Abstract
Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. Here, we analyzed pediatric and adult pineoblastoma samples (n = 23) using a combination of genome-wide DNA methylation profiling and whole-exome sequencing or whole-genome sequencing. Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower-grade pineal tumors and normal pineal gland. Recurrent variants were found in genes involved in PKA- and NF-κB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expresion of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain.
Highlights
Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors
We compared 10 samples from normal autopsy pineal glands, 16 tumors clinically and histologically diagnosed as PB and five tumors diagnosed as pineal parenchymal tumor of intermediate differentiation (PPTID)
Review of the clinical information showed that all three tumors were PB that arose in adults
Summary
Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. PBs are very rare tumors, accounting for less than 1% of pediatric brain tumors, and our current knowledge of the molecular genetics and biology of PB is limited. In this study we sought to identify molecular drivers of sporadic PB to gain insights into the biology of this rare disease. We show that adult and pediatric PBs have different methylation profiles and harbor recurrent homozygous deletions of DROSHA, as well as microduplication of PDE4DIP containing the ancient DUF1220 domain, representing novel molecular drivers of PB. Larger retrospective and prospective studies will be necessary to further delineate the diagnostic, prognostic, and therapeutic relevance of our findings for children afflicted with this rare cancer
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