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

Abstract

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.

Keywords: ARMC5 gene; germinal and somatic alterations; multiple endocrine neoplasia type 1 (MEN1); neuroendocrine tumors.

Figure 1.

Armadillo repeat-containing 5 (ARMC5) expression in tumor tissues. Cytoplasmic ARMC5 expression in tumor tissue with documented loss of heterozygosity (LOH) at chromosome 16p (column A with magnification of 12.5×, and column B with magnification of 200×). ARMC5 expression in peritumoral tissues (column C; 200×). Nuclear coexpression of MENIN in tumors (column D; 200×). All tumors but nodular parathyroid hyperplasia (nPHPT) displayed LOH at chromosome 11q locus. The genetics of these tumors are presented in Table 3 (ID P49, P80, and P97). Nodular parathyroid hyperplasia delineated by arrowheads in rows 1 and 5; pancreatic neuroendocrine tumor (PNET) delineated with arrowheads in rows 2, 3, 4, and 7; macronodular adrenocortical hyperplasia (MAH), row 6 (arrowheads); ductal breast carcinoma in situ (DCIS), (arrowheads in row 8); lung neuroendocrine tumor (LNET), (arrowheads, row 9); colorectal carcinoma (CRC), (row 10); parathyroid hyperplasia (hPHPT) in row 11.