Reference : Molecular and Clinical Evidence for an ARMC5 Tumor Syndrome: Concurrent Inactivating ...

	Document type :	Scientific journals : Article
	Discipline(s) :	Human health sciences : Endocrinology, metabolism & nutrition
	To cite this reference:	http://hdl.handle.net/10993/18547

Title :	Molecular and Clinical Evidence for an ARMC5 Tumor Syndrome: Concurrent Inactivating Germline and Somatic Mutations are Associated with both Primary Macronodular Adrenal Hyperplasia and Meningioma
Language :	English
Author, co-author :	Eibelt, Ulf [> >]
	Trovato, Alissa [> >]
	Kloth, Michael [> >]
	Gentz, Enno [> >]
	Finke, Reinhard [> >]
	Spranger, Joachim [> >]
	Galas, David J. [> >]
	Weber, Susanne [> >]
	Wolf, Cristina-Alexandra [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
	König, Katharina [> >]
	Arlt, Wiebke [> >]
	Büttner, Reinhard [> >]
	May, Patrick [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
	Allolio, Bruno [> >]
	Schneider, Jochen [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Publication date :	3-Oct-2014
Journal title :	Journal of Clinical Endocrinology and Metabolism
Publisher :	Endocrine Society
Peer reviewed :	Yes
Audience :	International
ISSN :	0021-972X
City :	Chevy Chase
Country :	MD
Abstract :	[en] Context:Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome (CS), which may present in the context of different familial multitumor syndromes. Heterozygous inactivating germline mutations of armadillo repeat containing 5 (ARMC5) have very recently been described as cause for sporadic PMAH. Whether this genetic condition also causes familial PMAH in association with other neoplasias is unclear. Objective: The aim of the present study was to delineate the molecular cause in a large family with PMAH and other neoplasias. Patients and Methods: Whole genome sequencing and comprehensive clinical and biochemical phenotyping was performed in members of a PMAH affected family. Nodules derived from adrenal surgery and pancreatic and meningeal tumor tissue were analysed for accompanying somatic mutations in the identified target genes. Results: PMAH presenting either as overt or subclinical CS was accompanied by a heterozygous germline mutation in ARMC5 (p.A110fs*9) located on chromosome 16. Analysis of tumor tissue showed different somatic ARMC5 mutations in adrenal nodules supporting a “second hit” hypothesis with inactivation of a tumor suppressor gene. A damaging somatic ARMC5 mutation was also found in a concomitant meningioma (p.R502fs) but not in a pancreatic tumor suggesting biallelic inactivation of ARMC5 as causal also for the intracranial meningioma. Conclusions: Our analysis further confirms inherited inactivating ARMC5 mutations as a cause of familial PMAH and suggests an additional role for the development of concomitant intracranial meningiomas.
Research centres :	Luxembourg Centre for Systems Biomedicine (LCSB): Medical Translational Research (J. Schneider Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) ; University of Luxembourg: High Performance Computing - ULHPC
Permalink :	http://hdl.handle.net/10993/18547
DOI :	10.1210/jc.2014-2648
Other URL :	http://dx.doi.org/10.1210/jc.2014-2648

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