Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma

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.

DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis

“…These mutations result in aberrant cleavage of precursor microRNAs (2,6). DICER1 is the only miRNA biogenesis gene in which germline mutations have been identified to cause a syndrome; however, somatic mutations in other genes encoding miRNA biogenesis proteins (DROSHA, TARBP2, XPO5, and DGCR8) have been found in Wilms tumors, and DROSHA somatic homozygous deletions are reported in pineoblastomas (7)(8)(9).…”

Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

“…Although new chemotherapy regimens have improved outcome, 5-year OS of trilateral RB patients is only 44%, with the presence of leptomeningeal metastases associated with reduced survival 5 . Germline mutation in DICER1 also predisposes to PB [6][7][8] , whereas DROSHA loss and PDE4DIP duplication are found in sporadic cases 9 . Recent molecular classification of PBs identified several subtypes with distinct oncogenic alterations and clinical/pathological features.…”

Recurrent KBTBD4 small in-frame insertions and absence of DROSHA deletion or DICER1 mutation differentiate pineal parenchymal tumor of intermediate differentiation (PPTID) from pineoblastoma

“…PPTIDs are morphologically heterogeneous with intermediate histologic features and variable clinical outcomes [3,5]. Recently, pineoblastomas were identified to harbor frequent mutations of the DICER1 gene or homozygous deletion of the DROSHA gene that both encode microRNA-processing enzymes [2,6,7]. However, the genetic alterations responsible for driving PPTID and pineocytoma are unknown.…”