PMID- 32901291 OWN - NLM STAT- MEDLINE DCOM- 20210226 LR - 20210909 IS - 1945-7197 (Electronic) IS - 0021-972X (Print) IS - 0021-972X (Linking) VI - 105 IP - 12 DP - 2020 Dec 1 TI - ARMC5 Alterations in Patients With Sporadic Neuroendocrine Tumors and Multiple Endocrine Neoplasia Type 1 (MEN1). PG - e4531-42 LID - dgaa631 [pii] LID - 10.1210/clinem/dgaa631 [doi] AB - 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. CI - Published by Oxford University Press on behalf of the Endocrine Society 2020. FAU - Damjanovic, Svetozar S AU - Damjanovic SS AD - Medical School, University of Belgrade, Belgrade, Serbia. FAU - Antic, Jadranka A AU - Antic JA AD - Clinic for Endocrinology, Diabetes and Metabolic Diseases, Medical School, University of Belgrade, Department for Neuroendocrine Tumors and Hereditary Cancer Syndromes, Belgrade, Serbia. FAU - Elezovic-Kovacevic, Valentina I AU - Elezovic-Kovacevic VI AD - Clinic for Endocrinology, Diabetes and Metabolic Diseases, Medical School, University of Belgrade, Department for Neuroendocrine Tumors and Hereditary Cancer Syndromes, Belgrade, Serbia. FAU - Dundjerovic, Dusko M AU - Dundjerovic DM AD - Institute for Pathology, Medical School, University of Belgrade, Belgrade, Serbia. FAU - Milicevic, Ivana T AU - Milicevic IT AD - Clinic for Endocrinology, Diabetes and Metabolic Diseases, Medical School, University of Belgrade, Department for Neuroendocrine Tumors and Hereditary Cancer Syndromes, Belgrade, Serbia. FAU - Beleslin-Cokic, Bojana B AU - Beleslin-Cokic BB AD - Clinic for Endocrinology, Diabetes and Metabolic Diseases, Medical School, University of Belgrade, Department for Neuroendocrine Tumors and Hereditary Cancer Syndromes, Belgrade, Serbia. FAU - Ilic, Bojana B AU - Ilic BB AD - Clinic for Endocrinology, Diabetes and Metabolic Diseases, Medical School, University of Belgrade, Department for Neuroendocrine Tumors and Hereditary Cancer Syndromes, Belgrade, Serbia. FAU - Rodic, Gordana S AU - Rodic GS AD - Clinic for Endocrinology, Diabetes and Metabolic Diseases, Medical School, University of Belgrade, Department for Neuroendocrine Tumors and Hereditary Cancer Syndromes, Belgrade, Serbia. FAU - Berthon, Annabel AU - Berthon A AD - Section on Genetics & Endocrinology, Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development, Bethesda, Maryland. FAU - Maria, Andrea Gutierrez AU - Maria AG AD - Section on Genetics & Endocrinology, Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development, Bethesda, Maryland. FAU - Faucz, Fabio R AU - Faucz FR AD - Section on Genetics & Endocrinology, Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development, Bethesda, Maryland. FAU - Stratakis, Constantine A AU - Stratakis CA AD - Section on Genetics & Endocrinology, Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development, Bethesda, Maryland. LA - eng PT - Journal Article PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Clin Endocrinol Metab JT - The Journal of clinical endocrinology and metabolism JID - 0375362 RN - 0 (ARMC5 protein, human) RN - 0 (Armadillo Domain Proteins) SB - IM MH - Adenoma/epidemiology/genetics MH - Adolescent MH - Adrenal Gland Neoplasms/epidemiology/genetics MH - Adult MH - Aged MH - Armadillo Domain Proteins/*genetics MH - Child MH - Cohort Studies MH - DNA Mutational Analysis MH - Female MH - Germ-Line Mutation MH - Humans MH - Loss of Heterozygosity MH - Male MH - Middle Aged MH - Multiple Endocrine Neoplasia Type 1/epidemiology/*genetics MH - Neuroendocrine Tumors/epidemiology/*genetics MH - Pancreatic Neoplasms/epidemiology/genetics MH - Paraganglioma/epidemiology/genetics MH - Parathyroid Neoplasms/epidemiology/genetics MH - Pituitary Neoplasms/epidemiology/genetics MH - Sequence Analysis, DNA MH - Thyroid Neoplasms/epidemiology/genetics MH - Young Adult PMC - PMC7547841 OTO - NOTNLM OT - ARMC5 gene OT - germinal and somatic alterations OT - multiple endocrine neoplasia type 1 (MEN1) OT - neuroendocrine tumors EDAT- 2020/09/10 06:00 MHDA- 2021/02/27 06:00 PMCR- 2021/09/08 CRDT- 2020/09/09 05:31 PHST- 2020/05/14 00:00 [received] PHST- 2020/09/07 00:00 [accepted] PHST- 2020/09/10 06:00 [pubmed] PHST- 2021/02/27 06:00 [medline] PHST- 2020/09/09 05:31 [entrez] PHST- 2021/09/08 00:00 [pmc-release] AID - 5903053 [pii] AID - dgaa631 [pii] AID - 10.1210/clinem/dgaa631 [doi] PST - ppublish SO - J Clin Endocrinol Metab. 2020 Dec 1;105(12):e4531-42. doi: 10.1210/clinem/dgaa631.