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
Author(s)
Type
Journal Article
Abstract
Context:
Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, 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 analyzed for accompanying somatic mutations in the identified target genes.
Results:
PMAH presenting either as overt or subclinical Cushing's syndrome 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.
Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, 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 analyzed for accompanying somatic mutations in the identified target genes.
Results:
PMAH presenting either as overt or subclinical Cushing's syndrome 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.
Date Issued
2015-01-01
Date Acceptance
2014-09-09
Citation
Journal of Clinical Endocrinology and Metabolism (JCEM), 2015, 100 (1), pp.E119-E128
ISSN
0021-972X
Publisher
Oxford University Press
Start Page
E119
End Page
E128
Journal / Book Title
Journal of Clinical Endocrinology and Metabolism (JCEM)
Volume
100
Issue
1
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/25279498
Subjects
ABERRANT HORMONE-RECEPTORS
ACTIVATING MUTATIONS
ADRENOCORTICAL TUMORS
CORTISOL HYPERSECRETION
ENDOCRINE NEOPLASIA TYPE-1
Endocrinology & Metabolism
GASTRIC-INHIBITORY POLYPEPTIDE
INDEPENDENT CUSHINGS-SYNDROME
Life Sciences & Biomedicine
MCCUNE-ALBRIGHT-SYNDROME
PHOSPHODIESTERASE 11A PDE11A
Science & Technology
VASOPRESSIN
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2015-01-01