Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors.
Emilia Modolo PintoFabio R FauczLuana Z PazaGang WuElizabeth Soares FernandesJerome BertheratConstantine A StratakisEnzo LalliRaul C RibeiroCarlos Rodriguez-GalindoBonald C FigueiredoGerard P ZambettiPublished in: Cancers (2020)
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).
Keyphrases
- copy number
- dna repair
- germ cell
- protein kinase
- genome wide
- signaling pathway
- binding protein
- end stage renal disease
- ejection fraction
- gene expression
- nitric oxide
- dna damage
- chronic kidney disease
- dna methylation
- squamous cell carcinoma
- epithelial mesenchymal transition
- childhood cancer
- pi k akt
- single molecule
- transcription factor
- peritoneal dialysis
- genome wide identification
- circulating tumor
- induced apoptosis
- circulating tumor cells