title: ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome.
abstract: BACKGROUND
  Corticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing's syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition.
  
  
  METHODS
  We genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo repeat containing 5 (ARMC5) inactivation and overexpression were tested in cell-culture models.
  
  
  RESULTS
  The most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival.
  
  
  CONCLUSIONS
  Some cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management. (Funded by Agence Nationale de la Recherche and others.).
authors.affiliation: From INSERM Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin (G.A., R.L., S.E., M.R.-R., A.G., W.L., O.B., L.L., S.R., K.P., F.R.-C., F.L., L. Groussin, X.B., B.R., J.B.), Faculté de Médecine Paris Descartes, Université Paris Descartes, Sorbonne Paris Cité (G.A., S.E., A.G., O.B., L.L., M.S., K.P., F.R.-C., L. Groussin, X.B., J.B.), Department of Endocrinology, Referral Center for Rare Adrenal Diseases (G.A., R.L., O.B., L. Guignat, L. Groussin, X.B., J.B.), and Department of Pathology (M.S.), Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, and Unit of Endocrinology, Department of Obstetrics and Gynecology, Hôpital Tenon (N.C.-B.) - all in Paris; Unit of Endocrinology, Centre Hospitalier du Centre Bretagne, Site de Kério, Noyal-Pontivy (B.T.), Unit of Endocrinology, Hôtel Dieu du Creusot, Le Creusot (A.P.), and Department of Endocrinology Lyon-Est, Groupement Hospitalier Est, Bron (F.B.-C.) - all in France; and the Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics and the Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (C.A.S.).
authors.forename: Guillaume
authors.initials: G
authors.lastname: Assié
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Espiard
authors.forename: Marthe
authors.initials: M
authors.lastname: Rizk-Rabin
authors.forename: Anne
authors.initials: A
authors.lastname: Guimier
authors.forename: Windy
authors.initials: W
authors.lastname: Luscap
authors.forename: Olivia
authors.initials: O
authors.lastname: Barreau
authors.forename: Lucile
authors.initials: L
authors.lastname: Lefèvre
authors.forename: Mathilde
authors.initials: M
authors.lastname: Sibony
authors.forename: Laurence
authors.initials: L
authors.lastname: Guignat
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rodriguez
authors.forename: Karine
authors.initials: K
authors.lastname: Perlemoine
authors.forename: Fernande
authors.initials: F
authors.lastname: René-Corail
authors.forename: Franck
authors.initials: F
authors.lastname: Letourneur
authors.forename: Bilal
authors.initials: B
authors.lastname: Trabulsi
authors.forename: Alix
authors.initials: A
authors.lastname: Poussier
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chabbert-Buffet
authors.forename: Françoise
authors.initials: F
authors.lastname: Borson-Chazot
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
mesh_terms: D000311:Adrenal Glands / Q000473:pathology; D000328:Adult; D000368:Aged; D051186:Armadillo Domain Proteins; D003480:Cushing Syndrome / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005260:Female; D016147:Genes, Tumor Suppressor; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D059467:Transcriptome; D025521:Tumor Suppressor Proteins
chemical_list: C000590373:ARMC5 protein, human; D051186:Armadillo Domain Proteins; D025521:Tumor Suppressor Proteins