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Nat Commun. 2018 Jul 20;9(1):2868. doi: 10.1038/s41467-018-05029-3.

Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma.

Author information

1
Division of Neuropathology, NYU Langone Health, New York, 10016, NY, USA.
2
Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, 10016, NY, USA.
3
Department of Neurology, NYU Langone Health, New York, 10016, NY, USA.
4
Department of Pathology, NYU Langone Health, New York, 10016, NY, USA.
5
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, 69120, Germany.
6
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
7
Department of Pediatric Oncology, Hematology & Immunology, Heidelberg, University Hospital, Heidelberg, 69120, Germany.
8
Division of Pediatric Hematology/Oncology, NYU Langone Health, New York, 10016, NY, USA.
9
Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York, 10016, NY, USA.
10
Genome Technology Center, NYU Langone Health, New York, 10016, NY, USA.
11
Johns Hopkins All Children's Hospital, Cancer and Blood Disorders Institute, St Petersburg, 33701, FL, USA.
12
Department of Neurosurgery, NYU Langone Health, New York, 10016, NY, USA.
13
Division of Pediatric Neurosurgery, NYU Langone Health, New York, 10016, NY, USA.
14
Department of Neuropathology, Institute of Pathology, University of Heidelberg, Heidelberg, 69120, Germany.
15
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
16
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Berlin, 10117, Germany.
17
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
18
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
19
Neuroscience Institute and Kimmel Center for Stem Cell Biology, NYU Langone Health, New York, 10016, NY, USA.
20
Division of Pediatric Oncology, Johns Hopkins Hospital, Baltimore, 21218, MD, USA.
21
Department of Pathology, Johns Hopkins Hospital, Baltimore, 21218, MD, USA.
22
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA. karajanm@mskcc.org.

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.

PMID:
30030436
PMCID:
PMC6054684
DOI:
10.1038/s41467-018-05029-3
[Indexed for MEDLINE]
Free PMC Article

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