Article (Scientific journals)
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
Eibelt, Ulf; Trovato, Alissa; Kloth, Michael et al.
2014In Journal of Clinical Endocrinology and Metabolism
Peer reviewed
 

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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 center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Medical Translational Research (J. Schneider Group)
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
ULHPC - University of Luxembourg: High Performance Computing
Disciplines :
Endocrinology, metabolism & nutrition
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)
More authors (5 more) Less
Language :
English
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
Publication date :
03 October 2014
Journal title :
Journal of Clinical Endocrinology and Metabolism
ISSN :
0021-972X
Publisher :
Endocrine Society, Chevy Chase, United States - Maryland
Peer reviewed :
Peer reviewed
Available on ORBilu :
since 28 October 2014

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