ARMC5 mutation identified in patients with macronodular adrenal hyperplasia

Image: PD 

1. 55% of tumors from patients with macronodular adrenal hyperplasia possessed mutations in ARMC5, suggesting a common genetic cause of this condition. 

2. AMRC5 appears to be a tumor suppressor gene. 

Study Rundown:  Corticotropin-independent macronodular adrenal hyperplasia causes adrenal excess and ultimately, Cushing’s syndrome. These cortisol-secreting tumors are often bilateral and have been reported to occur in familial clusters, suggesting there may be a common genetic cause. The authors of this study aimed to identify a genetic basis for the condition. They analyzed the DNA of tumors taken from 33 patients with corticotropin-independent macronodular adrenal hyperplasia and found that 55% contained inactivating mutations in the armadillo repeat containing 5 (ARMC5) gene. They found that the alleles carried a germline mutation and somatic mutation – consistent with a genetic predisposition to developing the disease. The function of ARMC5 was not previously known, however this study suggests that it is a tumor suppressor gene. The study was small, comprised of a cohort of 33 patients, of whom 18 possessed ARMC5 mutations. Additionally, the study did not further analyze the genomes of older relatives of patients with ARMC5 mutations. Ultimately, this study appears to have identified a new tumor-suppressor gene and linked it to a familial cause of Cushing’s syndrome.

Click to read the study in NEJM

Click to read an accompanying editorial in NEJM

Relevant Reading: Classification, diagnosis and treatment of ACTH-independent macronodular hyperplasia

In-Depth [genetic cohort analysis study]: This study examined the genomes of tumors from 33 patients aged 30 to 73 years with corticotropin-independent macronodular adrenal hyperplasia.  Patients had already been diagnosed via histologic confirmation of surgical biopsies of their tumors. The authors genotyped blood and tumor DNA from patients using multiple molecular techniques. They found a consistent alteration of the gene ARMC5 on 16p11.2. The study authors subsequently performed direct sequencing of tumor DNA and found ARMC5 mutations in 18 of 33 (55%) of the patients. All tumors from these patients exhibited 2 genetic alterations in the ARMC5 gene. Only one of these mutations was identified in control DNA samples obtained from the National Heart, Lung and Blood Institute. To clarify the function of ARMC5, the authors performed a transcriptome analysis of the tumor cells and found they had significantly higher levels of RNA-processing genes. They also found that HeLa cells transfected with non-mutated ARMC5 became apoptotic, while those transfected with ARMC5 with germline missense mutations lived. This suggested that ARMC5 plays a significant role in cell death.

By Akira Shishido, MD and Adrienne Cheung

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