ARMC5 Alterations in Patients With Sporadic Neuroendocrine Tumors and Multiple Endocrine Neoplasia Type 1 (MEN1).

CONTEXT: Adrenal lesions are frequent among patients with sporadic neuroendocrine tumors (spNETs) or multiple endocrine neoplasia type 1 (MEN1). Armadillo repeat-containing 5 (ARMC5)-inactivating variants cause adrenal tumors and possibly other neoplasms. OBJECTIVE: The objective of this work is to investigate a large cohort spNETs or MEN1 patients for changes in the ARMC5 gene. PATIENTS AND METHODS: A total of 111 patients, 94 with spNET and 17 with MEN1, were screened for ARMC5 germline alterations. Thirty-six tumors (18 spNETs and 18 MEN1 related) were collected from 20 patients. Blood and tumor DNA samples were genotyped using Sanger sequencing and microsatellite markers for chromosomes. ARMC5 and MEN1 expression were assessed by immunohistochemistry. RESULTS: In 76 of 111 (68.4%) patients, we identified 16 different ARMC5 germline variants, 2 predicted as damaging. There were no differences in the prevalence of ARMC5 variants depending on the presence of MEN1-related adrenal lesions. Loss of heterozygosity (LOH) at chromosome 16p and ARMC5 germline variants were present together in 23 or 34 (67.6%) tumors; in 7 of 23 (30.4%) their presence led to biallelic inactivation of the ARMC5 gene. The latter was more prevalent in MEN1-related tumors than in spNETs (88.9% vs 38.9%; P = .005). LOH at the chromosome 16p (ARMC5) and 11q (MEN1) loci coexisted in 16/18 MEN1-related tumors, which also expressed lower ARMC5 (P = .02) and MEN1 (P = .01) proteins compared to peritumorous tissues. CONCLUSION: Germline ARMC5 variants are common among spNET and MEN1 patients. ARMC5 haploinsufficiency or biallelic inactivation in spNETs and MEN1-related tumors suggests that ARMC5 may have a role in modifying the phenotype of patients with spNETs and/or MEN1 beyond its known role in macronodular adrenocortical hyperplasia.

The Occurrence of Subclinical Hypercortisolism and Osteoporosis in Patients with Incidentally Discovered Unilateral and Bilateral Adrenal Tumors.

BACKGROUND: Adrenal incidentalomas (AI) are clinically silent adrenal masses that are detected incidentally during imaging procedures performed for unrelated diseases. The aim of this study was to investigate the prevalence of sub-clinical hypercortisolism (SH) and associated co-morbidities in patients with unilateral AI (UAI) and bilateral AI (BAI). METHODS: We evaluated 152 patients, 105 (69.1%) with UAI and 47 (30.9%) with BAI. SH was diagnosed in the presence of serum cortisol levels after 1 mg dexamethasone suppression test (DST) or after 2-day low-dose DST (LDDST) > 50 nmol/L with at least one of the following parameters: midnight serum cortisol > 208 nmol/L, 24-h urinary free cortisol > 245 nmol/24 h, or ACTH < 10 ng/L. Bone mineral density (BMD) was measured at lumbar spine (LS) and femoral neck (FN). RESULTS: Age, BMI, and waist circumference were comparable, and diabetes, hypertension and dyslipidemia occurred with similar frequency in both groups. The overall prevalence of SH was 20.5% based on post-1 mg DST, and 20.0% based on post-LDDST cortisol levels, and it was more prevalent in BAI than UAI patients (31.1% vs 15.2%, respectively, p=0.026). LS BMD was lower in BAI than in UAI patients (0.96±0.14 vs 0.87±0.15, p=0.002). There were no differences in FN BMD. The prevalence of osteoporosis was higher in BAI compared to UAI patients (37.1% vs 15.9%, respectively, p=0.011). CONCLUSIONS: Patients with BAI had higher prevalence of SH and osteoporosis than those with UAI. Frequency of other co-morbidities was similar. This may be due to the higher degree of autonomous cortisol secretion or different tissue-specific sensitivity to glucocorticoids.