Pinto Emilia Modolo, Faucz Fabio R, Paza Luana Z, Wu Gang, Fernandes Elizabeth S, Bertherat Jerome, Stratakis Constantine A, Lalli Enzo, Ribeiro Raul C, Rodriguez-Galindo Carlos, Figueiredo Bonald C, Zambetti Gerard P
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
Section on Genetics and Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892-1862, USA.
Cancers (Basel). 2020 Feb 22;12(2):506. doi: 10.3390/cancers12020506.
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 alleles and uniparental disomy of chromosome 11p15 (Beckwith-Wiedemann syndrome).
磷酸二酯酶（PDEs）构成了一个酶的超家族，该家族催化环核苷酸3',5'-环磷酸腺苷（cAMP）和3',5'-环磷酸鸟苷（cGMP）水解为无活性的5'-单磷酸。cAMP作为内分泌组织中的第二信使发挥关键作用，并且在内分泌肿瘤中已报道有cAMP信号激活。PDEs的种系变异与良性分泌皮质醇的肾上腺皮质腺瘤和睾丸生殖细胞癌有关，但与肾上腺皮质癌无关。我们对37例儿童肾上腺皮质肿瘤（ACTs）的配对血液和肿瘤样本进行了全基因组测序（WGS）和全外显子组测序（WES）。在37例患者中的9例（24%）观察到PDEs的种系失活变异。肿瘤DNA分析显示杂合性缺失，所有病例中突变等位基因均得以保留。我们的结果表明，PDEs和cAMP信号通路的其他调节因子中的种系变异可能通过与种系低表达突变等位基因和11p15染色体单亲二倍体（贝克威思-维德曼综合征）协同作用，从而促成儿童肾上腺皮质肿瘤的发生。
