Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors
- Others:
- St Jude Children's Research Hospital
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Pelé Pequeno Príncipe Research Institute [Curitiba, Brazil]
- Hôpital Cochin [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
- Service d'endocrinologie et maladies métaboliques (Hôpital Cochin) ; Hôpital Cochin [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
- Centre de référence des maladies rares de la surrénale ( CHU Cochin [AP-HP]) ; Hôpital Cochin [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
- Institut de pharmacologie moléculaire et cellulaire (IPMC) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS) ; COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
- Faculdades Pequeno Príncipe [Curitiba, Brazil]
- Centro de Genética Molecular e Pesquisa do Câncer em Crianças [Curitiba, Brazil] (CEGEMPAC) ; Instituto de Pesquisa Pelé Pequeno Principe
- Federal University of Paraná [Curitiba, Brazil]
- This research was funded by the American Lebanese Syrian Associated Charities (ALSAC).
Description
Phosphodiesterases (PDEs) form a superfamily of enzymes that catalyze the hydrolysis of cyclic nucleotides adenosine 3 5-cyclic monophosphate (cAMP) and guanosine 3 5-cyclic monophosphate (cGMP) to their inactive 5 monophosphates. cAMP plays a critical role as a second messenger in endocrine tissues, and activation of cAMP signaling has been reported in endocrine tumors. Germline variants in PDEs have been associated with benign cortisol-secreting adrenocortical adenomas and testicular germ cell cancer but not adrenocortical carcinoma. We performed whole genome sequencing (WGS) and whole exome sequencing (WES) of paired blood and tumor samples from 37 pediatric adrenocortical tumors (ACTs). Germline inactivating variants in PDEs were observed in 9 of 37 (24%) patients. Tumor DNA analysis revealed loss of heterozygosity, with maintenance of the mutated allele in all cases. Our results suggest that germline variants in PDEs and other regulators of the cAMP-signaling pathway may contribute to pediatric adrenocortical tumorigenesis, perhaps by cooperating with germline hypomorphic mutant TP53 alleles and uniparental disomy of chromosome 11p15 (Beckwith-Wiedemann syndrome).
Abstract
International audience
Additional details
- URL
- https://www.hal.inserm.fr/inserm-02508379
- URN
- urn:oai:HAL:inserm-02508379v1
- Origin repository
- UNICA