare syndromic forms of PBMAH are known to be of genetic origin, non-syndromic forms of PBMAH have only been recognized as a genetic disease in the past 10 years. Genomics studies have highlighted the molecular heterogeneity of PBMAH and identified molecular subgroups, allowing improved understanding of the clinical heterogeneity of this disease. Furthermore, the generation of these subgroups permitted the identification of new genes responsible for PBMAH. Constitutive inactivating variants in ARMC5 and KDM1A are responsible for the development of distinct forms of PBMAH. To date, pathogenic variants of ARMC5 are responsible for 20-25% of PBMAH, whereas germline KDM1A alterations have been identified in >90% of PBMAH causing food-dependent Cushing syndrome. The identification of pathogenic variants in ARMC5 and KDM1A demonstrated that PBMAH, despite mostly being diagnosed in adults aged 45-60 years, is a genetic disorder. This Review summarizes the important progress made in the past 10 years in understanding the genetics of PBMAH, which have led to a better understanding of the pathophysiology, opening new clinical perspectives.

KDM1A inactivation causes hereditary food-dependent Cushing syndrome.

PURPOSE: This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS. METHODS: A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing). RESULTS: The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10-12 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS. CONCLUSION: KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.

Predictors of complication after adrenalectomy

ABSTRACT Purpose: To investigate risk factors for complications in patients undergoing adrenalectomy. Materials and Methods: A retrospective search of our institutional database was performed of patients who underwent adrenalectomy, between 2014 and 2018. Clinical parameters and adrenal disorder characteristics were assessed and correlated to intra and post-operative course. Complications were analyzed within 30-days after surgery. A logistic regression was performed in order to identify independent predictors of morbidity in patients after adrenalectomy. Results: The files of 154 patients were reviewed. Median age and Body Mass Index (BMI) were 52-years and 27.8kg/m2, respectively. Mean tumor size was 4.9±4cm. Median surgery duration and estimated blood loss were 140min and 50mL, respectively. There were six conversions to open surgery. Minor and major post-operative complications occurred in 17.5% and 8.4% of the patients. Intra-operative complications occurred in 26.6% of the patients. Four patients died. Mean hospitalization duration was 4-days (Interquartile Range: 3-8). Patients age (p=0.004), comorbidities (p=0.003) and pathological diagnosis (p=0.003) were independent predictors of post-operative complications. Tumor size (p<0.001) and BMI (p=0.009) were independent predictors of intra-operative complications. Pathological diagnosis (p<0.001) and Charlson score (p=0.013) were independent predictors of death. Conclusion: Diligent care is needed with older patients, with multiple comorbidities and harboring unfavorable adrenal disorders (adrenocortical carcinoma and pheocromocytoma), who have greater risk of post-operative complications. Patients with elevated BMI and larger tumors have higher risk of intra, but not of post-operative complications.

Predictors of complication after adrenalectomy.

PURPOSE: To investigate risk factors for complications in patients undergoing adrenalectomy. MATERIALS AND METHODS: A retrospective search of our institutional database was performed of patients who underwent adrenalectomy, between 2014 and 2018. Clinical parameters and adrenal disorder characteristics were assessed and correlated to intra and post-operative course. Complications were analyzed within 30-days after surgery. A logistic regression was performed in order to identify independent predictors of morbidity in patients after adrenalectomy. RESULTS: The files of 154 patients were reviewed. Median age and Body Mass Index (BMI) were 52-years and 27.8kg/m2, respectively. Mean tumor size was 4.9±4cm. Median surgery duration and estimated blood loss were 140min and 50mL, respectively. There were six conversions to open surgery. Minor and major post-operative complications occurred in 17.5% and 8.4% of the patients. Intra-operative complications occurred in 26.6% of the patients. Four patients died. Mean hospitalization duration was 4-days (Interquartile Range: 3-8). Patients age (p=0.004), comorbidities (p=0.003) and pathological diagnosis (p=0.003) were independent predictors of post-operative complications. Tumor size (p<0.001) and BMI (p=0.009) were independent predictors of intra-operative complications. Pathological diagnosis (p<0.001) and Charlson score (p=0.013) were independent predictors of death. CONCLUSION: Diligent care is needed with older patients, with multiple comorbidities and harboring unfavorable adrenal disorders (adrenocortical carcinoma and pheocromocytoma), who have greater risk of post-operative complications. Patients with elevated BMI and larger tumors have higher risk of intra, but not of post-operative complications.

The role of ARMC5 in human cell cultures from nodules of primary macronodular adrenocortical hyperplasia (PMAH).

The participation of aberrant receptors and intra-adrenal ACTH in hyperplastic tissue are considered mechanisms that regulate hypercortisolism in PMAH. Additionally, germline ARMC5 mutations have been described as the most frequent genetic abnormality found in patients diagnosed with PMAH. Previous functional studies analyzed ARMC5 role using H295R cells. Therefore, we investigated the role of ARMC5 in cell cultures obtained from PMAH nodules containing steroidogenic cells, aberrant receptors and intra-adrenal ACTH. ARMC5 silencing in non-mutated PMAH cell cultures decreased steroidogenesis-related genes and increased CCNE1 mRNA expression and proliferative capacity without affecting cell viability. Additionally, ARMC5 overexpression induced cell death in PMAH mutated cell cultures, thereby decreasing cell viability. We confirmed the role of ARMC5 as an important pro-apoptotic protein involved in PMAH-related steroidogenesis. We also report for the first time the involvement of ARMC5 in controlling proliferation and regulating cell cycle in PMAH cell cultures; these effects need to be explored further.