Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors

Abstract

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).

Clinical prognostic factors in pediatric adrenocortical tumors: A meta‐analysis

“…Thirty‐six papers 2,5,16–18,20–47,49,50 allowed the evaluation of gender effect on outcome: females were found to have RR of 1.21, without reaching a significance ( P = .14; 95% CI 0.94‐1.55; I 2 0%).…”

“…Twenty‐seven studies 2,5,16–19,23,24,26,29–34,36–41,43,45,46,48,51 assessed the outcomes between these two groups, and being affected by Cushing syndrome resulted in a worse outcome ( P < .0001; RR 1.88; 95% CI 1.38‐2.58; I 2 6%). Secondly, 19 studies 5,18,20,26,30–33,36–38,40,41,43,45,46,49,51 compared the secreting tumors and nonsecreting masses, identifying hormonal secretion as a negative prognostic factor ( P = .004; RR 1.63; 95% CI 1.17‐2.27; I 2 0%). Finally, the comparison between patients affected by Cushing syndrome and nonsecreting tumors was performed in 17 studies 5,18,20,26,30–33,37,38,40,41,43,45,46,49,51 and no difference in outcome was found ( P = .40; RR 1.19; 95% CI 0.79‐1.79; I 2 0%) (Figure 3B).…”

“…I 2 6%). Secondly, 19 studies 5,18,20,26,[30][31][32][33][36][37][38]40,41,43,45,46,49,51 compared the secreting tumors and nonsecreting masses, identifying hormonal secretion as a negative prognostic factor (P = .004; RR 1.63; 95% CI 1.17-2.27; I 2 0%). Finally, the comparison between patients affected by Cushing syndrome and nonsecreting tumors was performed in 17 studies 5,18,20,26,[30][31][32][33]37,38,40,41,43,45,46,49,51 and no difference in outcome was found (P = .40; RR 1.19; 95% CI 0.79-1.79; I 2 0%) ( Figure 3B).…”

Prognostic and Clinicopathological&nbsp;Insights of Phosphodiesterase 9A Gene&nbsp;As Novel Biomarker in Human Colorectal Cancer

“…cGMP performs crucial roles in cell proliferation, differentiation, and apoptosis via intracellular cGMP signaling [58,59] and regulates diverse physiological functions covering platelet aggregation [60], neurotransmission [61], and vascular smoothmuscle modulation [62]. Several studies have been reported that dysregulation of PDE activities is associated with diverse tumors and carcinomas like chronic lymphocytic leukemia, glioblastoma, prostate cancer, breast cancer, adrenocortical tumor, etc [24,63,64]. However, the distinct role of PDE9A in CRC is yet to be explored.…”

“…The regulation and expression of PDEs (cyclic nucleotide phosphodiesterases) play a signi cant role in tumor progression and inhibition [23]. Many hematological malignancies and carcinomas have been connected with decreased levels of cAMP and/or cGMP by the PDE gene family [24]. PDE2A, PDE8B, and PDE11A expression are involved with adrenocortical tumors [25], high expression of PDE4 has been detected in brain tumors [26], in glioblastoma multiforme PDE5 is strongly expressed [27], and increased PDE7B expression found in Chronic lymphocytic leukemia [28].…”